Summary

James is ill (apparent in his voice)! Find out what gets James to show up to an ASCO meeting, and stay tuned for the fact check to hear the infamous tweet from Omid Hamid regarding James' scrubs.

In this episode of Melanoma Matters, hosts James Larkin and Sapna Patel discuss sequencing of immunotherapy and targeted therapy for BRAF-positive melanoma. They review the SECOMBIT study 4-year update from Nature Communications. The sandwich approach is unpacked as an approach to debulk the tumor and increase immune fitness of the patient. They also review lactate dehydrogenase as a selection criteria for treatment, the role of LDH, the phrase 'par excellence', the difference in impact factor between Nature journals, CNS incidence and autopsy series.

Keywords

SECOMBIT trial, BRAF positive melanoma, lactate dehydrogenase, LDH, immunotherapy, targeted therapy, CNS incidence, autopsy series

Titles

The Role of LDH

CNS Incidence and Autopsy Series

Sound Bites

"You're rocking the scrubs"

"How to define par excellence"

"Difference in impact factor"

Summary

In this conversation, Sapna puts Santa Fe, NM on the map of her all time favorite places in the USA.

James and Sapna go on to discuss the DreamSeq study, which focuses on the sequencing of systemic therapy in patients with BRAF mutant metastatic melanoma. They explore the historical context of melanoma treatments, the design and endpoints of the trial, and the implications for clinical practice. The discussion highlights the importance of treatment sequencing, the potential underestimation of benefits in the study, and considerations for future research and patient care.

Keywords

DreamSeq, melanoma, BRAF mutant, immunotherapy, targeted therapy, clinical trials, treatment sequencing, overall survival, patient outcomes, cancer research

Takeaways

Santa Fe, New Mexico is a personal favorite for quiet and art.

DreamSeq is a significant study in melanoma treatment.

The historical context of melanoma treatments is crucial for understanding current practices.

Immunotherapy may take time to show effects, impacting treatment sequencing.

The trial design of DreamSeq focused on overall survival as a primary endpoint.

Real-world applications of trial findings are essential for patient care.

The sequencing of therapies can significantly affect patient outcomes.

Understanding the tumor microenvironment is key in treatment decisions.

The choice of BRAF-MEK therapy may be less critical than the choice of immunotherapy.

Future studies should consider the incidence of brain metastases in treatment outcomes.

Titles

The Art of Sequencing: DreamSeq Explained

DreamSeq: A New Era in Melanoma Treatment

Sound Bites

"DreamSeq may even underestimate the benefit."

"Combination Nivo/ipi first should be the preferred treatment sequence."

"There's an optimal window for treatment sequencing."

Chapters

00:00 Optimizing Treatment Strategies and Individualized Approaches

25:48 Introduction to DreamSeq Study

27:00 Demographics and Treatment Regimens

28:56 Discussion on Figures: Webergram and Rebogram

30:43 Impact of Trial Design on Treatment

32:02 Underestimating the Benefit of Immunotherapy First Strategy

Summary

James is ageist in his music preferences! Or he's just very fond of Bob Dylan. He claims to have no knowledge of Taylor Swift poetry, which is just begging for a TTPD vinyl EP.

Sapna and James go on to discuss the implications of triplet studies in melanoma treatment, focusing on the combination of BRAF and MEK inhibitors with checkpoint inhibitors. They explore the results of key studies such as Keynote 022, COMBI, and Imspire 150, analyzing their efficacy, toxicity, and the challenges in clinical practice. The discussion highlights the need for further research and understanding of treatment strategies in melanoma, particularly regarding the sequencing and combination of therapies.

Keywords

melanoma, triplet studies, combination therapy, BRAF, MEK, checkpoint inhibitors, oncology, Keynote 022, COMBI, Imspire 150

Takeaways

The combination of drugs in oncology has been a longstanding practice.

Keynote 022 showed promising results but did not meet statistical significance.

The PFS across triplet studies appears similar, raising questions about efficacy.

Toxicity remains a significant concern in triplet therapy.

Clinical practice often diverges from study results due to various factors.

Long-term follow-up data can change the interpretation of study results.

The need for better biomarkers to predict treatment responses is critical.

Patients may experience unexpected benefits from targeted therapies after checkpoint inhibitors.

The role of brain metastases in treatment decisions is an important consideration.

Future studies are needed to refine treatment strategies in melanoma.

Sound Bites

"The way we've done things in oncology is to combine drugs."

"The question is about what could you put the checkpoint inhibitor together with."

"Keynote 022 did not meet statistical threshold significance."

Chapters

00:00 Introduction to Triplet Studies in Melanoma

04:07 Keynote 022: Efficacy and Interpretation

09:23 Long-Term Follow-Up and Interpretation of Keynote 022

14:14 Combi-I: Efficacy and Interpretation

19:06 Clinical Practice and Uptake of Triplet Therapy

27:11 Treatment Sequencing and Combination: Challenges and Considerations

30:20 Implications for Clinical Practice and Future Research

Summary

Snoozing versus getting up before the alarm - guess which host is which. In this conversation, Sapna Patel and James Larkin discuss the recent approval of Lifileucel, a cellular therapy for melanoma. They delve into the study schema, the differences between cryopreserved and non-cryopreserved cells, and the mechanism of action involving T cells and interleukin-2. The discussion also covers the efficacy and durability of responses seen with Lifileucel, challenges related to reimbursement and access, and the future of this therapy in clinical practice. They conclude with a light-hearted wager on future approvals of Lifileucel in different countries.

Keywords

Lifileucel, cellular therapy, melanoma, TIL therapy, interleukin-2, cryopreservation, treatment refractory, FDA approval, reimbursement, cancer treatment

Takeaways

Lifileucel is now approved in the US as Amtagvi.

The study involved various cohorts focusing on treatment refractory melanoma.

Cryopreservation is a technical aspect of cell therapy manufacturing.

Patients' immune cells are expanded and reinvigorated before infusion.

The efficacy of Lifileucel shows durable responses in refractory populations.

Reimbursement for cellular therapies remains a complex issue.

The turnaround time for Lifileucel production is about 21 days.

Future studies will confirm the efficacy of Lifileucel in broader settings.

The FDA's approval is a significant milestone for cellular therapies.

There is optimism for Lifileucel's application in other cancers.

Sound Bites

"I normally wake up before the alarm actually."

"This is cellular therapy and the Chesney paper."

"The analysis is basically done in cohorts two and four."

Chapters

00:00 Introduction and Morning Routines

02:40 Overview of Lifileucel and Study Schema

04:51 Cryopreservation and Non-Cryopreservation in Cell Therapy

13:00 Reimbursement Challenges for Cell Therapy

15:50 Promising Durability of Response with Lifileucel

20:37 Considerations for Access and Scalability of Lifileucel

22:52 The Uncertain Future: Next Country Approval and UK Timeline

Summary

What is the plural of myocarditis? Prof Larkin claims it is myocarditities. In this episode of Melanoma Matters, James Larkin and Sapna Patel discuss the recent study on neoadjuvant therapy using Nivolumab and Relatlimab for melanoma treatment. They explore the study's design, results, and implications for future therapies, particularly focusing on the high rate of complete pathological responses observed. The conversation also delves into the toxicity associated with these treatments, particularly myocarditis, and the need for careful monitoring and understanding of these side effects. They conclude by discussing the future of NivoRela in the neoadjuvant space and the importance of ongoing research and clinical trials.

Keywords

Neoadjuvant therapy, NivoRela, melanoma, myocarditis, immunotherapy, toxicity, clinical trials, cancer treatment, PD-1 blockade, LAG-3 blockade

Takeaways

The study involved 30 patients, with 29 undergoing surgery.

57% of patients achieved a complete pathological response.

Myocarditis is a significant concern with LAG-3 blockade.

NivoRela appears to have less toxicity than full-dose Nivo Ipi.

The need for randomized trials to establish efficacy is critical.

Correlatives in the study showed dynamic markers post-treatment.

Myocarditis can be subtle and difficult to diagnose clinically.

Troponin levels are not definitive for diagnosing myocarditis.

The regulatory framework can complicate the implementation of new therapies.

The conversation emphasizes the importance of ongoing research in melanoma treatment.

Sound Bites

"This is really just such a nice commentary."

"57% complete pathological response."

Chapters

00:00 Introduction and Quick Fire Question

01:58 Overview of the Study

05:26 Discussion on Myocarditis

07:41 Comparison of NivoRela Toxicities

13:53 Correlatives and Diagnostic Criteria for Myocarditis

Why make the bed? Who needs a mnemonic for washing? In the opening quickfire discussion, James and Sapna get SERIOUS.

In this episode, they discuss a paper from Nature Medicine 2019 titled 'Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma.' They explore the significance of the study, which showed that a single dose of preoperative PD-1 blockade can induce complete and major pathologic responses in a subset of patients with resectable melanoma. They also discuss the implications of the study for future research and the challenges of tumor heterogeneity and biomarker testing. Overall, the conversation highlights the potential of neoadjuvant PD-1 blockade in melanoma treatment.

Keywords

neoadjuvant PD-1 blockade, resectable melanoma, clinical outcomes, complete response, major pathologic response, tumor heterogeneity, biomarker testing

Takeaways

A single dose of preoperative PD-1 blockade can induce complete and major pathologic responses in a subset of patients with resectable melanoma.

The study highlights the potential of neoadjuvant PD-1 blockade in melanoma treatment.

Tumor heterogeneity poses challenges in biomarker testing and predicting treatment response.

Further research is needed to explore different regimens and durations of neoadjuvant PD-1 therapy.

Correlative analysis and in-depth studies are valuable in understanding the mechanisms and outcomes of neoadjuvant therapy.

Titles

Challenges of Tumor Heterogeneity in Biomarker Testing

The Potential of Neoadjuvant PD-1 Blockade in Melanoma Treatment

Sound Bites

"You know, what are additional doses actually doing? Are they blocking the receptor better? Are they adding to toxicity?"

"They gave a dose, they didn't lose resectability on patients, they found that they could actually induce complete response with a single dose of neoadjuvant PD-1."

Chapters

00:00 Introduction and Bed-Making

03:04 The Study: Single Dose of Neoadjuvant PD-1 Blockade

06:11 Context and Future Directions of Neoadjuvant Therapy

09:09 Biomarker Testing and Tumor Heterogeneity

Summary

Sapna reveals her most used emoji is a heart (awww..... <3) and James just avoids the question. Neither has decided on their theme song as a wrestler which means they won't be quitting their day jobs anytime soon.

In this episode, James and Sapna discuss the injectable treatment SD101, its mechanism, efficacy in different patient populations, and the challenges faced in its development. They explore the significance of the study results of SD101 plus pembrolizumab, particularly in PD-1 naive and refractory patients, and the implications for future research and treatment strategies in melanoma.

Keywords

SD101, pembrolizumab, melanoma, immunotherapy, PD-1, toll-like receptor, cancer treatment, clinical trials, efficacy, safety

Takeaways

SD101 shows a high response rate in PD-1 naive patients.

The mechanism of SD101 involves toll-like receptor 9 agonism.

Safety and tolerability of SD101 were confirmed in the study.

Efficacy in PD-1 refractory patients is lower but shows potential.

The study included correlative analyses that revealed immune responses.

Manufacturing and development challenges have impacted SD101's progress.

Not all toll-like receptor agonists have the same effects.

The concept of 'turning cold tumors hot' is crucial in treatment.

Future studies are needed to explore SD101's full potential.

The development of SD101 has shifted focus to rare tumors.

Sound Bites

"High response rate in PD-1 naive patients."

"Turning cold tumors hot is a challenge."

"SD101 is safe and tolerable."

Chapters

00:00 Introduction and Quick Questions

03:44 Overview of the SD101 Trial

05:39 Efficacy in PD-1 Naive and PD-1 Refractory Patients

08:04 Efficacy in the Refractory Setting

11:17 Development and Future of SD101

13:59 Comparison with Other Toll-Like Receptor 9 Agonists

15:51 Summary and Conclusion

Summary

This one's for you Dennie Jones (and Alex Nguyen & Shagufta Naqvi)! And the incredible experience they provided one of us as a medical student that shaped a future path. (Honorable mention to GI Fellow at the time Binh Pham and his turtles & friendship.)

In this conversation, James Larkin and Sapna Patel discuss the combination of TVEC and IPI in treating melanoma, focusing on recent studies and their implications. They explore the methodology, results, and efficacy of the treatment, comparing it to other studies in the field. The discussion also touches on future directions for research, particularly the potential for neoadjuvant therapy and the importance of patient demographics in treatment outcomes.

Keywords

TVEC, IPI, melanoma, immunotherapy, clinical trials, checkpoint inhibitors, treatment naive, neoadjuvant therapy, patient demographics, overall survival

Takeaways

TVEC is administered in a test dose followed by maintenance doses.

Dr. Dennie Jones inspired Sapna Patel to become an oncologist.

The study compared TVEC plus IPI to IPI alone in treatment-naive patients.

The primary endpoint was the objective response rate confirmed at least four weeks later.

The study showed improved objective response rates with TVEC plus IPI.

Median overall survival was significantly higher with the combination therapy.

The study's findings suggest a potential biological rationale for combining CTLA-4 with TVEC.

Neoadjuvant therapy with TVEC may be a future consideration.

Patient demographics play a crucial role in treatment efficacy.

The conversation highlights the need for further research in this area.

Titles

Insights from Recent TVEC Studies

The Journey of a Medical Oncologist

Sound Bites

"That's the beauty of cancer patients, the grace that they have."

"This was a positive study for that primary endpoint."

"There might be a patient population where you just want intralesional as your frontline."

Chapters

00:00 Introduction and Background

02:30 Study Design and Results

08:00 Comparison with Other Studies

10:18 Discussion on the Biological Rationale

12:12 Potential Role of TVEC in the Neoadjuvant Setting

13:35 Future Research and Conclusion

15:24 TVEC Dose and Schedule

Summary

James gives a response of plausible deniability that hints at activities as a spy for MI6. But is Sapna perhaps the optimal agent for the clandestine services?

In this episode of Melanoma Matters, hosts Sapna Patel and James Larkin discuss the intricacies of the MASTERKEY 265 study, focusing on the combination of TVEC and pembrolizumab in melanoma treatment. They explore the study's design, patient demographics, and the implications of geographical variations on trial outcomes. The conversation highlights the importance of understanding patient selection and trial design in oncology, as well as the lessons learned from the study's overall negative results.

Keywords

TVEC, Master Key 265, melanoma, immunotherapy, clinical trials, patient demographics, efficacy, safety, geographical variations, oncology

Takeaways

The Master Key 265 study had dual primary endpoints of PFS and OS.

TVEC was combined with Pembrolizumab in the study.

The phase 1B trial showed significant efficacy but the phase 3 trial was negative.

Patient demographics can greatly influence trial outcomes.

Geographical variations can lead to different efficacy results.

Toxicity levels were similar between the treatment arms.

The study design must consider patient selection carefully.

The Optim study had different eligibility criteria than Master Key 265.

Understanding baseline characteristics is crucial for interpreting trial results.

Future trials should learn from the design of Master Key 265.

Titles

Lessons Learned from Master Key 265

The Role of Trial Design in Oncology

Sound Bites

"This was an interesting study because it was a phase 1B."

"The toxicity between the two arms was really exceptionally similar."

Chapters

00:00 Combining Intratumoral Therapies with Checkpoint Inhibitors

04:51 Master Key 265 Study: TVEC and Pembrolizumab Combination

09:42 Primary Endpoint: Progression-Free Survival

11:44 Importance of Durable Response Rate as an Endpoint

13:37 Limited Activity of TVEC and Pembrolizumab Combination

14:52 Geographical Variation in Treatment Outcomes

Summary

One wonders if Prof Martin Gore ever dreamed he would be mentioned in the same context as HRH and Taylor Swift. If he's listening, he must know which of the goldilocks chairs he occupies.

In this episode of Melanoma Matters, hosts Sapna Patel and James Larkin discuss injectable therapies for melanoma, focusing on Talimogene Laherparepvec (TVEC) and the Optim trial. They explore the trial's design, patient selection criteria, and practical considerations for administering TVEC in clinical settings. The conversation also touches on the implications of patient characteristics and treatment history on the effectiveness of TVEC, as well as future directions for combination therapies in melanoma treatment.

Keywords

melanoma, Talimogene Laherparepvec, TVEC, injectable therapy, Optim trial, cancer treatment, oncolytic virus, patient selection, clinical trials, immunotherapy

Takeaways

Talimogene Laherparepvec (TVEC) is the only approved oncolytic viral therapy for melanoma.

The Optim trial demonstrated the efficacy of TVEC compared to GMCSF.

Patient selection is crucial for the success of TVEC treatment.

Injectable therapies are often used for patients with low visceral disease.

Size and volume of tumors significantly impact the effectiveness of TVEC injections.

The control arm of the Optim trial was not a standard therapy.

TVEC administration requires careful consideration of tumor characteristics.

Combination therapies may enhance the effectiveness of TVEC.

Understanding patient history is important for treatment decisions.

Future research may lead to more approvals in the field of oncolytic therapies.

Chapters

00:00 Introduction and Rapid Fire Questions

03:52 Overview of the Optim Trial

10:09 Practical Considerations for Using T-VEC in Clinic

14:15 Patient Selection for T-VEC Therapy

16:23 Dosing and Injection Techniques for T-VEC