Oncology On The Go

As part of the Breaking Barriers: Women in Oncology program, CancerNetwork® spoke with Julie M. Vose, MD, MBA, and Avyakta Kallam, MD, about the evolution of their careers in the hematology-oncology space, including some of the critical advances and challenges associated with their work in the lymphoma field.


Vose is division chief, Neumann M. and Mildred E. Harris Professor at the University of Nebraska Medical Center, and co-editor-in-chief of ONCOLOGY®. Kallam is an assistant professor in the Division of Lymphoma and Department of Hematology & Hematopoietic Cell Transplantation from City of Hope in Duarte, California.


Vose and Kallam discussed how they first developed a passion for researching lymphoma, which led them to become involved in various breakthroughs related to the use of treatment strategies such as autologous stem cell transplantation, bispecific antibodies, and CAR T-cell therapy. The conversation highlighted how this evolution of therapy options has helped improve patient outcomes while reducing hospitalization periods and minimizing toxicity.


The discussion also extended to the topic of overcoming various physical and social barriers while trying to advance in the lymphoma field. For example, Kallam described her experience with moving to the United States from India to complete her medical training, which involved adapting to a new culture and a new style of approaching treatment. 


In the early stages of Vose’s career, there were far fewer women involved in oncology and medicine in general, contributing to the challenge of needing to work extremely hard to prove that she was equal to her male colleagues. Vose noted in the early days, she was considered a rarity in the field as one of very few women. 


Vose and Kallam also brought up how their mentors have given them key pieces of advice from mentors that have stuck with them throughout their careers. They, in turn, offered wisdom to any woman looking to advance in the hematology-oncology space. 


“The biggest piece of advice [I received] is to see the patient as a person—not just as a patient—to be able to get to know them and their families understand some of their struggles so that you can relate to them as a person,” Vose said.


The conversation also focused on the challenge of achieving work/life balance while making advances in the lymphoma space. Dedicating time to hobbies and finding support from friends and family members emerged as potential strategies for balancing professional responsibilities with one’s personal life.


“Life is too unpredictable to not do things that you enjoy doing,” Kallam said, recounting a bit of advice she had received from one of her mentors. “What we’re doing is important; we are impacting lives. We’re doing a lot of research, but at the same time, keep in mind to have fun along the way.”

Tycel Phillips, MD, spoke with CancerNetwork® ahead of the FDA’s accelerated approval of epcoritamab-bysp (Epkinly) for patients with relapsed/refractory follicular lymphoma to discuss how this agent may impact the treatment paradigm.


Phillips, an associate professor in the Division of Lymphoma and Department of Hematology & Hematopoietic Stem Cell Transplantation at City of Hope in Duarte, California, reviewed data from the phase 1/2 EPCORE NHL-1 trial (NCT03625037), which ultimately supported the approval of epcoritamab in the aforementioned population. Topline results reported at the time of the agent’s approval showed an overall response rate (ORR) of 82% (95% CI, 74.1%-88.2%), with 60% of patients experiencing a complete response. Additionally, the median duration of response was not reached (NR; 95% CI, 13.7-NR). 


Beyond the supporting data, Phillips highlighted how this approval may increase availability of treatment options for patients with follicular lymphoma, especially those who lack access to alternative therapies. He stated that readily available off-the-shelf bispecific antibodies like epcoritamab may bridge the gap for patients who are unable to access CAR T-cell therapies or travel to a major academic center for treatment. 


Phillips also detailed strategies for mitigating some of the common toxicities that may occur following treatment with epcoritamab, which include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Although Phillips said that epcoritamab is usable in the third-line setting, he noted that bispecific antibodies like it “have a lot of potential for upward mobility,” as he anticipates further assessment of these treatments in the first or second line.


“As community oncologists get more and more comfortable with these drugs and have the structure to set up to safely administer [them] for the first month when most of the complications happen, more and more patients will be able to be treated, which will be a great benefit based on what we’ve seen in early response rates for these drugs,” Phillips said regarding the utility of bispecific antibodies like epcoritamab. “There’ll be a big benefit for the patient population in the long term as more community settings implement these drugs into their clinical practice.”

Reference


FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. News release. FDA. June 26, 2024. Accessed June 26, 2024. https://tinyurl.com/26s9myey

In a conversation with CancerNetwork®, James B. Yu, MD, MHS, FASTRO, and Julian C. Hong, MD, MS, spoke about their study titled AI Use in Prostate Cancer: Potential Improvements in Treatments and Patient Care, which was published in the May issue of the journal ONCOLOGY®.


Yu is a radiation oncologist in the Department of Radiation Oncology at Smilow Cancer Center Hospital at Saint Francis Hospital and an adjunct assistant professor of Medical Oncology at Yale School of Medicine. Hong is an assistant professor in the Department of Radiation Oncology of Bakar Computational Health Sciences Institute at the University of California, San Francisco (UCSF).


Yu and Hong focused on the growing overlap between the advancement of artificial intelligence (AI)–based tools and the prostate cancer treatment field. In their study, they detailed AI-based developments related to diagnostic image analysis, the ability to “predict” prostate cancer outcomes, evaluating prostate cancer histopathology, and defining tumors and normal tissue to help plan radiation oncology treatment strategies. Additionally, they reviewed how these tools make use of machine learning algorithms, a subset of AI in which computers can assess data and interact with users without explicit instructions. 


“We’re trying to incorporate AI and machine learning into more trials to make these types of predictions because, at the end of the day, we’re trying to deliver better care and improve outcomes for patients…. It takes trials to figure those things out, so it’s a little bit of a work in progress.” Hong said, regarding potential next steps for improving the utility of these tools in the prostate cancer field.


According to the authors, pushing the boundaries of AI would need to involve building upon prior retrospective data with additional sources of information to affirm that such tools can impact patient care. Additionally, the discussion highlighted potential future implications related to data ownership or privacy and how patients and physicians interact with these programs as AI becomes more prevalent in medical practice. 


“We’re not going to be replaced [by AI]. There will always be the need for the human connection any time there’s disease or cancer,” Yu said. “It’s a super exciting area, and the more people understand the limitations of AI rather than thinking of it as a panacea, the more the field will move forward.”

At the 2024 European Hematology Association (EHA) Congress, CancerNetwork® spoke with a variety of experts in the hematologic oncology space about optimizing outcomes across different patient populations and subgroups based on updated research they presented at the meeting. 


Manali Kamdar, MD, an associate professor of medicine-hematology and clinical director of Lymphoma Services at the University of Colorado Anschutz Medical Campus, in Colorado, spoke about data from the phase 1 TRANSCEND NHL 001 trial (NCT02631044) supporting the use of lisocabtagene maraleucel (liso-cel; Breyanzi) in earlier lines of therapy for patients with relapsed/refractory mantle cell lymphoma (MCL).1 


Specifically, Kamdar highlighted how research should continue to focus on the potential utility of liso-cel in MCL subgroups such as those with TP53 mutations or blastoid morphology. Additionally, she stated that liso-cel may need to be further tested in earlier lines of therapy for patients with diffuse large B-cell lymphoma, including those with double-hit lymphoma.


Michael R. Grunwald, MD, chief of the Leukemia Division and director of the Transplantation and Cellular Therapy Program at Atrium Health’s Levine Cancer Institute, in North Carolina, discussed findings from the Prospective Observational Study of Patients With Polycythemia Vera (PV) in US Clinical Practices Trial (REVEAL) exploring risk factors for disease progression in patients with polycythemia vera (PV).2


According to Grunwald, a history of thromboembolic events, elevated white blood cell counts, and higher variant allele frequencies may contribute to a patient’s likelihood of experiencing progression to myelofibrosis or acute myeloid leukemia (AML). Additionally, he highlighted ongoing research into the potential molecular factors that may prognosticate disease transformation in PV among a small cohort of patients enrolled on the REVEAL trial.3


Harry P. Erba, MD, PhD, a professor of medicine in the Division of Hematologic Malignancies and Cellular Therapy and the director of the Leukemia Program and Phase I Development in Hematologic Malignancies at Duke Cancer Institute, in North Carolina, discussed the clinical implications of data from the phase 3 QuANTUM-First study (NCT02668653).4 


Specifically, findings demonstrated that continuation therapy with quizartinib (Vanflyta) elicited a more pronounced survival benefit vs placebo in patients with newly diagnosed FLT3-ITD–positive AML who did not undergo allogeneic hematopoietic stem cell transplant (allo-HSCT). However, Erba noted that survival outcomes were not significantly different in the quizartinib and placebo arms among patients who received allo-HSCT.

References


1.        Palomba ML, Siddiqi T, Gordon LI, et al. Subgroup analyses in patients with R/R MCL treated with lisocabtagene maraleucel by prior lines of therapy and response to Bruton tyrosine kinase inhibitor from the TRANSCEND NHL 001 MCL cohort. Presented at the European Hematology Association (EHA) 2024 Congress; Madrid, Spain; June 13-16, 2024. P1126.

2.        Grunwald M, Zwicker J, Gerds A, et al. A real-world evaluation of risk factors for disease progression in patients with polycythemia vera (PV) enrolled in REVEAL. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract P1047.

3.        Crowgey E, Timmers C, Xue Z, et al. Analysis of molecular mechanisms and predictive biomarkers of disease transformation in polycythemia vera. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract S217.

4.        Sekeres MA, Erba H, Montesinos P, et al. QuANTUM-First: efficacy in newly diagnosed patients with FMS-like tyrosine kinase 3-internal tandem duplication–positive (FLT3-ITD+) acute myeloid leukemia (AML) who received continuation therapy. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract S142.

Following the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Neil M. Iyengar, MD, and Paolo Tarantino, MD, co-hosted a live X Space with CancerNetwork® and discussed the latest trial updates that may impact clinical practice in the breast cancer field.


Iyengar is an associate attending physician at Memorial Sloan Kettering Cancer Center and a co-editor-in-chief of ONCOLOGY®. Tarantino is a clinical research fellow at Dana-Farber Cancer Institute and Harvard Medical School. 


Iyengar and Tarantino discussed data regarding several trials and studies presented at the meeting. These presentations included: 


·      Phase 3 DESTINY-Breast06 Trial (NCT04494425)1

o   Investigators evaluated treatment with trastuzumab deruxtecan (T-DXd; Enhertu) compared with investigator’s choice of chemotherapy among patients with hormone receptor (HR)–positive, HER2-low or HER2-ultralow metastatic breast cancer.

o   The median progression-free survival (PFS) was 13.2 months with T-DXd compared with 8.1 months in patients who received chemotherapy across the HER2-low population (HR, 0.62; 95% CI, 0.51-0.74; P <.0001).

o   Primary analysis overall survival (OS) data show favorable trends in the T-DXd arm across the HER2-low group (HR, 0.83; 95% CI, 0.66-1.05; P = .1181) and the intent-to-treat (ITT) population (HR, 0.81; 95% CI, 0.65-1.00). However, the OS data only reached 40% maturity at the time of the analysis.

·      Phase 3 postMONARCH Study (NCT05169567)2

o   Patients with HR-positive, HER2-negative breast cancer and disease progression on CDK4/6 inhibitors and endocrine therapy were assigned to receive abemaciclib (Verzenio) or matched placebo plus fulvestrant (Faslodex).

o   The median PFS per investigator assessment was 5.6 months (95% CI, 5.4-9.2) with abemaciclib-based therapy vs 3.9 months (95% CI, 3.7-5.4) with placebo plus fulvestrant (HR, 0.66; 95% CI, 0.48-0.91; P = .01). 

o   The investigator-assessed objective response rate (ORR) was 17% vs 7% in each respective arm.

·      Phase 2 SACI-IO HR+ Trial (NCT04448886)3

o   Investigators assessed sacituzumab govitecan-hziy (Trodelvy) alone or in combination with pembrolizumab (Keytruda) for HR-positive, HER2-negative metastatic breast cancer regardless of PD-L1 status.

o   Combination therapy yielded a numerical improvement in median PFS (8.12 months; 95% CI, 4.51-11.12) compared with sacituzumab govitecan monotherapy (6.22 months; 95% CI, 3.85-8.68), although this improvement did not reach statistical significance (HR, 0.81; 95% CI, 0.51-1.28; P = .37). 

o   Immature OS data presented at the meeting highlighted a median OS of 18.52 months (95% CI, 16.55-not applicable [NA]) vs 17.96 months (95% CI, 12.50-NA) in each respective arm (HR, 0.65; 95% CI, 0.33-1.28; P = .21).

References


1.        Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

2.        Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. J Clin Oncol. 2024;42(suppl 17):LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001

3.        Garrido-Castro A, Kim, SE, Desrosiers J, et al. SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. J Clin Oncol. 2024;42(suppl 17):LBA1004. doi:10.1200/JCO.2024.42.17_suppl.LBA1004

In a conversation with CancerNetwork®, Jagoda Misniakiewicz, PharmD, a clinical pharmacy specialist in the Clinical Pharmacy and Outcomes Sciences Department at Hollings Cancer Center of the Medical University of South Carolina, spoke about the use of fruquintinib (Fruzaqla) as a treatment option for those with metastatic colorectal cancer (CRC).

The FDA previously approved fruquintinib as a treatment for those with metastatic CRC and prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy in November 2023.1


Misniakiewicz detailed the agent’s mechanism of action as a potent, orally available small molecule kinase inhibitor and its potential to inhibit blood vessel growth, thereby yielding vascular regression, normalization, and construction. Additionally, the clinical benefit of switching from intravenous therapy to this oral treatment appears to extend to any patient who has progressed on prior therapy, although she noted that there are currently no specific biomarkers or tumor characteristics that would make patients suitable candidates for fruquintinib.


The discussion also focused on the efficacy and safety data supporting the clinical utility of fruquintinib in this patient population. Specifically, Misniakiewicz highlighted the “exciting” progression-free survival (PFS) findings from the phase 3 FRESCO-2 trial (NCT04322539), which may affirm fruquintinib as a “promising treatment option” for those with refractory disease. 


According to previous findings from the FRESCO-2 trial published in Lancet Oncology, the median PFS was 3.7 months (95% CI, 3.5-3.8) with fruquintinib plus best supportive care vs 1.8 months (95% CI, 1.8-1.9) with placebo plus best supportive care (HR, 0.32; 95% CI, 0.27-0.39; P <.0001).2 Additionally, the median overall survival (OS) was 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) in each respective arm (HR, 0.66; 95% CI, 0.55-0.80; P <.0001). PFS and OS benefits across various patient subgroups—in which investigators stratified patients based on previous treatment with trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga), RAS mutation status, and duration of metastatic disease—were comparable with those observed in the intent-to-treat population.


“The truth is that treatment options for metastatic [CRC] are limited, and the approval of fruquintinib will hopefully bridge that gap a little bit,” Misniakiewicz said. “Oral agents have changed the landscape of treatment for patients with cancer. Furthermore, targeted agents allow us to tailor therapy with the goal of improving clinical outcomes while minimizing off target toxicities; fruquintinib will hopefully allow us to do this in patients with metastatic colorectal cancer.”

References


1.        Takeda receives U.S FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed June 6, 2024. https://bit.ly/3SwkD8U

2.        Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. Published online June 15, 2023. doi:10.1016/S0140-6736(23)00772-9

In a conversation with CancerNetwork®, Terence T. Sio, MD, MS, discussed how technological advancements in radiation oncology have impacted the modern treatment landscape for patients with non–small cell lung cancer (NSCLC).


Sio, a professor of radiation oncology at Mayo Clinic in Phoenix, Arizona, first outlined the use of immunotherapy and other systemic treatment options for this patient population. He detailed how the use of these modalities and other factors such as the risk of radiation-induced pneumonitis often inform the extent of subsequent radiotherapy. Treatment decision making may also involve collaboration with surgeons and medical oncologists as part of a multidisciplinary tumor board, which meets regularly at his institution to determine suitable strategies for those who require more than 1 course of therapy. 


Additionally, Sio spoke about currently prevalent radiotherapy treatment strategies for patients with NSCLC as well as possible toxicities that may be associated with these modalities. In terms of novel technology in the field, he highlighted the development of proton beam radiotherapy and the potential advantages it may offer over other therapies. 


According to Sio, use of proton beam radiotherapy may reduce excess radiation that usually extends beyond the targeted tumor, effectively lowering the risk of adverse effects (AEs) during treatment. Specifically, proton beam radiotherapy may benefit patient subgroups including those who have previously experienced a heart attack or those who are older and frailer. With an adequate treatment plan that encompasses the use of proton beam radiation, Sio stated that it may be possible to treat these subgroups with fewer AEs than those observed in patients who undergo standard radiotherapy. 


“We can actually be helping some of the patients who otherwise may not be able to stand as intensive of a method of combining radiation and chemotherapy for their lung cancer treatments,” Sio said regarding the use of proton beam radiotherapy in this population. “Right now, we have shown that proton [beam radiotherapy] has a role in lung cancer treatments.”

Through elaborate multidisciplinary collaboration, institutions with National Accreditation Program for Rectal Cancer (NAPRC) standards can deliver a “high level of care” in the surgical treatment of patients with rectal cancer, according to Steven Wexner, MD, PhD, and Arielle Kanters, MD.


In a conversation with CancerNetwork®, Wexner and Kanters detailed the history and advancement of the NAPRC as an interdisciplinary initiative to improve the outcomes of those undergoing surgery for rectal cancer.


Wexner is the chair in the Department of Colorectal Surgery and director of the Ellen Leifer Shulman & Steven Shulman Digestive Disease Center at Cleveland Clinic, Florida, the founding chair of the NAPRC for the American College of Surgeons Commission on Cancer, and part of the executive committee of the Commission on Cancer. Kanters is a colorectal surgeon, associate fellowship program director, and surgeon leader of the NAPRC program at Cleveland Clinic Main Campus.


Wexner spoke about the inspiration for developing the NAPRC as a mission to elevate the level of surgical outcomes in patients with rectal cancer across the United States to those he observed in European countries such as the United Kingdom and Scandinavia. He enlisted leaders from organizations including the Society of Surgical Oncology and the College of American Pathologists to outline and apply appropriate standards for surgical care in rectal cancer.


Additionally, Kanters highlighted how enforcing precise guidelines and compliance measures through the NAPRC program facilitates multidisciplinary efforts with colleagues who specialize in radiology and pathology. She stated that these principles help individuals develop their skills across each department, thereby maintaining a high level of treatment for patients with rectal cancer. 

Findings from a study published in the Journal of the American College of Surgeons indicated that mortality and complication rates appeared to be lower for patients who received surgery for rectal cancer at NAPRC-accredited institutions compared with those who were treated at non-accredited practices.


Wexner and Kanters also discussed how potential advancements related to the use of neoadjuvant or adjuvant therapy may further improve patient outcomes in the field. Additionally, they spoke about updated research on immunotherapy and other modalities that they anticipate at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Reference


Harbaugh CM, Kunnath NJ, Suwanabol PA, Dimick JB, Hendren SK, Ibrahim AM. Association of National Accreditation Program for Rectal Cancer Accreditation with outcomes after rectal cancer surgery. J Amer College Surg. Published March 28, 2024. doi:10.1097/XCS.0000000000001064

In a conversation with CancerNetwork® at Memorial Sloan Kettering Cancer Center (MSKCC), Neil M. Iyengar, MD, spoke about developments and challenges in his career as a medical oncologist and clinical investigator as well as ongoing research efforts in improving outcomes among patients with breast cancer. 


Iyengar, a breast oncologist in in the Department of Medicine at MSKCC and Weill Cornell Medicine in New York City, New York, as well as the co–editor-in-chief of the journal ONCOLOGY®, detailed his work in the emerging field of exercise oncology. Based on preclinical data supporting the potential anti-tumor effects of exercise, he and his colleagues are organizing several clinical trials to validate whether exercise intervention can improve cancer-specific end points. Although some findings may support implementing exercise as part of a cancer treatment plan, Iyengar noted the observational and self-reported nature of the prior data and said that it would be necessary to test exercise intervention in the same way “you would develop any new drug for treating cancer.”


Additionally, Iyengar discussed the fulfillment of ensuring patient care, a passion that has fueled his interest in lifestyle interventions such as exercise oncology. He highlighted how his cancer treatment philosophy extends beyond the goal of reducing tumor volumes to safeguarding the patient’s physical and emotional well-being.


“You can certainly hammer away at a tumor and give all kinds of chemotherapy and anti-cancer therapies, but if that [patient] is feeling miserable and has no quality of life and a short duration of response to that therapy, that’s not necessarily the type of outcome that I would consider to be successful,” Iyengar said. “If you’re able to either control or cure a cancer while also improving a [patient’s] quality of life and general well-being, that’s the kind of outcome that I strive for. When I see that in my patients and in the patients of my colleagues, that certainly brings a lot of fulfillment.”


Iyengar also highlighted how he found excitement and passion in off-hours responsibilities to help achieve work-life balance. Looking ahead, he spoke about data on anti-estrogen agents, antibody drug conjugates, and other breast cancer treatment strategies that he is looking forward to hearing at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

In a discussion with CancerNetwork® at John Theurer Cancer Center, Gregory Charak, MD, highlighted advancements in surgical treatment strategies for patients with colorectal cancer (CRC) as well as other ongoing challenges in the field.


Specifically, Charak, a board-certified colorectal surgeon at Palisades Medical Center and Hackensack University Medical Center of Hackensack Meridian Health, described how minimally invasive strategies such as laparoscopic and robotic surgery have become more prevalent in the field, which have appeared to confer improvements in pain and length of hospital stay for patients. Although these minimally invasive techniques are typically preferred in this population compared with open surgery, Charak stated that he would still employ the latter depending on factors such as tumor size.


Charak also discussed the rise in CRC incidence among younger populations, which has impacted how practices conduct screening. He highlighted that patients who are in their late 20s or 30s receive recommendations to undergo colonoscopy in the event of weight changes or blood appearing in their stool, noting that he would not hesitate to perform screening even if there’s a small but real possibility of disease.


Regarding other treatment modalities in this population, Charak emphasized the potential benefits of neoadjuvant therapy. Administering neoadjuvant treatment with agents including cytotoxic chemotherapy and immunotherapy, for example, may help achieve negative-margin resections, thereby yielding less morbidity for patients.


“It’s a very exciting time to be a surgical oncologist. [There are] tremendous new treatment modalities coming down the pike. Immunotherapy, in particular, is extremely exciting because it’s such an elegant way to treat cancer: to harness and augment the body’s own defense system to eliminate a cancer rather than using cytotoxic chemicals or invasive surgery,” Charak said. “It’s a beautiful thing. If we can get it to apply to more and more tumors and figure out how to make it work, it couldn’t be more exciting.”