In this JCO Precision Oncology Article Insights episode, Dr. Jiasen He summarizes JCO PO article "Synthetic Lethal Co-Mutations in DNA Damage Response Pathways Predict Response to Immunotherapy in Pan-Cancer" by Hua Zhong et al.

TRANSCRIPT

Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today we will be discussing the JCO Precision Oncology article, "Synthetic Lethal Co-mutations in DNA Damage Response Pathway Predict Response to Immunotherapy in Pan-Cancer" by Dr. Zhang and colleagues.

Immunotherapy has emerged as a groundbreaking treatment option for many types of cancer. However, the overall response rate to immunotherapy is low, around 10% to 30%. This highlights the critical need to identify which patients are most likely to benefit from immunotherapy. Two of the most extensively studied biomarkers are PD-L1 expression and tumor mutation burden (TMB). High levels of PD-L1 and TMB have been associated with better response to immune checkpoint inhibitors, which are now widely used in clinical practice. The predictive value of these markers is inconsistent across all settings. Some tumors with high PD-L1 or TMB still respond poorly to immunotherapy.

One reason is that TMB reflects new antigen production, but recent studies suggest that new antigen levels do not always correlate with tumor immunogenicity. Many new antigens are not effectively recognized by T cells, limiting the immune response. Emerging evidence indicates that mutations in the DNA damage response (DDR) pathway play a critical role in moderating tumor immune interactions. Tumors harboring DDR pathways frequently exhibit increased genome instability, which may enhance their sensitivity to immune checkpoint inhibitors. While all these pathways are under active investigation, the optimal DDR pathway biomarkers for patient selection remain unclear.

Notably, tumor cells with a defect in one DDR pathway may acquire greater reliance on alternative DDR pathways. Recent studies suggest that synthetic lethal co-mutations within DDR pathways are associated with immune-inflamed or hot tumor microenvironments. Based on this rationale, Dr. Zhang is investigating if synthetic lethal co-mutations in DDR pathway response pathway can serve as a treatment biomarker for immune checkpoint inhibitors. To address this question, Dr. Zhang and colleagues first utilized SynLethDB 2.0, a comprehensive database that integrated multiple data sets.

Synthetic lethal (SL) gene pairs in this resource are identified through both experimental and computational approaches, with confidence scores assigned to each pair. These SL pairs were then mapped to gene sequencing results from several clinical cohorts. SL co-mutation status was defined as positive when both genes in a synthetic lethal pair were mutated. From this, SL co-mutation pairs specifically involving DDR pathway genes were selected. Patients were classified as DDR co-mutation positive if both genes in a synthetic lethal pair, each belonging to the defined DDR pathways, were mutated.

In total, 431 DDR-related SL pairs were identified and matched to sequencing data from clinical cohorts. Clinical information was extracted from the cBioPortal, while further analysis of immune infiltration was performed using DNA mutation and RNA expression data from The Cancer Genome Atlas (TCGA) pan-cancer data set. The author first examined the correlation between SL co-mutation status and response to ICI therapy. They discovered that patients with SL co-mutation showed significantly improved outcome to ICI therapy across various clinical cohorts.

Notably, in patients who did not receive ICI treatment, patients with SL co-mutation showed markedly compromised overall survival. Further analysis focused on the predictive value of SL co-mutation within DDR pathway genes. The author found that patients with DDR SL co-mutation had a longer overall survival compared to those with mutations in a single DDR gene, implying that SL co-mutations may be more effective biomarkers within the DDR pathway.

To explore this further, in the TMB-MSKCC cohort, the author found that patients with DDR co-mutation constituted approximately 20% of various cancer types, including non-small cell lung cancer, melanoma, and bladder cancer. These patients demonstrated significantly better survival outcomes and disease control rates when treated with ICIs compared to DDR co-mutation negative patients. Notably, the TMB level was substantially higher in patients with DDR co-mutation, a finding consistent with data from the Miao-lung cohort.

Furthermore, in cohorts not treated with ICIs, patients with DDR co-mutation had a shorter overall survival compared to their counterparts. Upon stratifying by PD-L1 expression, the author observed that patients with DDR co-mutation who were also PD-L1 positive derived the greatest clinical benefit from ICI therapy. Upon analyzing the frequency of co-mutation within the DDR pathway, the authors found that patients with SL co-mutation in the CPF-CPF pathway experienced remarkable survival benefit from ICIs. Within this group, one of the most common co-mutation combinations was TP53-ATM, observed in approximately 45% of cases, which was associated with a better response to ICI therapy.

Further analysis of immune cell infiltration revealed that patients with TP53-ATM co-mutation exhibited a distinct tumor immune microenvironment. As the authors stated, the study's main limitation lies in the nature of retrospective analysis, which lacked the control over confounding variables and was subject to non-random sampling. For instance, patients with both SL co-mutations and DDR SL co-mutations exhibited high TMB, and TMB was known to be associated with improved response to ICI therapy itself. So, these findings require validation through prospective studies, and immune infiltration analysis needs confirmation via laboratory experiments.

In conclusion, the authors found that patients with SL co-mutations in DDR pathways showed favorable clinical response and prolonged survival following ICI therapy. They also identified TP53-ATM co-mutations as a clinically relevant biomarker for predicting ICI treatment response.

Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO authors Dr. Abhishek Tripathi and Dr. Salvador Jaime-Casas at City of Hope Comprehensive Cancer Center share insights into their article, “Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma.”  Host Dr. Rafeh Naqash and Drs. Tripathi and Jaime-Casas discuss a novel understanding of the genomic alterations underlying SCBC, revealing actionable mutations that could serve as potential targets for improved clinical outcomes.

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.

Today, I am thrilled to be joined by Dr. Abhishek Tripathi, Associate Professor in the Department of Medical Oncology and Experimental Therapeutics Research at the City of Hope Comprehensive Cancer Center, as well as his mentee, Dr. Salvador Jaime-Casas, postdoctoral research fellow and first author of the JCO Precision Oncology article entitled "Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared with Urothelial Carcinoma and Small Cell Lung Carcinoma".

At the time of this recording, our guest disclosures will be linked in the transcript.

Abhishek and Salvador, welcome to our podcast and thank you for joining us today. This is a very interesting topic given that at least the landscape for neuroendocrine carcinomas, where small cell lung cancer is on one end of the spectrum, has been changing, at least on the lung cancer side, with recent approvals and some new ADCs. So, of course, understanding the genomic and transcriptomic similarities or differences between pulmonary small cell and extrapulmonary small cell is of huge interest. Could you tell us a little bit about small cell bladder cancer, current approaches to treatment of small cell bladder cancer, and then why you wanted to investigate that in this project as far as the genomic differences or similarities are concerned?

Dr. Salvador Jaime-Casas: Well, first of all, thank you very much for having me. I am very excited to be here. And really what served as backbone for this research project was the notion that there is a currently evolving genomic landscape in the area of bladder cancer. We know this is a highly heterogeneous disease when it comes to molecular underpinnings and mutational profile. Specifically, we know that the most common histologic subtype is urothelial carcinoma. Small cell bladder cancer represents a histology that is found in less than 1% of all bladder cancer cases. However, it is one of the most aggressive histologies. It presents with a very poor prognosis to patients and very poor response to treatment, which is why we attempted to really elucidate what is the mutational profile behind this and provide a comparison contrast between small cell bladder cancer, small cell lung cancer, and conventional urothelial carcinoma.

As your question mentioned, in terms of treatment, the conventional urothelial carcinoma and small cell bladder cancer are two distinct pathways when it comes to treatment algorithms. We know that in the current era there are newer and newer drugs being developed for conventional urothelial carcinoma. We have perioperative immunotherapy in the context of metastatic disease. We have antibody-drug conjugates such as enfortumab vedotin. But really, this amazing track record of drug development hasn't been mirrored in small cell bladder cancer. And here most of the therapy is usually extrapolated from studies from other small cell histologies like you mentioned earlier, small cell lung cancer has given some form of background in terms of what therapies are used here. Cytotoxic chemotherapy, for some patients with localized disease and small cell bladder cancer, concurrent chemotherapy and radiotherapy or perioperative cytotoxic chemotherapy have been the cornerstone of treatment for many years now. However, like I mentioned, the oncologic outcomes are very suboptimal when it comes to comparing it with other disease histologies, which is why we really wanted to describe the landscape here and provide this comparison across three different groups.

For this particular study, we leveraged the Tempus dataset. So, include patients with urothelial carcinoma with small cell bladder cancer and small cell lung cancer. We included their demographic information, as well as the frequency of most common genomic alterations identified. And really, it was a very comparable Table 1. We see the demographic data across the three groups was very similar. One key thing that we identified was the female prevalence was a little bit lower in patients with small cell bladder cancer when compared to small cell lung cancer. But other than that, the age, race, ethnicity, was comparable across groups, and even the smoking history. Most of the patients in this cohort were former smokers, which we believe comes to explain that regardless of any mutational profile that we talked about in a few minutes, there are shared commonalities between these histologies and shared environmental exposures and risk factors that are going to be implicated in the disease biology for these three histologies.

Dr. Rafeh Naqash: Thank you so much, Salvador, for that useful background.

I would like to shift to Abhishek real quick. Abhishek, you are a practicing clinician, you have led several studies in the GU space, especially bladder. Based on what you see in the small cell lung cancer space, how drug development is shaping up, which aligns with what you are trying to evaluate in this paper as targets, how do you see some of that being implemented for small cell bladder cancer in the current era and age?

Abhishek Tripathi: Thanks so much for the excellent question, Rafeh. As a GU investigator, small cell bladder cancer has always lagged behind in some regards regarding enrollment abilities for the novel clinical trials. And small cell lung cancer has paved the way and led the development of a lot of these drugs across the board. With the most recent sort of drugs targeting DLL3 already approved and several antibody-drug conjugates currently in development. That actually translates really well to how we should approach drug development in bladder cancer.

What we saw in the study is that although there are overlaps and similarities between small cell lung cancer and small cell bladder cancer, there are also certain differences. So the long-term assumption that all therapies for small cell bladder cancer can be extrapolated to small cell bladder], may or may not be true, and I think it is high time that we specifically investigate these novel agents in tissue-specific small cell carcinomas. To that effect, we are excited to be participating in trials that are looking at some of the novel DLL3 targeted agents, specifically bispecific antibodies and T cell engagers so to speak, and antibody-drug conjugates that are now starting to open enrollment specifically in non-lung cancer cohorts to evaluate its efficacy. So overall, I think studies like this have the opportunity to identify more putative targets for organ-specific development of these novel agents.

Dr. Rafeh Naqash: Absolutely, I could not agree more. I think tumor-agnostic therapies definitely have a place, but not all therapies work the same in different tumors with a similar histological or genomic background because there are definitely differences.

So now going to the comparison that Salvador, you guys did in this project, could you help us understand what are some of the things you looked at, what were some of the commonalities and the differences, and what were some of the conceptual thoughts that come out from those results?

Dr. Salvador Jaime-Casas: Of course. So, the first thing that we identified was which were the most frequent molecular alterations across these histologies. We actually provided a table showcasing how the most common mutations that we identified were TP53, TERT, RB1. However, like Dr. Tripathi mentioned, the distinction between these histologies is notable in the sense that some are more predominant in small cell-pertaining cancers such as bladder cancer and lung cancer. While some others are more common in bladder-pertaining malignancies like urothelial carcinoma and small cell bladder cancer. For instance, we saw that TP53 and RB1 were significantly more evident in small cell histologies, both small cell bladder cancer and small cell lung cancer, as opposed to conventional urothelial carcinoma, which really this mirrors what is known about these mutations and what has been published. These are markers associated with more aggressive disease with a worse prognosis and even to resistance to treatment.

We also identified how TERT mutations were characteristically more prevalent in small cell bladder cancer as opposed to small cell lung cancer, as well as in urothelial carcinoma. TERT mutations were more commonly identified than in small cell lung cancer. And we give a long list of these mutations that we identified, but really what we wanted to underscore here was, A, the most common mutations across histologies; B, the most common co-occurring mutations where we saw that these are not mutually exclusive. A lot of patients had co-occurring TP53 and RB1 or RB1 and TERT or RB1 and ARID1A, really elucidating how heterogeneous this molecular landscape is across histologies.

And the third one that we believe really brings down the clinical impact of this research was evidencing the idea of clinically actionable mutations. We also provided a table here showcasing how mutations like FGFR, DLL notch pathway, HER2, were evident in these histologies, and what is the current status of some clinical trials evaluating different drug designs for these mutations. Like Dr. Tripathi mentioned in the context of FGFR, approximately 6% of our cohort with small cell bladder cancer showcased mutations in FGFR3. However, up to 14% of them had mutations in any FGFR gene, which really underscores the notion that drugs like erdafitinib, which have been introduced in the market in recent years, could potentially showcase some response in the space of small cell bladder cancer. We actually provide the description of two trials, phase two, phase three trials, that are evaluating erdafitinib in the context of high-risk non-muscle invasive bladder cancer and even metastatic urothelial carcinoma.

Like Dr. Tripathi mentioned as well, antibody-drug conjugates, another very interesting area of drug development targeting HER2, we included evidence on how disitamab vedotin and trastuzumab deruxtecan are currently being explored across different phase two and phase three clinical trials, both as part of basket trial designs for solid malignancies expressing HER2, but also for patients with urothelial carcinoma where there is evidence of HER2 expression. So, we believe that the landscape is shifting in the right direction in the sense that therapies are becoming much more personalized and targeted against these known molecular profiles.

Dr. Rafeh Naqash: Thank you, Salvador, for summarizing some of those very interesting results and providing a very unique conceptual context to that.

I would like to go to Abhishek this last portion. Of course, I am sure you guys will expand on this work and there are a lot of other interesting things that will likely come out from this work and hopefully you will publish that in JCO PO. But one of the very important things that I wanted to highlight from this podcast specifically was the science is obviously very interesting, but I feel the more important interesting aspect is giving trainees and fellows, residents, mentorship opportunities, mentoring them and giving them lead roles in projects like this, which is what Dr. Tripathi has successfully done for you in this project, Salvador. So, Abhishek, as somebody I have known for a couple of years now, more than a couple of years, as a very successful clinical translational investigator in the GU space in the early phase setting, Abhishek, really briefly, within a minute, could you tell us about your journey and what are some of the things that have worked for you as an early career investigator that you have learned from, and then your journey of mentorship, how has that been for you and what are some of the things that you take home from your mentorship role?

Abhishek Tripathi: Absolutely. And as you mentioned, mentorship has been pivotal for all early career investigators for them to really succeed. So, my journey, as you know, I started off as an early career investigator at another institution, and I think I owe it to my mentors even at that time and even now who are helping me develop some of these newer translational and clinical trial ideas, creating opportunities where we could really showcase some of the interesting work that we are doing. That actually goes a long way in terms of creating independence as an established investigator. And I think the sooner we start off with mentorship prospects, I think the better it is.

And paying it forward, I think I have been lucky to have mentees like Salvador who are just extremely talented, really committed, and goal-oriented. He really led the project right from the beginning in terms of initial analyses and looking up all the sort of correlative studies that we could do and the contextual data between small cell lung cancer and bladder cancer that we have delved into for the past several years. And it really showcases the ability of young mentees like Salvador to really excel given the right guidance and the support.

As a mentor, it has been a really rewarding experience. It is really helpful to actually learn from some of these mentees as well as to approach the same problem from a different angle and different thought process and guide them through the study. So, it has been incredibly helpful and rewarding both being a mentee and a mentor over the past several years as I have transitioned.

Dr. Rafeh Naqash: Thank you, Abhishek, for those very insightful comments on how both being a mentee and being a mentor helps shape you as an individual as well. And then you take a lot of pride in the success of your mentees.

Now real quick, Salvador, could you tell us a little bit about yourself, you know, how you ended up at City of Hope under Dr. Tripathi’s mentorship and what are some of the next important things that you are looking forward to doing?

Dr. Salvador Jaime-Casas: So, a little bit about who I am. I did medical school in Mexico City. I was born and raised there, and towards the end of my medical training, I started to be engaged in research projects. And through one of my mentors in Mexico, I was actually introduced to the team here at City of Hope, including Dr. Tripathi. And through this, we got the opportunity to have some conversations about what I wanted to do, become a physician-researcher in the area of genitourinary oncology and hopefully my transition to residency in a few years. And that is how I came to be his mentee here at City of Hope. I think it has been a very rewarding experience, like Dr. Tripathi said, having such an incredible mentor and really being with him both in the academic setting and in the clinical setting, in patients with clinic, seeing this curiosity and all these clinical trials, all of this evidence that we have coming together to generate this insight.

Dr. Rafeh Naqash: Thank you so much for both the scientific insights, as well as the journey of being a mentee for you, Salvador, and as a mentor for you, Abhishek. I really enjoyed talking to you guys about both aspects here today and hopefully we will see more of your work, Abhishek and Salvador, as far as understanding the transcriptomic heterogeneity in neuroendocrine tumors or neuroendocrine cancers of the bladder.

Dr. Salvador Jaime-Casas: Thank you very much. Thank you for having us.

Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Abhishek Tripathi Disclosures

Consulting or Advisory Role:  Company: Aadi biosciences, Seattle Genetics/Astellas, Exelixis, Bayer, Gilead Sciences, Pfizer, Deka biosciences Speakers' Bureau: Company: Sanofi

In this JCO PO Article insights episode, Dr. Jiasen He summarized the JCO PO article "Mucin 16–Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implications for Other Sarcoma Subtypes" by Connolly et al.

TRANSCRIPT

Jiasen He: Hello, and welcome to JCO Precision Oncology Article Insights. I'm your host, Jiasen He, and today we'll be discussing the JCO Precision Oncology article, "Mucin 16-Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implication for Other Sarcoma Subtypes" by Connolly et al.

Epithelioid sarcoma and malignant rhabdoid tumor are rare pediatric soft tissue sarcomas, characterized by INI1 loss, high recurrence rates, and poor outcome despite multimodal treatments. Emerging evidence has shown that Mucin 16 is expressed in both tumor types. Mucin 16 is a transmembrane glycoprotein whose extracellular domain can be cleaved and released as CA-125. Both Mucin 16 and CA-125 are well-established biomarkers in several adult epithelioid malignancies, particularly ovarian cancer. Ubamatamab is a specific T-cell engager targeting CD3 and Mucin 16. It has demonstrated antitumor activity in patients with recurrent ovarian cancer, and clinical trials are ongoing to evaluate its efficacy as monotherapy or in combination regimens.

In this manuscript, Connolly et al. present the first reported case of a heavily pretreated patient with epithelioid sarcoma who responded to ubamatamab, followed by an investigation into mechanisms of resistance after disease progression. Furthermore, the authors retrospectively assessed Mucin 16 expression in a cohort of pediatric and young adult sarcomas, finding high expression in both epithelioid sarcoma and malignant rhabdoid tumor.

In this case report, the authors describe a 23-year-old woman with relapsed metastatic epithelioid sarcoma. Initially diagnosed at age 12, she had received multiple lines of treatments, including surgery, radiotherapy, targeted therapy, and immunotherapy. Following disease progression after all these treatments, her tumor was tested for Mucin 16 expression and it demonstrated 100% positivity with markedly elevated CA-125 levels, providing a rationale for treatment with the Mucin 16-CD3 bispecific T-cell engager, ubamatamab.

Ubamatamab was administered in an escalating dose schedule up to 250 mg once weekly during cycle one and continued for a total of 162 weeks. The best response was observed at week 11, with a 40% reduction and a marked decline in CA-125 levels. Disease progression was first detected in a single left lower lobe lung nodule, which on biopsy showed a reduction in Mucin 16 expression from 100% to less than 5%. Post-treatment analysis revealed changes in the tumor microenvironment, including increased expression of T-cell exhaustion markers such as PD-1 and LAG-3.

Ubamatamab was generally well tolerated. Cytokine release syndrome occurred during the escalating phase of cycle one, presenting with fever and hypoxia. Other notable adverse events included pleural and pericardial effusion, both of which resolved spontaneously. Given its favorable safety profile and limited alternative treatment options, ubamatamab was continued beyond the initial progression. The patient ultimately received 28 cycles of treatment before she passed away due to disease progression.

In the second part of the paper, the authors examined Mucin 16 expression in a cohort of pediatric and young adult sarcomas. Among 91 samples, Mucin 16 was expressed in six out of eight epithelioid sarcomas and two out of four malignant rhabdoid tumors. H-score analysis showed that all Mucin 16-positive tumors showed moderate to high expression levels.

In conclusion, this manuscript presents the first reported use of a Mucin 16-CD3 bispecific T-cell engager for epithelioid sarcoma, along with an investigation into resistance mechanisms following progression. The treatment achieved a substantial partial response with a favorable safety profile. The findings suggest that resistance may be associated with loss of Mucin 16 expression and T-cell exhaustion. Follow-up studies are needed to confirm these mechanisms. Notably, the study also identifies INI1-deficient sarcoma as a group with high Mucin 16 expression, warranting additional validation and mechanism exploration. These findings offer valuable insight for future therapeutic strategies and support the use of Mucin 16/CA-125 as both a treatment target and a biomarker for patient selection and disease monitoring.

Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO author Dr. Alison M. Schram at Memorial Sloan Kettering Cancer Center shares insights into her JCO PO article, “Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors.” Host Dr. Rafeh Naqash and Dr. Schram discuss relevant genomic and clinical features of patients with BRCA-altered uterine sarcoma and the efficacy of PARPis in this population.

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and associate professor at the OU Health Stephenson Cancer Center.

Today, we are excited to be joined by Dr. Alison Schram, Associate Attending Physician and Section Head of Oral Therapeutics with Early Drug Development and Gynecologic Medical Oncology Services at the Memorial Sloan Kettering Cancer Center, and the senior author of the JCO Precision Oncology article titled, "Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors."

At the time of this recording, our guest's disclosures will be linked in the transcript.

Dr. Schram, thank you for joining us today. I am excited to be discussing this very interesting, unique topic based on what you published in JCO PO.

Dr. Alison Schram: Thank you for having me.

Dr. Rafeh Naqash: What we like to do for these podcasts is try to make them scientifically interesting but at the same time, keep them at a level where our trainees and other community oncology professionals understand the implications of what you've published. So I'd like to start by asking you, what is leiomyosarcoma for those of us who don't necessarily know a lot about leiomyosarcoma, and what are some of the treatment options for these uterine sarcomas?

Dr. Alison Schram: Uterine leiomyosarcoma is a rare subtype of uterine cancer, and it represents about 1% of all female cancers in the reproductive tract. This is a rare malignancy that arises from the myometrial lining of the uterus, and it is generally pretty aggressive. In terms of the standard therapy, the standard therapy for uterine leiomyosarcoma includes chemotherapy, generally combination chemotherapy, but despite a few regimens that tend to be effective, the duration of effectiveness is relatively short-lived, and patients with advanced uterine leiomyosarcoma eventually progress and require additional therapy. I will say that localized uterine leiomyosarcoma can be treated with surgery as well.

Dr. Rafeh Naqash: Thank you for that description. Now, there are two aspects to what you published. One is the sarcoma aspect, the leiomyosarcoma, and the second is the BRCA mutation. Since we are a precision medicine journal, although we've discussed BRCA a couple of times before, but again, for the sake of our listeners, could you highlight some of the aspects of BRCA and PARP sensitivity for us?

Dr. Alison Schram: Yes. So BRCA is a gene that's important for DNA repair, and BRCA mutations can be either inherited as a germline mutation, so one of your parents likely had a BRCA mutation and you inherited one copy. In patients who have an inherited BRCA mutation, the normal cells tend to have one abnormal copy of BRCA, but if a second copy in the cell becomes altered, then that develops into cancer. And so these patients are at increased risk of developing cancers. Specifically, they are at an increased risk of developing ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, and a few others. These cancers are considered BRCA-associated tumors.

Alternatively, some patients, more rarely, can develop BRCA-altered cancers completely sporadically. So it's a mutation that happens in the tumor itself, and that can lead to impaired DNA repair and promote cancer progression. And those patients are not, they don't have any inherited risk, but just a random event caused a BRCA mutation in the tumor. The reason this is important is because, in addition to it being potentially important for family members, there are certain treatments that are more effective in BRCA-altered cancers. And the main example is PARP inhibitors, which are small molecule inhibitors that inhibit the PARP enzyme, and there is what we call synthetic lethality. So PARP is important for DNA repair, for single-stranded DNA repair, BRCA is important for double-stranded DNA repair, and in a patient that has a cancer that has a BRCA mutation, that cancer becomes more reliant on single-stranded DNA repair. And if you inhibit it with a PARP inhibitor, the cancer cells are unable to repair DNA, and the cells die. So we call that synthetic lethality. PARP inhibitors are FDA approved in several diseases, predominantly the BRCA-associated diseases I mentioned: breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

Dr. Rafeh Naqash: That was very beautifully explained. Honestly, I've heard many people explain BRCA before, but you kind of put it in a very simple, easy to understand format.

You mentioned this earlier describing germline or hereditary BRCA and somatic BRCA. And from what I gather, you had a predominant population of somatic BRCA, but a couple of germline BRCA as well in your patient population, which we'll go into details as we understand the study. You mentioned the second hit on the germline BRCA that is required for the other copy of the gene to be altered. In your clinical experience, have you seen outside of the study that you published, a difference in the sensitivity of PARP for germline BRCA versus a somatic BRCA that has loss of both alleles?

Dr. Alison Schram: So we will get into what's unique about uterine sarcomas in just a minute. In uterine sarcomas, what we have found is that the BRCA mutations tend to be somatic and not germline, as you mentioned. That is in contrast to the other diseases we mentioned, where the vast majority of these tumors are in patients that have germline BRCA alterations. So one thing that's really unique about the uterine sarcoma population and our paper, I believe, is that it is demonstrating an indication for PARP inhibitors in a population that is not characterized by germline BRCA alterations, but truly these by somatic BRCA alterations.

If you look at the diseases that PARP inhibitors are validated to be effective in, including the, you know, the ones I mentioned, the BRCA-associated tumors, there's some data in specific context that suggests that perhaps germline alterations are more sensitive to PARP inhibitors, but that's not universal, and it's really tricky to do because the genetic testing that we have doesn't always tell you if you have two hits or just one hit. So you need more complex genetic analysis to truly understand if there is what we call a biallelic loss. And sometimes it's not a second mutation in BRCA. Sometimes it's silencing of the gene by hypermethylation or epigenetics. Some of our clinical trials are now incorporating this data collection to really understand if biallelic loss that we can identify on more complex genetic testing predicts for better outcomes. And we think it's probably true that the patients that have biallelic loss, whether it be germline or somatic biallelic loss, are more likely to benefit from these treatments. That still needs to be tested in a larger cohort of patients prospectively.

Dr. Rafeh Naqash: In your clinical experience, I know you predominantly use MSK-IMPACT, but maybe you've perhaps used some other NGS platforms, next-generation sequencing platforms. Have you noticed that these reports for BRCA alterations the report mentioning biallelic loss in certain cases? I personally don't- I do lung cancer, I do early-phase lung cancer as well, but I personally don't actually remember if I've seen a report that actually says biallelic loss. So after this podcast, I'm going to check some of those NGS reports and make sure I look at it. But have you seen it, or what would be a learning point for the listeners there?

Dr. Alison Schram: Exactly. And they usually do not. They usually do not explicitly say, “This looks like biallelic loss,” on the reports. The exception would be if there's a deep deletion, then that implies both copies of the gene have been deleted, and so then you can assume that it's a biallelic loss. But oftentimes, when you see a frameshift alteration or a mutation, you don't know whether or not it's a biallelic loss. And you may be able to get some clues based on the variant allele frequencies, but due to things like whole genome duplication or more complex tumor genomics, it's not clear from these reports, and you really do need a more in-depth bioinformatic analysis to understand whether these are biallelic or not. So that is why I suggest that this really needs to be done in the context of a clinical trial, but there is definitely a theoretical rationale for reporting and treating patients with biallelic losses perhaps more so than someone who has a variant of unknown significance that seems to be monoallelic.

The other tricky part, as I mentioned, is the fact that there could be epigenetic changes that silence the second copy, so that wouldn't be necessarily evident on a DNA report, and you would need more complex molecular testing to understand that as well.

Dr. Rafeh Naqash: Sure. Now, going to your study, could you tell us what prompted the study, what was the patient population that you collected, and how did you go about this research study design?

Dr. Alison Schram: It's actually a great story. I was the principal investigator for a clinical trial enrolling patients regardless of their tumor type to a combination of a PARP inhibitor and immunotherapy. And this was a large clinical trial that was being done as a basket study, as I mentioned, for patients that have either germline or somatic alterations with advanced solid tumors that had progressed on standard therapy. And the hypothesis was that the combination of a PARP inhibitor and immunotherapy would be synergistic and that there would be increased efficacy compared to either agent alone and that patients who had BRCA alterations were a sensitive population to test because of their inherent sensitivity to PARP inhibitors and perhaps their increased neoantigen burden from having loss of DNA repair.

So this large study, it's been published, really did show that there was efficacy across several tumor types, but it didn't seem to clearly demonstrate synergy between the immunotherapy and the PARP inhibitor as compared to what you might expect from a PARP inhibitor alone, and in addition to a couple of cases, perhaps attributable to the immunotherapy. So maybe additive rather than synergistic efficacy.

However, what really struck me looking at the data was that there were three patients with uterine leiomyosarcoma with BRCA deletions who had the best responses of anyone on the study. So incredible, durable responses. One of my patients with a complete response that continues to not have any evidence of cancer eight years after the initiation of this regimen. And for those of us that treat uterine leiomyosarcoma, this is unheard of. These patients generally, as I mentioned, respond, if they do respond to chemotherapy, it's generally short-lived and the cancer progresses. And so a complete response nearly a decade later turns heads in this field.

The other interesting thing was that these uterine leiomyosarcoma patients had somatic alterations rather than a germline alteration with a second hit, and the diseases that are best validated for being responsive to PARP inhibitors include the BRCA-associated diseases, the ones that you're at increased risk for if you have a germline BRCA mutation, including breast, pancreas, prostate, and ovarian. And so it was very interesting that this disease type that seemed to be uniquely sensitive to PARP inhibitors with immunotherapy was also different in that patients with uterine leiomyosarcoma don't tend to have a high frequency of BRCA alterations, and in patients that are born with a BRCA alteration, there doesn't seem to be a clearly increased risk of uterine sarcomas. So this population really jumped out as a uniquely sensitive population that differed from the prior indications for PARP inhibitors.

Given this patient and these couple of patients that we observed on the combination, in addition to some other case reports and case series that had started to come out in small numbers, we wanted to look back at our large cohort of patients at Memorial Sloan Kettering to see if we could really get a better sense of the numbers. How many patients at Sloan Kettering with uterine sarcomas have BRCA alterations? Are they generally somatic or germline? Are there unique features about these patients in terms of their clinical characteristics? How many of them have received PARP inhibitors, and if so, is this just luck that these three patients did so well, or is this really a good treatment option for patients with BRCA-altered uterine sarcomas? And so we did this retrospective analysis identifying the patients at Sloan Kettering who met these criteria.

So in total, we found 35 patients with uterine sarcomas harboring BRCA alterations, and the majority were leiomyosarcoma, about 86% of them had leiomyosarcoma, which is interesting because there are other uterine sarcomas, but it does seem like BRCA alterations tend to be more often in the leiomyosarcomas. And 13 of these patients with uterine leiomyosarcoma were treated with PARP inhibitors in the recurrent or metastatic setting with about half of those patients having an overall response, so that's a significant tumor shrinkage that sustained, and a clinical benefit rate of 62%. And if we look at the patients that had these BRCA2 deep deletions, which was the patient I had that had this amazing response, the overall response rate jumped to 60% and the clinical benefit rate to 80%. And we defined clinical benefit rate as having maintained on the PARP inhibitor without evidence of progression at six months. So this is really impressive for patients with a difficult to treat disease. And we couldn't do a randomized controlled trial comparing it to chemotherapy, but looking retrospectively at outcomes on chemotherapy studies, this was very favorable, particularly because many of these patients were heavily pretreated.

So to get a sense of, you know, how this might compare to chemotherapy, we tried to use patients as their own internal controls, and we looked at how long patients were maintained on the PARP inhibitor as compared to how long they were on the treatment just prior. And we used a ratio of 1.3 to say if they were on the PARP inhibitor for 1.3 times what their previous treatment was or longer, that is pretty clearly better, more of a benefit from that regimen. And the majority of patients did meet that bar. So 58% had a PFS ratio greater than 1.3, and the average PFS ratio was 1.9, suggesting, you know, you would expect the the later lines of therapy to actually not work as well, but this suggests that it's actually working better than the immediately prior line of therapy, to me, suggesting that this is truly a good treatment option for these patients.

Dr. Rafeh Naqash: Very interesting. And you mentioned that individuals with tumors having deep deletions were probably more responsive. How did you figure out that there was biallelic loss or deep deletions? Was that part of an extended analysis that was done subsequently?

Dr. Alison Schram: So the deletions reported on our report, if it's a biallelic deletion, that is the one biallelic molecular alteration that would be reported. So those are, by definition, biallelic, and I think that that may be one of the reasons that's a good biomarker. But also, what's interesting is that if you have both copies deleted of BRCA, you can't develop reversion mutations. So one of the the known mechanisms of resistance to PARP inhibitors in patients who have BRCA alterations are something called a reversion mutation where, if you have a frameshift alteration, for example, in BRCA that makes BRCA protein nonfunctional, you can develop a second mutation that actually puts the DNA back in frame, and a functional protein is now made. And so a mechanism of resistance to PARP inhibitors is actually reverting BRCA to a wild-type protein, and then BRCA's synthetic lethality no longer makes sense and is no longer effective. But if you've deleted both copies of BRCA, you don't have the ability to restore the function, and you can't develop reversion mutations. And that's perhaps why, you know, my patient and others have had these prolonged responses to PARP inhibitors because you don't have the same ability to develop that mechanism of resistance.

Dr. Rafeh Naqash: I remember thinking a year and a half back, I had an individual with prostate cancer and with BRCA2, and using liquid biopsy, I had a reversion mutation that we caught. In your practice, have you seen the utility of doing the serial liquid biopsies in these individuals to catch these reversion mutations?

Dr. Alison Schram: Yes, absolutely. And in patients that have the ability to develop a reversion mutation, serial cell-free DNA can catch it, but the caveat is that it doesn't always. So if you see an acquired reversion mutation in cell-free DNA, that can be helpful, particularly if you're planning on putting the patient on another line of therapy that might require a dysfunctional BRCA. So if you're putting them on a clinical trial with a PARP combination and the rationale is that they're sensitive because they don't have a functional BRCA, you would want to know if they developed a reversion mutation, and serial cell-free DNA can definitely identify these reversion mutations. Some of the major clinical trials in ovarian cancer have done serial cell-free DNA and have demonstrated the utility of that approach.

The caveat is that some of these reversion mutations are not readily caught on cell-free DNA because they're more complex reversion mutations, or they're not, the part of the gene that develops the reversion mutation is not tiled on the panel. And so it doesn't always catch the reversion mutations. Also, depends on the cell-free DNA shedding, depends on the tumor volume and other factors. And we published a related paper of a patient, it was a really interesting case of a patient with prostate cancer who was on a PARP inhibitor and developed what appeared to be a single reversion mutation on one sample, had negative cell-free DNA, single reversion mutation in a tissue biopsy, and then developed disease progression. And we did an autopsy, and the patient kindly consented to an autopsy, and at the time of autopsy, there were 10 unique reversion mutations identified across 11 metastases. So almost each metastasis had a unique reversion mutation, and only one of them had been seen premortem on a tissue biopsy and not on a cell-free DNA. But that autopsy really drove home to me how much we're missing by doing clinical testing in real time and we really don't know the entire genomic complexity of our patients by doing single samples. And theoretically, cell-free DNA can catch DNA from all the metastases, so you might think that that would be a solution, and it definitely can catch reversion mutations that are not seen in a single biopsy, but you really need to do it all. I mean, you need to do the tissue biopsy sampling, you need to do cell-free DNA, and probably one cell-free DNA test is not enough.

Dr. Rafeh Naqash: Thank you, again, for that very nice explanation.

Now, one quick provocative question. I remember when I was training, the lab that I used to work in, they used to do a lot of phosphorylation markers for DNA damage response, like phospho NBS, RAD51. Have you seen anything of that sort on these biallelic BRCA mutations where tumors are responding, but they also have a very high signature on the phosphorylation side, and it may or may not necessarily correspond to HRD signatures, but have you noticed or done any of that analysis?

Dr. Alison Schram: I think that it would be great to do that analysis. And some of the work we're doing now is actually trying to dig a little bit deeper in our cohort of patients to understand are these HRD-positive tumors? Does HRD positivity correlate with response to BRCA alterations? In terms of the functional assays, I would love to be able to do a functional assay in these samples.

One of the challenges is that this was a retrospective study and many of the patients were previously treated as standard of care or off-label with these agents, and so we didn't have prospective tissue collection, and so we're really limited by the tissue that was collected as part of standard of care and the consent forms that the patient signed that allow us to do genomic and molecular testing on their samples. So, I think that is hopefully future work that we will do and others will do.

Dr. Rafeh Naqash: Sure.

Shifting gears to your career trajectory, I'd like to spend a couple of minutes there before we end the podcast. So Dr. Schram, you've obviously been a trailblazer in this space of drug development, early-phase trials. Can you give us a brief synopsis of your journey and how you've successfully done what you're doing and what are some of the things that drive you?

Dr. Alison Schram: Well, thank you for saying that. I don't know if that's true, but I'll take the bait. I've been interested in oncology since college and was always very interested in not only the science of oncology but of course, treating patients. And in medical school, I did basic science research in a laboratory and it was very inspiring and made me want to do research in oncology in addition to clinical care. When I became an oncology fellow, I was presented with a very difficult question, which is, “Do you want to be a lab PI and be in the lab, or do you want to do clinical care and clinical research?” And I couldn't choose. I found a mentor who thankfully really had this amazing vision of combining the two and doing very early drug development, taking the data that was being generated by labs and translating it into patients at the earliest stage. So, you know, phase one drug development in molecularly targeted therapies. And so I became very interested as a fellow in early drug development and this ability to translate brand new molecular insights into novel drugs.

And I joined the- at Sloan Kettering, there was the Early Drug Development, it was actually a clinic, it was called something different, and it was very fortuitous. My last year of fellowship, the clinic became its own service with the ability to hire staff at Sloan Kettering, and I was the first ever hire to our Early Drug Development Service. And that really inspired me to try and bring these drugs to patients and to really translate the amazing molecular insights that my colleagues here at Sloan Kettering are discovering, and you know, of course, at other institutions and in pharma. And you know, there 's been an amazing revolution in in drug development over the last several years, and I feel very grateful that I've been here for it. You know, I've been able to take the brilliant insights from my colleagues and put these drugs in patients, and I have the amazing privilege of watching patients in many cases that benefit from these treatments. And so I do mostly phase one drug development and molecularly targeted therapies, and truthfully, I am just very fortunate to be around such brilliant people and to have both patients and labs trust me to be able to deliver these new drugs to patients and hopefully develop better drugs that move forward through FDA approval and reach patients across the country.

Dr. Rafeh Naqash: Thank you so much. That was very nicely put. And hopefully our trainees and junior faculty find that useful based on their own career trajectories.

Thank you, Dr. Schram, for joining us today. Hopefully, we'll see more of your subsequent work in JCO PO. Thank you for giving us all these insights today.

Dr. Alison Schram: Thank you for having me.

Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Alison Schram Disclosures

Consulting or Advisory Role Company: Mersana, Merus NV, Relay Therapeutics, Schrodinger, PMV Pharma ,Blueprint Medicines, Flagship Pioneering, Redona Therapeutics, Repare Therapeutics, Endeavor BioMedicines Research Funding Company: Recipient: Your Institution  Merus, Kura, Surface Oncology, AstraZeneca, Lilly, Pfizer , Black Diamond Therapeutics, BeiGene, Relay Therapeutics, Revolution Medicines,  Repare Therapeutics, PMV Pharma, Elevation Oncology, Boehringer Ingelheim Travel, Accommodations, Expenses Company: PMV Pharma 

In this JCO Precision Oncology Article Insights episode, Natalie DelRocco summarizes "Prognostic Value of the G2 Expression Signature and MYC Overexpression in Childhood High-Grade Osteosarcoma" by Roelof van Ewijk et al. published on May 29, 2025.

TRANSCRIPT

Natalie Del Rocco: Hello, and welcome to JCO Precision Oncology Article Insights. I'm your host, Natalie DelRocco, and today we will be discussing the original report, "Prognostic Value of the G2 Expression Signature and MYC Overexpression in Childhood High-Grade Osteosarcoma." This original report by van Ewijk et al. describes a study of the association between 2 biomarkers and survival outcomes among patients with high-grade osteosarcoma. Osteosarcoma is a disease where not much progress has been made in risk stratification factors that could potentially help patients target lower-risk therapies, less toxic therapies, or therapies that might be more toxic but could help their high-risk osteosarcoma.

So, it's important to identify risk factors that can help target therapies. The G1/G2 gene expression signature is a prognostic risk score developed by a French osteosarcoma group in 2022. They showed in a cohort of 79 osteosarcoma patients that risk score was associated with poorer event-free survival and overall survival. This considers expression of 15 individual genes. MYC amplification was shown in 2023 by a North American osteosarcoma group to be associated with poor overall survival in a cohort of 92 osteosarcoma patients, and this group validated that finding in a localized cohort in the same publication. 

The goal of this particular original report was to assess the prognostic significance of each of these biomarkers in a population independent to those prior publications and, hence, to serve as an external validation of prior findings and to assess these 2 biomarkers in the same study. The investigators considered MYC amplification, defined as having greater than 7 copies; MYC expression as a continuous rather than the previously categorized variable; and G2 expression defined as a continuous variable; and then G2 expression defined as a dichotomous variable with the cut point at the median, as done in the original paper. 

What the investigators found in their primary multivariable Cox proportional hazards regression model, which controlled for additional clinical risk factors such as age, tumor site, tumor size, is that G2 expression and MYC expression as continuous variables were associated with increased hazard of EFS and OS event. MYC amplification was not found to be prognostic. This is not surprising. When we have continuous variables, we have greater statistical power, we decrease the likelihood that an identified cut point in a previous study does not generalize well to either our genetic assay or our patient population. So, we don't have to worry about finding the optimal cut point in our particular patient sample.

Thank you for listening to our JCO Precision Oncology Article Insights. Don't forget to give us a rating or review, and be sure to like and subscribe so that you never miss an episode. You can find all ASCO shows at asco.org\podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Precision Oncology Article Insights episode, Natalie DelRocco summarizes "Real-Time Monitoring in Renal Cell Carcinoma With Circulating Tumor DNA: A Step Forward, but How Far?" by Zeynep B. Zengin et al. published on February 28, 2025.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Natalie DelRocco: Hello, and welcome to JCO Precision Oncology Article Insights. I'm your host, Natalie DelRocco, and today we will be discussing the editorial, "Real-Time Monitoring in Renal Cell Carcinoma With Circulating Tumor DNA: A Step Forward, but How Far?"

This editorial by Zengin and Kotecha discusses the impact of circulating tumor DNA (ctDNA) and its potential applications in renal cell carcinoma - we'll call this RCC for the remainder of the podcast.

This article was published in February of 2025, and I think this is really timely because ctDNA is currently an emerging biomarker of interest in many different cancers. Having shown promise in certain cancers, other types of cancers are really targeting ctDNA to see if it can be used as a prognostic or a predictive biomarker in their specific field of oncology. Sometimes it is found that ctDNA is a prognostic marker that's associated with outcome, but it's not always clear whether it is a predictive biomarker that can help modify treatment and to what extent it could be helpful modifying treatment.

This is what the authors of this editorial really focus on. They focus on the applications of ctDNA in RCC by interpreting the accompanying article, "Longitudinal Testing of Circulating Tumor DNA in Patients With Metastatic Renal Cell Carcinoma" by Basu et al.

So, the editorial authors begin by giving examples of cancers where ctDNA has been shown to be useful in cancer monitoring - for example, locally advanced urothelial carcinoma - and they give examples of when it has not been shown to be useful in monitoring colorectal cancer. And this just highlights the variability of ctDNA as a biomarker. It's not always a useful biomarker, but sometimes it is.

The authors note that RCC may fall into the latter category - that is, the "not useful" category - due to the low ctDNA shedding which characterizes RCC. However, metastatic RCC - we'll call this ‘mRCC’ for the remainder of the podcast - may be a target for use of ctDNA clinically due to advanced assay development, according to the authors. Basu et al, in the original work that the editorial accompanies, showed in a retrospective study of 92 patients with mRCC that ctDNA detectability was associated with poorer PFS, regardless of receipt of active treatment versus no receipt of active treatment. That's important because ctDNA can be directly affected by therapy.

The authors of the editorial believe that this is a particularly promising result for a few reasons. Firstly, the estimated hazard ratios were quite large. A hazard ratio of 3.2 was seen in the active treatment group versus a hazard ratio of 18 was observed in the no-active-treatment group. I will note that a hazard ratio of 18 with an extremely wide confidence interval is an unusual observation. So, when interpreting this result, I would consider the direction and magnitude of the effect to be suggestive of promise but needing to be validated in the future to improve precision. And the authors of the editorial do agree with this; they note the same.

The authors also note that a single-patient example was used to show how that ctDNA positivity can be used in mRCC to monitor and prompt imaging if disease progression is suspected. And then that way, disease progression can be caught earlier. That to say, there is a real target for clinical use, which isn't always the case. Sometimes we know that ctDNA is associated with outcome, but we don't quite know how we can modify when we know that ctDNA is positive. In this case, the editorial authors show that we can use ctDNA positivity to monitor patients for disease progression.

Despite the promise of the study, the editorial does highlight that the study inherits typical retrospective study limitations. For example, there is a heterogeneous cohort. There is variability in data collection, particularly nailing down specific time points, which can always be a challenge when collecting biological samples as part of a study. And small sample size - although 92 patients is great for renal cell carcinoma, it is a challenging sample size with respect to precision of those hazard ratio estimates, which we've already talked about.

The authors additionally note that ctDNA could be used to direct therapy, not just to monitor for disease progression. So, both monitoring and changing therapy would certainly require further study and validation, which is discussed by the authors of this editorial. We would want larger, prospective studies showing the same association before we would be comfortable modifying treatment for patients based on their ctDNA positivity level.

Thank you for listening to JCO Precision Oncology Article Insights. Don't forget to give us a rating or a review, and be sure to subscribe so that you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO author Dr. Philip Philip at Henry Ford Cancer Institute and Wayne State University shares insights into his JCO PO article, “Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.” Host Dr. Rafeh Naqash and Dr. Philip discuss how prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.

Today, we are excited to be joined by Dr. Philip Philip, Chair of Hematology and Oncology, as well as leader of GI and Neuroendocrine Oncology. He's also the Professor of Oncology and Pharmacology, as well as Co-Leader of the Pancreatic Cancer Program and Medical Director of the Cancer Clinical Trial and Translational Research Office at the Henry Ford Cancer Institute at Wayne State University. Dr. Philip is also the Senior Corresponding Author of the JCO Precision Oncology article entitled, "Incorporating Circulating Tumor DNA Testing into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group."

At the time of this recording, our guest’s disclosures will be linked in the transcript.

Dr. Philip, welcome to our podcast, and thank you so much for joining us today.

Dr. Philip Philip: Thank you so much, Dr. Naqash, for providing me this opportunity to be discussing this with you.

Dr. Rafeh Naqash: This is a very timely and interesting topic. We've done a couple of podcasts on ctDNA before, but none that is an opinion piece or a guidance piece based on what you guys have done. Could you tell us what led to this perspective piece or guidance manuscript being published? There is some background to this. Could you tell us, for the sake of our listeners, what was the initial thought process of why you all wanted to do this?

Dr. Philip Philip: The major reason for this was the fact that investigators were considering using ctDNA as a primary endpoint in clinical trials. Obviously, you hear my focus will be on gastrointestinal cancers. So, the idea was, can we use ctDNA instead of using the traditional endpoints such as disease-free survival, progression-free survival, or overall survival? And the question was, do we have enough data to support that in patients with gastrointestinal cancers? Now, the article obviously goes over some review of the data available, but the core of the article was not to do a comprehensive review of ctDNA use and the evidence so far, although we used that in really putting our recommendations. So, we really had to evaluate available data. But the focus was, what are the gaps? What do we need to do? And are we ready to use ctDNA as a primary endpoint in clinical trials?

Dr. Rafeh Naqash: Thank you for giving us that background. Obviously, a very broad, complicated topic with a bunch of emerging data that you've highlighted. But most importantly, for the sake of, again, trainees and listeners, could you help us understand the difference between tumor-informed and non-tumor-based ctDNA assessments?

Dr. Philip Philip: Sure. So, the tumor-informed is simply meaning that you're taking the genomic makeup or the DNA fingerprint of the cancer in a given patient, and you create a profile, and then use that profile to see whether that DNA is present in the blood. So, it's very simple. It's like barcoding DNA and then going and looking for it in the blood, which means that you have to have the primary tumor. When I say primary tumor, you need to have the tumor to start off with. It doesn't really apply, maybe easily, if you just have a fine-needle aspirate and things like that. So, you really have to have a good amount of the tumor for you to be able to do that. So, that's a tumor-informed, and from the name, you can easily understand how it's done, compared to the other one, which is uninformed, whereby off-the-shelf probes are used to look for tumor DNA. And again, they're based on prior experience and prior identification of the key DNA changes that will be seen in tumors. So, that's the difference between the two in terms of the principle of the test.

The uninformed will not require you to send the original tumor that you're trying to test. However, the informed, you do. The turnaround time is, again, a bit different because, as you would expect, it's shorter in the uninformed. And the reason for that, again, is the initial preparation of the profile that is going to be used in the future when you do serial testing. The sensitivity has been a bit of a discussion. Initially, people have thought that tumor-informed assays are more sensitive, more specific, more sensitive, et cetera. But in our review, we come to the conclusion saying that we don't think that's going to be a major difference. And there are obviously improvements happening in both types of assays. The sensitivities have been improving. So, at this point in time, we do feel that you have two types of assays, and we didn't feel strongly about recommending one over the other.

Dr. Rafeh Naqash: Thank you for that description. You mentioned something about sensitivity, specificity. Obviously, many of us who have ordered both tumor-informed and tumor-uninformed, we understand the differences with respect to the timing. The tumor-informed one can take more time. The uninformed one, being a sort of a liquid biopsy, may not necessarily have as much of a turnaround time. Could you briefly speak to those limitations or advantages in the context of the two versions?

Dr. Philip Philip: I just really want to also highlight that when we say turnaround time, so for the tumor-informed assays, the first assay that we do will be requiring a turnaround time. But once the pattern has been set and the profile has been documented, the subsequent testing doesn't require much in the way of waiting. However, when you're using this for the minimal residual disease, then you have a window of opportunity to work at. That's number one. So, it means that in patients who have resected cancer, you may end up having to wait longer than the tumor-uninformed assay, especially if you don't have easy access to your material for the baseline material to send.

And also, what we'd like to do is not do the test immediately after the operation or soon after the operation. Give it some time. There's a window where you can work at, and starting minimally two weeks after the surgery. But in my experience, I'd like to wait at least four weeks just to make sure that we got an accurate reading. Sometimes when you do it very early after surgery, because of the effect of the surgery and the release of the normal DNA is also, it may dilute the tumor DNA, and then you may get a false negative. So, basically, it depends on the clinical situation.

And your question is, is one better to be used than the other? I think ultimately, it ends up with the turnaround time not being as much of an issue. It might be in certain situations, depending on when you see the patients after the operation or any definitive treatment you've done and you want to look for minimal residual disease. But in general, I don't think that's going to be a real major issue.

Dr. Rafeh Naqash: I remember discussing this with one of the tumor-informed platforms with regards to this barcode you mentioned. They generate a fingerprint of sorts for the tumor on the tissue, then they map it out in the blood and try to assess it longitudinally. And one of the questions and discussions we had was around the fact that most of the time, these barcoded genes are not the driver genes. If you have a KRAS mutant tumor, it's not going to be the KRAS gene that they map out. It's something that is specific.

So, is there a possibility that when you are mapping out, let's say, a metastatic tumor where there is truncal and subclonal mutations at different sites, that you capture something that is not necessarily truncal, and that does not necessarily reflect some other metastatic site having a recurrence? So basically, over time, you don't see a specific mutational pattern or the signature on the tumor-informed, and then you see something on the scan which makes you think, "Well, it was not the right test," but actually it could be a different subclone or a clone mutation at a different site. Is there a concept that could help us understand that better?

Dr. Philip Philip: I think you raise a very important point. Although, I have to say from my practical experience, that is not a common thing to see. In fact, for some reason, we don't see it that often in any frequency that should, at this point in time, make us concerned about the serial testing. But what you were mentioning is a real challenge which can happen. Now, the question is, how often does the clonal evolution or the divergence happen to the point that it's going to be like a false negative, is what you're saying. At this point in time, we don't really have good information on that, or any good information, practical information. And when we went through the literature and we were looking for the evidence, that wasn't something which was there clearly telling us. Although, this is something that has to be studied further prospectively. And I don't know of a study, but I might be missing it, I don't know of a study which is systematically looking at this. Although it's a very valid hypothesis and theoretical basis for it, but in real life, we still have to see how much does it really interfere with the validity of this kind of testing.

Dr. Rafeh Naqash: Which brings us to the more important discussion around your manuscript. And I think that the overarching theme here is the consensus panel that you guys had recommended that ctDNA-based metrics be used as a co-primary endpoint.

Could you tell us, for early-phase trials, maybe phase two studies for that matter, could you tell us what were some of the aspects that led to this consensus being formed from your working group?

Dr. Philip Philip: Well, there were a number of reasons, in any order of priority, but one of them is we don't have a good sense of dynamics of the ctDNA. And again, remember this article was about gastrointestinal cancers. Maybe we know more about colon cancer, but, or colorectal cancer, but we don't know that well about the upper GI, like gastroesophageal, pancreatic, et cetera. So, we don't know what is the false negative percentages. And in fact, we know that there are certain sites of the disease, metastases, that do not lead to enough shedding of the DNA into the circulation. So, that was something else. I mean, false negativity, not knowing exactly what the dynamics are, especially in different disease types. So, that was another reason, which we felt that it may not be at this time primetime to really have those ctDNA tests as a primary endpoint.

We wanted to make sure that, on the other hand, we wanted to make sure that people consider including ctDNA more like a secondary endpoint so that we can gain the information that we're lacking, at least the ones I mentioned to you. So, that was an important point of our discussions and deliberations when we were writing the article.

Dr. Rafeh Naqash: And I myself have been on both sides of the aisle where - I treat people with lung cancer, you mentioned appropriately that most of the data that we have for ctDNA is generated from GI cancers, especially colorectal - on the lung cancer side, I myself had a patient with an early-stage cancer, had treatment, surgery, immunotherapy, and then had ctDNA that was tumor-informed, was positive four to five months before the imaging actually showed up. And on the other side, I've also had an individual where early-stage lung cancer, surgery, immunotherapy, and then had PET scans that showed a positive finding, but the ctDNA, tumor-informed ctDNA, was negative multiple times. So, I've seen both aspects of it, and your paper tries to address some of these questions on how to approach a negative, radiologically negative imaging but positive ctDNA potentially, and vice versa. Could you elaborate upon that a little bit?

Dr. Philip Philip: Well, obviously, we do see this in practice. Again, I do GI oncology. I have patients who, you do ctDNA. I mean, my advice to anyone, when you order a test, you have to make sure that you know what you're going to do with the test, because that's the most important thing. You get a positive test, you do something. You get a negative test, you do something. But most importantly, our patients who you're following up, they are very anxious for a diagnosis they have that is not- I mean, it's cancer. If you're doing these tests, if we get continuous, repeatedly negative testing, then you really have to also tell the patient that there's a false negativity. And I mentioned to you earlier, there are certain sites of disease, like peritoneal, they may not be producing enough, or there are some tumors, their biology is such that they don't release as much to be detected in the blood. Now, one day we will get maybe a more sensitive test, but I'm talking about the tests we have now.

On the other hand, if you get a positive testing, you have to make a distinction for ctDNA in the minimal residual disease situation. If you get a positive test, there is enough evidence that the patient has a worse prognosis. There's evidence for that. No one can dispute that. Again, I'm talking about colorectal cancer where there are a lot of data for that. So, in that situation, there are studies that are looking, if you get a positive test in someone who you're not intending to give any adjuvant treatment, there are studies looking into that, both in terms of intensifying, like chemotherapy, in certain patients. And also, there's work being done, if you have a negative test in someone who has stage III disease, for example, or definitely stage II disease, they may not need to give them chemo. Those things are happening. But in metastatic disease, it's a different situation. Or even in someone who has received surgery, adjuvant chemotherapy, in those patients where they, whether they're now under, in the surveillance mode, those patients, if you have a positive, it may be positive. I had a recent patient like those, eight months before we saw anything on the scans. So, the question is, if you have a positive test, is there any advantage in giving them treatment, systemic treatment? Of course, we're assuming that the PET scan is negative. So, is there really any advantage in giving someone treatment ahead of time, before you see the imaging changes? That kind of data, in my opinion, is not really available or strong. You can always think of it in different ways, explain it in different ways. It's minimal disease, maybe you get a better response. But I don't know if we really can justify at this time. Therefore, in my practice, my own practice, I do not treat just a positive ctDNA. Again, that's different than after surgery when you're thinking of whether to give adjuvant treatment, no adjuvant treatment. But someone who's finished treatments and then you're just serially monitoring the disease, those patients, I do not treat them with chemotherapy. And that was something which, based on the literature we reviewed, there was nothing out there to definitely- I mean, if you see something positive, you will do a scan earlier, you will talk to the patient, examine the patient, whatever. But if there's nothing there, starting a treatment, that's not justified at this point in time.

Now, you need to do a study like that. Definitely, you need to do a study. But I can tell you that from my experience, having been involved with study design and all that, it's not an easy trial to do. It's going to be a trial- at a minimum, it will take many patients, it will take longer time to complete, and there are a number of variables there. If someone is willing to put a lot of money into it, it can be done. But I can tell you that that kind of intention to do a study like that has been very much a challenge at this time.

Dr. Rafeh Naqash: Of course, as you mentioned, the follow-up time that you need for a study like that is going to be very long to get to meaningful outcomes.

Dr. Philip Philip: You need to be very patient to do such a study. But the problem with a very long study is that things change, standard of care changes with time, and the assays will change. So, that's why we don't have that kind of data. I'm not sure if there are people in the community or in the academic centers who do treat based on only positive ctDNA.

The other thing is that you really have to always consider the psychological impact of these tests on patients and caregivers. Sometimes it can be really very stressful, burdensome to people to sit there just waiting for the disease to show up on a scan. And therefore, in my opinion, I'm not saying definitely don't use it in that situation, I'm just saying that you have to personalize it also, to see the patient who you would like to do it and then other patients who may not do it, or you think that it's not good for them to do it. And the patient also has to understand the outcome of the test and how you're going to be interpreting it.

Dr. Rafeh Naqash: That's a lot of great insights, Dr. Philip, and I know you've been involved in trial designs. I'm sure NCT and cooperative groups are actively thinking and incorporating ctDNA-based metrics as one of the endpoints in their trial. I know of a GU study that's, I think it's an Alliance study, trying to de-escalate treatment based on ctDNA. I have one of my colleagues who's also a GU investigator at OU, he's doing a ctDNA-based, tumor-informed-based de-escalation. So, obviously, more and more data, hopefully, that'll be generated in the next couple of years.

Dr. Philip Philip: But remember, these studies are not using it as an endpoint. They're using it as a means of optimizing treatment, which is a bit different. So, as an endpoint, can you do a phase III trial of, let's say, a thousand patients, and your primary endpoint is not survival, but you're saying, "Can I reduce the ctDNA, clear it earlier, or whatever?" That's the sort of thing this article was about. We can't do that at this time.

Dr. Rafeh Naqash: I totally understand. Thank you for explaining the difference, and hopefully more to come in this space in the next couple of years.

I briefly wanted to touch upon your personal career and journey based on all that you've done and accomplished. Could you tell us about how you started, what your journey has been like, and how that connects with what you're doing right now, including mentoring other trainees and junior faculty?

Dr. Philip Philip: Well, when I was in high school, I wanted to be an engineer, but I grew up in Baghdad, and all my friends wanted to do medicine, so I went with the tide, so I did medicine. I don't regret that. I would do it again if I had the opportunity. The reason why I did oncology was, I left the country and did a PhD in clinical pharmacology at the University of London. And that really got me, it was a topic which included, which was on cancer. So, I really got interested in a disease that is really a lot of science, and things are new, or were new at the time. And if I want to look back what I was doing, the beginning of my training in the 80s, second half of the 80s, and now, it's unbelievable how things have changed.

But one of the things which I really have to say is that almost all my life I've been in what we call academic institutions. But I firmly believe that for people, whether academic or not, you have to be a very good, astute clinician, because many of the things we do, really, we're trying to put the patients in the center. It's not only doing fancy science, it's to do things that help the patients. And you can bring in bits and pieces of fancy science or less fancy science, but that's something which is really extremely important for us to think about, being a very good clinician, very good doctor, because medicine is a science, whether you're practicing as a solo practitioner or you're part of a large academic center. It's the way you think, the way you interrogate things that you're not sure of, the way you collaborate, the way you learn every day. I mean, at my age, I still don't like to miss any tumor board, because in each tumor board, there's something you learn, even if you think that you know everything. So, that's really the whole thing of it, is that be a very good clinician, be open-minded. Always, you have to think of things that, they look interesting, they look somehow unexplained. Always try to help find the solutions and do that.

One of the major things that I feel that people should do is being also very focused on things. I mean, you have to also know what you want to do in the next 5, 10, 15 years. Because although everyone is in it in the same way when we start, but there are different things that drive people, people who want to do more of the formal research, like being an academic-like institution. But there are also a lot of people who are very successful outside of a- what we call an academic setting. In the United States, most people are not working in an academic kind of setting. Although, for me, the distinction between academic and community is getting less and less, because if you think that you do phase I trials in academia only, that's not true, because there are, in fact, in the state of Michigan, the most active phase I doctor is not even in academia, he's in private practice. So, you can do all these things. It's a matter of what you like to do, and you really have to make sure you know what you want to do. Because sometimes people are, especially early on, they get a bit confused, “What I want to do.” There's an issue of doing general oncology versus subspecialist. If you're a subspecialist doing only GI, you have to make sure that you really also have some kind of recognition that you're only a GI oncologist, recognition regional, national, international, but some degree of recognition that you feel that people are coming to you for advice as a second opinion or whatever it is. But again, you have to decide what you think you want to be, how you want to be, because there's a lot of options here between community practice, academic practice, industry, and of course, there's always the administrative thing. Some people tend to be more like going into the line of being an administrator. So, there's a lot of options for you.

Dr. Rafeh Naqash: Well, thank you again, Dr. Philip, for those pearls of wisdom. I think that was very insightful. I'm sure all the trainees and early-career investigators will find all that advice very helpful. Thank you again for joining us today.

Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.

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Uncompensated Relationships: Rafael Pharmaceuticals, Caris MPI

In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma” by Dr. Miles C. Andrews, et al. published on June 07, 2024.

The guest on this podcast episode has no disclosures to declare.

Jiasen He:

Hello and welcome to the JCO Precision Oncology Article Insights. I'm your host, Jiasen, and today we'll be discussing the JCO Precision Oncology article, "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma," by Dr. Miles C. Andrews and colleagues. This study was supported by Foundation Medicine, a for-profit company that conducts FDA-regulated molecular diagnostics, including assays used to measure tumor mutational burdens, or TMB, as described in this article.

Immune checkpoint inhibitor (ICI) therapy has become a cornerstone in the treatment of metastatic melanoma. They work by activating the patient's own immune system, representing a fundamentally different approach from traditional chemotherapy. Several biomarkers have emerged as promising tools to predict ICI therapy response, and TMB is one of the most extensively studied. TMB is defined as the number of somatic mutations per megabase of an interrogated genome sequence. In the KEYNOTE-158 study, patients with high TMB showed better response rates and longer progression-free survival compared to those with low TMB, which led to the FDA tumor-agnostic approval of TMB as a biomarker to guide ICI therapy.

In this manuscript, Dr. Andrews and colleagues set out to answer an important question: does TMB predict outcomes of ICI therapy in real-world patients with advanced melanoma? To explore this, they analyzed de-identified data from the nationwide Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). To be included, patients needed to have had at least two visits to a Flatiron Health clinic and a Foundation Medicine Comprehensive Genomic Profiling report. Eligible patients had received first-line treatment with either monotherapy (nivolumab or pembrolizumab) or dual therapy with the combination of ipilimumab and nivolumab for metastatic melanoma. They also needed a tissue-based TMB score from either the FoundationOne or FoundationOne CDx genomic test. For this study, TMB less than 10 mutations per megabase was considered low TMB; TMB equal to or more than 10 mutations per megabase was considered high TMB; and TMB equal to or more than 20 mutations per megabase was considered very high TMB. Of the 497 patients in the final cohort, 29% had low TMB, while 71% had high TMB, and 50% had very high TMB.

The authors observed that patients with very high TMB were more often male, had BRAF wild-type tumors, and were more likely to receive anti-PD-1 monotherapy. This group also had tumors more commonly sampled from brain and lung metastases. Patients with high TMB but not very high TMB were more likely to carry the BRAF V600K mutation and were least likely to have lung metastases. Meanwhile, those with low TMB tended to be younger and had disease limited to non-visceral sites. As expected, the presence of ultraviolet mutation signatures, a known driver of melanoma, was strongly associated with TMB. UV signatures were found in just 18% of the low TMB group, but in 89% of the high TMB and 93% of the very high TMB group. High TMB was found to be prognostic of improved real-world progression-free survival (PFS) and overall survival (OS) in patients receiving both monotherapy and dual immune checkpoint inhibitors, even after adjusting for other established prognostic factors. Interestingly, in the low TMB group, overall survival was likely confounded by the availability of effective second-line targeted therapy, particularly for BRAF-mutant patients. These patients had better outcomes compared to their BRAF wild-type counterparts, likely reflecting a greater reliance on salvage therapy in low TMB patients who derived less benefit from first-line immunotherapy.

The authors then further examined the ICI outcomes using stepwise TMB thresholds, with TMB less than 10 as low, 10 to 19 as high, and equal to or more than 20 as very high. For those receiving ICI monotherapy, both PFS and OS were highest in the very high TMB group, followed by the high TMB group, and lowest in the low TMB group. However, in patients treated with dual ICI therapy, the results diverged. While low TMB patients still had the poorest outcomes, those with high TMB (mutations 10 to 19 per megabase) had better PFS and overall survival than those with very high TMB (mutations equal to or more than 20 per megabase).

The authors then conducted exploratory multivariable modeling, showing that among very high TMB patients with BRAF mutations, dual ICI therapy was associated with a significantly higher hazard ratio compared to monotherapy. They concluded that dual ICI may not benefit, and could even harm, patients with very high TMB, whereas those with TMB between 10 and 20 mutations per megabase may get more from the intensified regimen. Importantly, as the authors stated in the manuscript, we need to note that in this cohort, very high TMB patients were more likely to have brain metastases at treatment initiation, be male, and lack BRAF V600E/K mutations—all factors associated with poorer prognosis. This might partially explain inferior outcomes to dual ICI in very high TMB patients, as patients were not randomly assigned to therapy in this retrospective, real-world study. As such, these findings should be interpreted with caution and validated in future studies.

In summary, this study showed that in a real-world setting, high tumor mutational burden predicts better outcomes with immune checkpoint inhibitor therapy in patients with advanced melanoma. Interestingly, the authors found that dual ICI therapy may offer no added benefit for patients with very high TMB compared to ICI monotherapy. However, this was a retrospective, non-randomized study, and the cohorts were imbalanced for some known risk factors, which could confound outcomes. As a result, these findings should be interpreted with caution and will need to be validated in future prospective studies.

Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO author Dr. Dean A. Regier at the Academy of Translational Medicine, University of British Columbia (UBC), and the School of Population and Public Health, BC Cancer Research Institute shares insights into his JCO PO article, “Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation.”

Host Dr. Rafeh Naqash and Dr. Regier discuss the real-world clinical effectiveness and cost-effectiveness of multigene panels compared with single-gene BRAF testing to guide therapeutic decisions in advanced melanoma.

Dr. Rafeh Naqash:Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center in the University of Oklahoma.

Today, we are excited to be joined by Dr. Dean A. Regier, Director at the Academy of Translational Medicine, Associate Professor at the School of Population and Public Health, UBC Senior Scientist at the British Columbia Cancer Research Institute, and also the senior author of the JCO Precision Oncology article entitled "Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation."

At the time of this recording, our guest's disclosures will be linked in the transcript. Dean, welcome to our podcast and thank you for joining us today.

Dr. Dean Regier:Thank you. I'm delighted to be here.

Dr. Rafeh Naqash:So, obviously, you are from Canada, and medicine, or approvals of drugs to some extent, and in fact approvals of gene testing to some extent is slightly different, which we'll come to learn about more today, compared to what we do in the US—and in fact, similarly, Europe versus North America to a large extent as well.

Most of the time, we end up talking about gene testing in lung cancer. There is a lot of data, a lot of papers around single-gene panel testing in non-small cell lung cancer versus multigene testing. In fact, a couple of those papers have been published in JCO PO, and it has shown significant cost-effectiveness and benefit and outcomes benefit in terms of multigene testing. So this is slightly, you know, on a similar approach, but in a different tumor type. So, could you tell us first why you wanted to investigate this question? What was the background to investigating this question? And given your expertise in health economics and policy, what are some of the aspects that one tends or should tend to understand in terms of cost-effectiveness before we go into the results for this very interesting manuscript?

Dr. Dean Regier:Yeah, of course, delighted to. So, one of the reasons why we're deeply interested in looking at comparative outcomes with respect to single- versus multigene testing— whether that's in a public payer system like Canada or an insurer system, a private system in the United States— is that the question around does multigene versus single-gene testing work, has not typically tested in randomized controlled trials. You don't have people randomized to multigene versus single-gene testing.

And what that does, it makes the resulting evidence base, whether it's efficacy, safety, or comparative cost-effectiveness, highly uncertain. So, the consequence of that has been uneven uptake around the world of next-generation sequencing panels. And so if we believe that next-gen sequencing panels are indeed effective for our patients, we really need to generate that comparative evidence around effectiveness and cost-effectiveness. So we can go to payers, whether it be single payer or a private insurer, to say, "Here are the comparative outcomes." And when I say that uptake has been uneven, uptake there's been actually plenty, as you know, publications around that uneven uptake, whether it be in Europe, in the United States, in Canada. And so we're really interested in trying to produce that evidence to create the type of deliberations that are needed to have these types of technologies accessible to patients. And part of those deliberations, of course, is the clinical, but also in some contexts, cost-effectiveness.

And so, we really start from the perspective of, can we use our healthcare system data, our learning healthcare system, to generate that evidence in a way that emulates a randomized controlled trial? We won't be able to do these randomized controlled trials for various, like really important and and reasons that make sense, quite frankly. So how can we mimic or emulate randomized controlled trials in a way that allows us to make inference around those outcomes? And for my research lab, we usually think through how do we do causal inference to address some of those biases that are inherent in observational data. So in terms of advanced melanoma, we were really interested in this question because first of all, there have been no randomized controlled trials around next-gen sequencing versus single-gene testing. And secondly, these products, these ICIs, immune checkpoint inhibitors, and BRAF and MEK inhibitors, they are quite expensive. And so the question really becomes: are they effective? And if so, to what extent are they cost-effective? Do they provide a good reason to have information around value for money?

Dr. Rafeh Naqash:So now going to the biology of melanoma, so we know that BRAF is one of the tumor-agnostic therapies, it has approvals for melanoma as well as several other tumor types. And in fact, I do trials with different RAF-RAS kinase inhibitors. Now, one of the things that I do know is, and I'm sure some of the listeners know, is the DREAMseq trial, which was a melanoma study that was an NCI Cooperative Group trial that was led by Dr. Mike Atkins from Georgetown a couple of years back, that did show survival benefit of first-line immunotherapy sequencing. It was a sequencing study of whether to do first-line BRAF in BRAF-mutant melanoma followed by checkpoint inhibitors, or vice versa. And the immune checkpoint inhibitors followed by BRAF was actually the one that showed benefit, and the trial had to stop early, was stopped early because of the significant benefit seen.

So in that context, before we approach the question of single-gene versus multigene testing in melanoma, one would imagine that it's already established that upfront nivolumab plus ipilimumab, for that matter, doublet checkpoint inhibitor therapy is better for BRAF-mutant melanoma. And then there's no significant other approvals for melanoma for NRAS or KIT, you know, mucosal melanomas tend to have KIT mutations, for example, or uveal melanomas, for that matter, have GNAQ, and there's no targeted therapies. So, what is the actual need of doing a broader testing versus just testing for BRAF? So just trying to understand when you started looking into this question, I'm sure you kind of thought about some of these concepts before you delved into that.

Dr. Dean Regier:I think that is an excellent question, and it is a question that we asked ourselves: did we really expect any differences in outcomes between the testing strategies? And what did the real-world implementation, physician-guided, physician-led implementation look like? And so, that was kind of one of the other reasons that we really were interested is, why would we go to expanded multigene panel sequencing at all? We didn't really expect or I didn't expect an overall survival a priori. But what we saw in our healthcare system, what happened in our healthcare system was the implementation in 2016 of this multigene panel. And this panel covered advanced melanoma, and this panel cost quite a bit more than what they were doing in terms of the single-gene BRAF testing. And so when you're a healthcare system, you have to ask yourself those questions of what is the additional value associated with that?

And indeed, I think in a healthcare system, we have to be really aware that we do not actually follow to the ideal extent randomized controlled trials or trial settings. And so that's the other thing that we have to keep in mind is when these, whether it's an ICI or a BRAF MEK inhibitor, when these are implemented, they do not look like randomized controlled trials. And so, we really wanted to emulate not just a randomized controlled trial, but a pragmatic randomized controlled trial to really answer those real-world questions around implementation that are so important to decision making.

Dr. Rafeh Naqash:Sure. And just to understand this a little better: for us in the United States, when we talk about multigene testing, we generally refer to, these days, whole-exome sequencing with whole-transcriptome sequencing, which is like the nuclear option of of the testings, which is not necessarily cheap. So, when you talk about multigene testing in your healthcare system, what does that look like? Is it a 16-gene panel? Is it a 52-gene panel? What is the actual makeup of that platform?

Dr. Dean Regier:Excellent question. Yeah, so at the time that this study is looking at, it was 2016, when we, as BC Cancer—so British Columbia is a population right now of 5.7 million people, and we have data on all those individuals. We are one healthcare system providing health care to 5.7 million people. In 2016, we had what I call our "home-brew" multigene panel, which was a 53-gene panel that was reimbursed as standard of care across advanced cancers, one of them being advanced melanoma. We have evolved since then. I believe in 2022, we are using one of the Illumina panels, the Focus panel. And so things have changed; it's an evolving landscape. But we're specifically focused on the 53-gene panel. It was called OncoPanel. And that was produced in British Columbia through the Genome Sciences Centre, and it was validated in a single-arm trial mostly around validity, etc.

Dr. Rafeh Naqash:Thank you for explaining that. So now, onto the actual meat and the science of this project. So, what are some of the metrics from a health economy standpoint that you did look at? And then, methodology-wise, I understand, in the United States, we have a fragmented healthcare system. I have data only from my institution, for that matter. So we have to reach out to outside collaborators and email them to get the data. And that is different for you where you have access to all the data under one umbrella. So could you speak to that a little bit and how that's an advantage for this kind of research especially?

Dr. Dean Regier:Yeah. In health economics, we look at the comparative incremental costs against the incremental effectiveness. And when we think about incremental costs, we think not just about systemic therapy or whether you see a physician, but also about hospitalizations, about all the healthcare interactions related to oncology or not that a patient might experience during their time or interactions with the healthcare system. You can imagine with oncology, there are multiple interactions over a prolonged time period depending on survival. And so what we try to do is we try to—and the benefit of the single-payer healthcare system is what we do is we link all those resource utilization patterns that each patient encounters, and we know the price of that encounter. And we compare those incremental costs of, in this case, it's the multigene panel versus the single-gene panel. So it's not just the cost of the panel, not just the cost of systemic therapy, but hospitalizations, physician encounters, etc.

And then similarly, we look at, in this case, we looked at overall survival - we can also look at progression-free survival - and ask the simple question, you know, what is the incremental cost per life-year gained? And in that way, we get a metric or an understanding of value for money. And how we evaluate that within a deliberative priority setting context is we look at safety and efficacy first. So a regulatory package that you might get from, in our case, Health Canada or the FDA, so we look at that package, and we deliberate on, okay, is it safe and is it effective? How many patients are affected, etc. And then separately, what is the cost-effectiveness? And at what price, if it's not cost-effective, at what price would it be cost-effective? Okay, so for example, we have this metric called the incremental cost-effectiveness ratio, which is incremental cost in the numerator, and in this case, life-years gained in the denominator. And if it is around $50,000 or $100,000 per life-year gained—so if it's in that range, this ratio—then we might say it's cost-effective. If it's above this range, which is common in oncology, especially when we talk about ICIs, etc., then you might want to negotiate a price. And indeed, when we negotiate that price, we use the economic evaluation, that incremental cost-effectiveness ratio, as a way to understand at what price should we negotiate to in order to get value for money for the healthcare system.

Dr. Rafeh Naqash:Thank you for explaining those very interesting terminologies. Now, one question I have in the context of what you just mentioned is, you know, like the drug development space, you talked about efficacy and safety, but then on the safety side, we talk about all-grade adverse events or treatment-related adverse events—two different terminologies. From a healthcare utilization perspective, how do you untangle if a patient on a BRAF therapy got admitted for a hypoxic respiratory failure due to COPD, resulting in a hospitalization from the cost, overall cost utilization, or does it not matter?

Dr. Dean Regier:We try to do as much digging into those questions as possible. And so, this is real-world data, right? Real-world data is not exactly as clean as you'd get from a well-conducted clinical trial. And so what we do is we look at potential adverse event, whether it's hospitalization, and the types of therapies around that hospitalization to try- and then engage with clinicians to try to understand or tease out the different grades of the adverse event. Whether it's successful or not, I think that is a real question that we grapple with in terms of are we accurate in delineating different levels of adverse events? But we try to take the data around the event to try to understand the context in which it happens.

Dr. Rafeh Naqash:Thank you for explaining that, Dean.

So, again to the results of this manuscript, could you go into the methodology briefly? Believe you had 147 patients, 147 patients in one arm, 147 in the other. How did you split that cohort, and what were some of the characteristics of this cohort?

Dr. Dean Regier:So, the idea, of course, is that we have selection criteria, study inclusion criteria, which included in our case 364 patients. And these were patients who had advanced melanoma within our study time period. So that was 2016 to 2018. And we had one additional year follow. So we had three total years. And what we did is that we linked our data, our healthcare system data. During this time, because the policy change was in 2016, we had patients both go on the multigene panel and on the single-gene BRAF testing. So, the idea was to emulate a pragmatic randomized controlled trial where we looked at contemporaneous patients who had multigene panel testing versus single-gene BRAF testing.

And then we did a matching procedure—we call it genetic matching. And that is a type of matching that allows us to balance covariates across the patient groups, across the multigene versus BRAF testing cohorts. The idea again is, as you get in a randomized controlled trial, you have these baseline characteristics that look the same. And then the hope is that you address any source selection or confounding biases that prohibit you to have a clean answer to the question: Is it effective or cost-effective? So you address all those biases that may prohibit you to find a signal if indeed a signal is there.

And so, what we did is we created—we did this genetic matching to balance covariates across the two cohorts, and we matched them one-to-one. And so what we were able to do is we were able to find, of those 364 patients in our pool, 147 in the multigene versus 147 in the single-gene BRAF testing that were very, very similar. In fact, we created what's called a directed acyclic graph or a DAG, together with clinicians to say, “Hey, what biases would you expect to have in these two cohorts that might limit our ability to find a signal of effectiveness?” And so we worked with clinicians, with health economists, with epidemiologists to really understand those different biases at play. And the genetic matching was able to match the cohorts on the covariates of interest.

Dr. Rafeh Naqash:And then could you speak on some of the highlights from the results? I know you did survival analysis, cost-effectiveness, could you explain that in terms of what you found?

Dr. Dean Regier:We did two analyses. The intention-to-treat analysis is meant to emulate the pragmatic randomized controlled trial. And what that does is it answers the question, for all those eligible for multigene or single-gene testing: What is the cost-effectiveness in terms of incremental life-years gained and incremental cost per life-years gained? And the second one was around a protocol analysis, which really answered the question of: For those patients who were actually treated, what was the incremental effectiveness and cost-effectiveness? Now, they're different in two very important ways. For the intention-to-treat, it's around population questions. If we gave single-gene or multigene to the entire population of advanced melanoma patients, what is the cost-effectiveness? The per-protocol is really around that clinical question of those who actually received treatment, what was the incremental cost and effectiveness? So very different questions in terms of population versus clinical cost and effectiveness.

So, for the intention-to-treat, what we found is that in terms of life-years gained is around 0.22, which is around 2.5 months of additional life that is afforded to patients who went through the multigene panel testing versus the single-gene testing. That was non-statistically significant from zero at the 5% level. But on average, you would expect this additional 2.5 months of life. The incremental costs were again non-statistically significant, but they're around $20,000. And so when we look at incremental cost-effectiveness, we can also look at the uncertainty around that question, meaning what percentage of incremental cost-effectiveness estimates are likely to be cost-effective at different willingness-to-pay thresholds? Okay? So if you are willing to pay $100,000 to get one gain of life-years, around 52.8% of our estimates, in terms of when we looked at the entire uncertainty, would be cost-effective. So actually that meets the threshold of implementation in our healthcare system. So it's quite uncertain, just over 50%. But what we see is that decision-makers actually have a high tolerance for uncertainty around cost-effectiveness. And so, while it is uncertain, we would say that, well, the cost-effectiveness is finely balanced.

Now, when we looked at the population, the per-protocol population, those folks who just got treatment, we actually have a different story. We have all of a sudden around 4.5 or just under 5 months of life gained that is statistically significantly different from zero, meaning that this is a strong signal of benefit in terms of life-years gained. In terms of the changes in costs or the incremental costs, they are larger again, but statistically insignificant. So the question now is, to what extent is it cost-effective? What is the probability of it being cost-effective? And at the $100,000 per life-year gained willingness-to-pay, there was a 73% chance that multigene panel testing versus single-gene testing is cost-effective.

Dr. Rafeh Naqash:So one of the questions I have here, this is a clarification both for myself and maybe the listeners also. So protocol treatment is basically if you had gene testing and you have a BRAF in the multigene panel, then the patient went on a BRAF treatment. Is that correct?

Dr. Dean Regier:It's still physician choice. And I think that's important to say that. So typically what we saw in both in our pre- and post-matching data is that we saw around 50% of patients, irrespective of BRAF status, get an ICI, which is appropriate, right? And so the idea here is that you get physician-guided care, but if the patient no longer performs on the ICI, then it gives them a little bit more information on what to do next. Even during that time when we thought it wasn't going to be common to do an ICI, but it was actually quite common.

Dr. Rafeh Naqash:Now, did you have any patients in this study who had the multigene testing done and had an NRAS or a KIT mutation and then went on to those therapies, which were not captured obviously in the single-gene testing, which would have just tried to look at BRAF?

Dr. Dean Regier:So I did look at the data this morning because I thought that might come up in terms of my own questions that I had. I couldn't find it, but what we did see is that some patients went on to clinical trials. So, meaning that this multigene panel testing allowed, as you would hope in a learning healthcare system, patients to move on to clinical trials to have a better chance at more appropriate care if a target therapy was available.

Dr. Rafeh Naqash:And the other question in that context, which is not necessarily related to the gene platform, but more on the variant allele frequency, so if you had a multigene panel that captured something that was present at a high VAF, with suspicion that this could be germline, did you have any of those patients? I'm guessing if you did, probably very low number, but I'm just thinking from a cost-effective standpoint, if you identify somebody with germline, their, you know, first-degree relative gets tested, that ends up, you know, prevention, etc. rather than somebody actually developing cancer subsequently. That's a lot of financial gains to the system if you capture something early. So did you look at that or maybe you're planning to look at that?

Dr. Dean Regier:We did not look at that, but that is a really important question that typically goes unanswered in economic evaluations. And so, the short answer is yes, that result, if there was a germline finding, would be returned to the patient, and then the family would be able to be eligible for screening in the appropriate context. What we have found in economic evaluations, and we've recently published this research, is that that scope of analysis is rarely incorporated into the economic evaluation. So those downstream costs and those downstream benefits are ignored. And when you- especially also when you think about things like secondary or incidental findings, right? So it could be a germline finding for cancer, but what about all those other findings that we might have if you go with an exome or if you go with a genome, which by the way, we do have in British Columbia—we do whole-genome and transcriptome sequencing through something called the Personalized OncoGenomics program. That scope of evaluation, because it's very hard to get the right types of data, because it requires a decision model over the lifetime of both the patients and potentially their family, it becomes very complicated or complex to model over patients' and families' lifetime. That doesn't mean that we should not do it, however.

Dr. Rafeh Naqash:So, in summary Dean, could you summarize some of the known and unknowns of what you learned and what you're planning in subsequent steps to this project?

Dr. Dean Regier:Our North Star, if you will, is to really understand the entire system effect of next-generation sequencing panels, exome sequencing, whole genomes, or whole genomes and transcriptome analysis, which we think should be the future of precision oncology. The next steps in our research is to provide a nice base around multigene panels in terms of multigene versus single-gene testing, whether that be colorectal cancer, lung cancer, melanoma, etc., and to map out the entire system implications of implementing next-generation sequencing panels.

And then we want to answer the questions around, “Well, what if we do exomes for all patients? What if we do whole genomes and transcriptomes for all patients? What are the comparative outcomes for a true tumor-agnostic precision oncology approach, accounting for, as you say, things like return of results with respect to hereditary cancers?” I think the challenge that's going to be encountered is really around the persistent high costs of something like a whole-genome and transcriptome sequencing approach. Although we do see the technology prices going down—the "$1,000 genome" or “$6,000 genome" on whatever Illumina machine you might have—that bioinformatics is continuing to be expensive.

And so, there are pipelines that are automated, of course, and you can create a targeted gene report really rapidly within a reasonable turnaround time. But of course, for secondary or what I call level two analysis, that bioinformatics is going to continue to be expensive. And so, we're just continually asking that question is: In our healthcare system and in other healthcare systems, if you want to take a precision oncology approach, how do you create the pipelines? And what types of technologies really lend themselves to benefits over and above next-generation sequencing or multigene panels, allowing for access to off-label therapies? What does that look like? Does that actually improve patients? I think some of the challenges, of course, is because of heterogeneity, small benefiting populations, finding a signal if a signal is indeed there is really challenging. And so, what we are thinking through is, with respect to real-world evidence methods and emulating randomized controlled trials, what types of evidence methods actually allow us to find those signals if indeed those signals are there in the context of small benefiting populations?

Dr. Rafeh Naqash:Thank you so much, Dean. Sounds like a very exciting field, especially in the current day and age where cost-effectiveness, financial toxicity is an important aspect of how we improve upon what is existing in oncology. And then lots more to be explored, as you mentioned.

The last minute and a half I want to ask about you as an individual, as a researcher. There's very few people who have expertise in oncology, biomarkers, and health economics. So could you tell us for the sake of our trainees and early career physicians who might be listening, what was your trajectory briefly? How did you end up doing what you're doing? And maybe some advice for people who are interested in the cost of care, the cost of oncology drugs - what would your advice be for them very briefly?

Dr. Dean Regier:Sure. So I'm an economist by training, and indeed I knew very little about the healthcare system and how it works. But I was recruited at one point to BC Cancer, to British Columbia, to really try to understand some of those questions around costs, and then I learned also around cost-effectiveness. And so, I did training in Scotland to understand patient preferences and patient values around quality of care, not just quantity of life, but also their quality of life and how that care was provided to them. And then after that, I was at Oxford University at the Nuffield Department of Population Health to understand how that can be incorporated into randomized control trials in children. And so, I did a little bit of learning about RCTs. Of course, during the way I picked up some epidemiology with deep understanding of what I call econometrics, what others might call biostatistics or just statistics.

And from there, it was about working with clinicians, working with epidemiologists, working with clinical trialists, working with economists to understand the different approaches or ways of thinking of how to estimate efficacy, effectiveness, safety, and cost-effectiveness. I think this is really important to think through is that we have clinical trialists, we have people with deep understanding of biostatistics, we have genome scientists, we have clinicians, and then you add economists into the mix. What I've really benefited from is that interdisciplinary experience, meaning that when I talk to some of the world's leading genome scientists, I understand where they're coming from, what their hope and vision is. And they start to understand where I'm coming from and some of the tools that I use to understand comparative effectiveness and cost-effectiveness. And then we work together to actually change our methods in order to answer those questions that we're passionate about and curious about better for the benefit of patients.

So, the short answer is it's been actually quite a trajectory between Canada, the UK. I spent some time at the University of Washington looking at the Fred Hutch Cancer Research Center, looking at precision oncology. And along the way, it's been an experience about interdisciplinary research approaches to evaluating comparative outcomes. And also really thinking through not just at one point in time on-off decisions—is this effective? Is it safe? Is it cost-effective?—not those on-off decisions, but those decisions across the lifecycle of a health product. What do those look like at each point in time? Because we gain new evidence, new information at each point in time as patients have more and more experience around it. And so what really is kind of driving our research is really thinking about interdisciplinary approaches to lifecycle evaluation of promising new drugs with the goal of having these promising technologies to patients sooner in a way that is sustainable for the healthcare system.

Dr. Rafeh Naqash:Awesome. Thank you so much for those insights and also giving us a sneak peek of your very successful career.

Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. Thank you.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO PO Article Insights episode, host Harold Tan summarizes Low Kynurenine Levels Among Exceptional Responders on Phase Ib Trial of the HDAC Inhibitor Abexinostat with Pazopanib by Tsang et al, published November 07, 2024.

Harold Nathan Tan:

Welcome to JCO Precision Oncology Article Insights, where we explore cutting-edge discoveries in the world of cancer treatment and research. I'm Harold Nathan Tan, your host, and today we're taking a focused look at a compelling phase Ib trial led by Dr. Tsang, which investigates a combination of abexinostat, a histone deacetylase inhibitor, with pazopanib, a VEGF-targeting tyrosine kinase inhibitor, in patients with advanced solid tumors.

VEGF inhibition has long been an established therapeutic strategy across a wide range of tumor types, including colorectal, ovarian, sarcoma, and renal cell carcinoma. These agents function by disrupting tumor angiogenesis, effectively limiting oxygen and nutrient delivery to malignant cells and contributing to improved survival outcomes. However, over time, acquired resistance remains a significant challenge.

A key mechanism implicated in this resistance involves the upregulation of hypoxia-inducible factor 1-alpha, or HIF-1-alpha for short, a master regulator of angiogenesis that restores VEGF signaling under hypoxic conditions. Interestingly, HIF-1-alpha overexpression is mediated by histone deacetylases, especially HDAC2. Preclinical studies suggest that HDAC2 inhibition can suppress tumor cell migration and downregulate HIF-1-alpha activity, effectively disabling a critical escape pathway used by tumors under VEGF pressure. Moreover, combining HDAC inhibition with VEGF blockade has demonstrated synergy in pazopanib-resistant tumor models, forming a compelling rationale for this dual approach.

The phase Ib trial by Tsang et al. was designed to evaluate the safety, tolerability, and preliminary efficacy of this dual-targeted approach in patients with heavily pretreated advanced solid tumors. A dose-expansion cohort focused on individuals with renal cell carcinoma, allowing for more detailed evaluation in this population.

A central component of this study was the incorporation of biomarker analysis, particularly regarding HDAC2 expression levels. The results were noteworthy. Patients with high HDAC2 expression achieved a progression-free survival of 7.7 months compared to only 3.5 months in those with low expression. Even more compelling, overall survival reached 32.3 months for those with a high HDAC2 expression versus just 9.2 months for those with low expression. This suggests the potential role for HDAC2 as a predictive biomarker for response to combination HDAC and VEGF-targeted therapy.

The authors also explored the metabolic landscape of these patients, conducting metabolomic analysis focused on kynurenine, a key tryptophan catabolite known to contribute to the immune suppression in the tumor microenvironment. Its reduction is driven by HIF-1-alpha and inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. What they found was striking. Exceptional responders, defined as patients with treatment responses lasting more than 3 years, had consistently lower levels of kynurenine both before and after treatment. This finding introduces kynurenine as a potential metabolic biomarker. It suggests that patients with lower kynurenine levels may have a less immunosuppressive microenvironment, making them more responsive to the combined effects of HDAC inhibition and VEGF blockade. Of note, VEGF levels themselves did not significantly differ between responders and nonresponders, highlighting that the treatment benefit is not purely VEGF-mediated but likely driven by epigenetic and metabolic modulation.

On the safety front, the combination of abexinostat and pazopanib was generally well tolerated. However, this study did report a correlation between higher plasma concentrations of abexinostat and an increased incidence of thrombocytopenia, a class effect associated with HDAC inhibitors.

This trial introduces several key considerations for future research. First, it calls for validation of HDAC2 as a predictive biomarker. If confirmed in larger cohorts, HDAC2 expression could be used to select patients most likely to benefit from HDAC inhibitor-based regimens, transforming how we approach trial enrollment and treatment planning. Second, the link between low kynurenine and exceptional response supports further investigation into how metabolic pathways can influence treatment response to combined HDAC and VEGF inhibition.

Overall, HDAC inhibitors hold significant promise in precision oncology. Realizing their full therapeutic potential requires a deeper understanding of HDAC biology, refined combination strategies, and thorough preclinical and clinical evaluations tailored to individual patient profiles. This study exemplifies the potential of epigenetic-metabolic crosstalk as a therapeutic vulnerability and underscores the importance of precision stratification in clinical trial design. As research in this space progresses, the integration of molecular, epigenetic, and metabolic profiling will be essential in optimizing the use of HDAC inhibitors and expanding their role within precision oncology.

Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.