Omid Hamid, MD, Chief of Translational Research/Immuno-Oncology at The Angeles Clinic & Research Institute, Los Angeles, and Co-Director of the Cutaneous Malignancy Program at Cedars-Sinai Cancer Institute, shared his thoughts on the RELATIVITY-047 study1 for The ASCO Post, referring to them as the “theory of relativity.”
“With the advent of checkpoint inhibition with [drugs targeting] PD-1 and CTLA-4, it felt like we were traveling at the speed of light: only moments until we solved the puzzle of immunotherapy. Recently, despite the plethora of immune agents, we have failed to move the needle where it was indicated, decreasing toxicity of combinatorial regimens while increasing clinical benefit of therapy,” Dr. Hamid said.
Omid Hamid, MD
Yet Many Unanswered Questions
“The failure of ‘novel immunotherapeutic combinations’ in phase III trials has been broken by the RELATIVITY-047 trial and its benefits in progression-free survival—just in time to produce a tolerable first-line regimen that brings with it many unanswered questions,” he said.
For instance, Dr. Hamid continued: “There is still work to be done to reinvigorate exhausted T cells,” noting that previous randomized trials lacked clarity on subset analyses and work in the area of biomarkers. It has been known that LAG-3 expression is indicative of response in the PD-1–refractory population, but whether this biomarker will hold true in first-line treatment is not clear.
Moreover, the question remains as to whether progression-free survival will be a surrogate for an overall survival benefit. Only long-term follow-up will reveal the answer to this question. Another question centers on where LAG-3 inhibition may fit in the treatment of mucosal melanoma, BRAF-mutant tumors, or brain metastases.
More From ASCO 2021
Dr. Hamid pointed to a number of interesting abstracts presented at the 2021 ASCO Annual Meeting that may be informative on the remaining questions. “RELATIVITY is only the beginning at ASCO 2021,” he noted.
“As single-agent therapies move to the adjuvant setting, a role for such combinations in the treatment of rapid recurrence is warranted with metastatic disease (Abstract 9515).2 A bigger adjuvant trial is likely soon to follow. Early neoadjuvant data on PD-1/LAG-3 combination indicating high pathologic complete response rates and a relapse-free survival benefit should not be missed (Abstract 9502),3” he suggested.
“As with previous breakthroughs in melanoma, this effort will be replicated in other solid tumors with the hope of similar success. Any therapy good enough to show a benefit in combination with anti–PD-1 will soon turn to triplets,” Dr. Hamid continued. “Combinations targeting PD-1/TIM-3/LAG-3 are already looking to overcome primary resistance to therapy.”
Dr. Hamid also made the following predictions: “Adoptive T-cell therapy (Abstract 9505) will take its place in melanoma,4 perhaps in the second/third-line checkpoint-refractory population. Flipped-dose PD-1/CTLA-4 long-term data may change our utilization of higher-dose CTLA-4 (Abstract 9516).5 We will also see an update in relation to brain metastases and leptomeningeal disease (Abstract 9519).6”
In short, Dr. Hamid said he believes research presented at this year’s ASCO meeting will take melanoma treatment to the next level: “ASCO 2021 illuminates the future of melanoma therapy and returns it to the speed of light.” ν
Find Dr. Hamid on Twitter @OmidHamidMD.
DISCLOSURE: Dr. Hamid has received honoraria from Bristol Myers Squibb, Novartis, Pfizer, and Sanofi/Regeneron; has served as a consultant or advisor to Aduro, Akeso Biopharma, Amgen, BeiGene, BioAtla, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Tempus, and Zelluna; has participated in a speakers bureau for Bristol Myers Squibb, Novartis, Pfizer, and Sanofi/Regeneron; and has received institutional research funding from Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, BioAtla, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Iovance Biotherapeutics, Merck, Merck Serono, Moderna Therapeutics, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Torque, and Zelluna.
1. Lipson EJ, Tawbi HAH, Schadendorf K, et al: Relatlimab plus nivolumab versus nivolumab in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). 2021 ASCO Annual Meeting. Abstract 9503. Presented June 4, 2021.
2. Hamid O, Wang D, Kim TM, et al: Clinical activity of fianlimab (REGN3767), a human anti–LAG-3 monoclonal antibody, combined with cemiplimab (anti–PD-1) in patients with advanced melanoma. 2021 ASCO Annual Meeting. Abstract 9515. Presented June 4, 2021.
3. Amaria RN, Postow MA, Tetzlaff MT, et al: Neoadjuvant and adjuvant nivolumab with anti-LAG3 antibody relatlimab for patients with resectable clinical stage III melanoma. 2021 ASCO Annual Meeting. Abstract 9502. Presented June 4, 2021.
4. Larkin J, Sarnaik A, Chesney JA, et al: Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma: Evaluation of impact of prior anti–PD-1 therapy. 2021 ASCO Annual Meeting. Abstract 9505. Presented June 4, 2021.
5. Lebbe C, Meyer N, Mortier L, et al: Two dosing regimens of nivolumab plus ipilimumab for advanced melanoma: Three-year results of CheckMate 511. 2021 ASCO Annual Meeting. Abstract 9516. Presented June 4, 2021.
6. John I, Foster AP, Haymaker CL, et al: Intrathecal and intravenous nivolumab for metastatic melanoma patients with leptomeningeal disease. 2021 ASCO Annual Meeting. Abstract 9519. Presented June 4, 2021.
Immune checkpoint inhibition has been established as an effective treatment for patients with metastatic melanoma. A novel immunotherapeutic combination—this one targeting the LAG-3 (lymphocyte-activation gene 3) and PD-1 immune checkpoints—delayed time to disease progression significantly more...