The Groundbreaking Approval of Tebentafusp for Uveal Melanoma With Richard Carvajal, MD

Recently, the FDA granted approval to tebentafusp for the treatment of patients with human leukocyte antigen (HLA)-A*02:01–positive unresectable or metastatic uveal melanoma, marking the first agent to be approved for this rare ocular malignancy. In this interview, Dr. Richard Carvajal, Associate Professor of Medicine at Columbia University Irving Medical Center and editorial board member of Oncology Data Advisor, discusses the practice-changing significance of the approval of tebentafusp and delves further into future directions in the development of treatments for uveal melanoma.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today I’m here with Dr. Richard Carvajal to discuss the recent approval of tebentafusp for uveal melanoma.

Richard Carvajal, MD: My name’s Rich Carvajal. I’m a medical oncologist here at Columbia University. I oversee the Cutaneous Oncology and Melanoma Program, as well as the Phase I Clinical Research Program.

Oncology Data Advisor: So what is the significance of the recent approval of tebentafusp for uveal melanoma?

Dr. Carvajal: I think the significance is really enormous. It’s remarkable to me that up until January of this year, we had a disease, uveal melanoma, for which there was no therapy with proven efficacy that had regulatory approval. It’s pretty remarkable in this day and age that there are diseases which really had no effective therapy.

Tebentafusp, as you may know, is a bispecific therapy. It’s a form of immunotherapy that binds very tightly to glycoprotein 100 (gp100), a melanoma-associated antigen. Then it basically functions as a magnet. It just sucks in resident polyclonal immune cells and brings them into proximity with the cancer cell. Just by doing that, you get tumor cell death.

The recent phase 3 trial that was published in the New England Journal of Medicine demonstrated that treatment with tebentafusp versus investigator’s choice—which for the most part was anti–programmed cell death protein 1 (PD-1)–based therapy—led to significant improvement in terms of overall survival, with a hazard ratio of 0.51. We had a reduction in the risk of death of 49% for the patients who received tebentafusp versus those who had investigator’s choice. We’ve never shown that in a randomized fashion, despite a number of single-arm and a few randomized trials in this disease. So it’s really practice-changing.

I think it is really important to note that this therapy is HLA-restricted, so the drug only recognizes the fragmented gp100 in the context of HLA- A*02:01. For our patient population, for the patients with ocular melanoma, that means that this therapy is one that might be available in about 40% to 50% of cases. So although we have this agent that meaningfully improves survival, we still need approvals for any patient with advanced disease, either in the frontline setting or in the treatment-refractory setting. There is still a major unmet need for the patients who are not HLA- A*02:01–positive. That’s about 50% to 60% of patients for whom this therapy is not going to be an option.

Despite the improvement in overall survival—and it is significant, moving the median from about 16 months to 22 months—the efficacy of the drug is not infinite. Patients will become refractory to this therapy, and they will need the next line of therapy. So although we’ve got an approved, effective therapy, there’s still a major need for continued drug development.

I would also note that this therapy is a little bit logistically challenging in that it’s an intravenous (IV) therapy that’s administered weekly. I think patients will come for weekly treatments to get that survival advantage—no question about it—but there is still the cost of financial toxicity with this therapy that is significant. I think it’s also important to note that because of the recurrent toxicities—which are, for the most part, cytokine-mediated or dermatologic—the first three doses require prolonged observation of 16 hours or more. Functionally, it’s an overnight stay for the first three doses in some sort of monitored setting.

So there are needs for patients who are either tebentafusp-ineligible or tebentafusp-refractory. There’s a need for patients who right now are not able to get that IV weekly treatment. Moving forward, we’ll need strategies to either make tebentafusp better, potentially through combinatorial strategies, or just other novel treatment modalities.

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About Dr. Carvajal

Richard Carvajal, MD, is an Associate Professor of Medicine at Columbia University Irving Medical Center, where he serves as Director of Experimental Therapeutics and Director of the Melanoma Service within the Division of Hematology/Oncology. He also serves as Co-Leader of the Precision Oncology and Systems Biology Program within the Herbert Irving Comprehensive Cancer Center. Dr. Carvajal’s research is focused on the development of novel therapies for patients with melanoma and other cancers, including uncommon clinical and molecular subsets such as those arising from the eye (uveal melanomas), mucosal surfaces of the body (mucosal melanomas), and palms of the hands, soles of the feet, or under the fingernails (acral melanomas). He has been the principal or co-investigator of over 500 clinical trials and has authored or coauthored over 200 peer-reviewed manuscripts, books, and book chapters. In addition, Dr. Carvajal serves as Co-Chair of the International Rare Cancer Initiative Uveal Melanoma working group, a joint initiative between the National Cancer Institute, the European Organization for Research and Treatment of Cancer, and the Cancer Research UK to enhance international collaboration in clinical trials for uveal melanoma

For More Information

Nathan P, Hassel JC, Rutkowski P, et al (2021). Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med, 385(13):1196-1206. DOI:10.1056/NEJMoa2103485

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of i3 Health. 

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