A Promising Neoadjuvant Combination Immunotherapy for Advanced Melanoma

Neoadjuvant relatlimab and nivolumab achieved high response rates with a favorable safety profile in patients with advanced melanoma, according to initial data from a small clinical trial conducted by researchers at Memorial Sloan Kettering Cancer Center (MSK) and the University of Texas MD Anderson Cancer Center (MD Anderson).

Results from the phase 2 trial (NCT02519322) were published recently in Nature. Neoadjuvant relatlimab and nivolumab resulted in a 57% pathologic complete response (pCR) rate and a 70% overall pathologic response rate in 30 patients with resectable clinical stage 3 or oligometastatic stage 4 melanoma. No grade 3 or 4 immune-related adverse events were observed in the neoadjuvant setting, a favorable contrast compared with other combination immunotherapy regimens. ⁽¹⁾

Most study participants remained cancer free after an average of two years. The one- and two-year recurrence-free survival rates were 100% and 92% for patients with any pathologic response versus 88% and 55% for patients with no pathologic response. Increased immune-cell infiltration at baseline and decreased M2 macrophages during treatment were associated with pathologic response. ⁽¹⁾

“The key takeaway from this trial is that most patients responded very well to neoadjuvant relatlimab plus nivolumab,” says surgical oncologist Charlotte Ariyan, MD, PhD, the Carol Bassok Lowenstein Chair at MSK and co-senior author of the paper. “Additionally, the side effects were less compared with other immunotherapy regimens and with no grade 3/4 toxicities prior to surgery, so no patients had to delay surgery after neoadjuvant treatment.”

The study authors acknowledged that while these initial findings are encouraging, the results are preliminary, based on findings at two academic research institutions, and require additional follow-up to assess fully the clinical impact and durability of responses.

Study Rationale and Design

Nivolumab and relatlimab are checkpoint inhibitors that bind with specific proteins, enabling the immune system to recognize and attack cancer cells. Nivolumab targets PD-1 found on T cells. Relatlimab is a monoclonal antibody that restores the effector function of exhausted T cells and has been investigated in checkpoint inhibitor–naive and refractory metastatic melanoma. ⁽¹⁾

The combination of relatlimab plus nivolumab in patients with treatment-naive unresectable stage 3 or 4 metastatic melanoma demonstrated a significant improvement in progression-free survival (PFS) compared with nivolumab alone, with a hazard ratio of 0.78, in the randomized phase 2/3 RELATIVITY-047 trial (NCT03470922) conducted at 127 sites across the United States, including MD Anderson. Further, the combination was well tolerated, with 21% of patients experiencing grade 3/4 treatment-related adverse events. ⁽²⁾ Accordingly, the U.S. Food and Drug Administration approved this combination immunotherapy for patients with metastatic melanoma in March 2022.

Investigators at MD Anderson published results of a randomized, investigator-initiated trial of neoadjuvant nivolumab or nivolumab plus ipilimumab, a checkpoint inhibitor that targets cytotoxic T-lymphocyte-associated antigen 4 on T cells. Neoadjuvant nivolumab alone showed modest efficacy with a 25% pCR rate, and only 8% of patients experienced grade 3/4 toxicities. By contrast, neoadjuvant nivolumab plus ipilimumab was effective with a 45% pCR rate, but grade 3/4 toxicities were prohibitively high, occurring in 73% of patients. ⁽³⁾

Taking this learning into account and with a view to optimizing pathologic response while minimizing toxicities, the MD Anderson investigators collaborated with MSK researchers and opened a new study arm to evaluate neoadjuvant relatlimab and nivolumab in patients with resectable advanced melanoma. Patients received two neoadjuvant doses of nivolumab and relatlimab intravenously every four weeks, followed by surgery, and then 10 doses of adjuvant combination therapy.

At MSK, investigators launched the trial in 2019 while relatlimab was still an experimental drug. “We opened the trial three years before relatlimab was approved, giving patients at MSK and MD Anderson access to a promising treatment option not available elsewhere,” says medical oncologist Michael Postow, MD, Chief of the Melanoma Service and Co-Director of the Melanoma Disease Management Team at MSK and co-first author of the study. “Since this drug combination is now FDA-approved for patients with advanced melanoma, many more patients may benefit.”

Additional Findings: Biomarkers and Safety Signals

Baseline LAG-3 and PD-1 levels in tumor samples did not correlate with response to treatment. However, the investigators observed differences in the tumor microenvironment and peripheral blood of patients who experienced a favorable treatment response. Specifically, they saw increased levels of memory CD4⁺ and effector CD8⁺ T cells and a reduction in M2-like macrophages in post-treatment tumor specimens of patients who experienced a pathologic response. Analysis of peripheral blood revealed higher levels of transcription factor eomesodermin⁺ (EOMES⁺) CD8⁺ T cells in post-treatment samples of responding patients, suggesting CD8⁺ T cells expressing EOMES factor may contribute to tumor regression. ⁽¹⁾

There were no grade 3/4 immune-related adverse events during the eight weeks of neoadjuvant treatment. However, 26% of patients developed grade 3/4 toxicities in the adjuvant setting, defined as week nine and beyond. Overall, 33% of patients elected to discontinue adjuvant therapy, most commonly due to transaminitis. Despite some patients experiencing asymptomatic troponin elevations, none experienced symptomatic troponin elevations, myocarditis, or other cardiac toxicity. The most frequent immune-related adverse event was secondary adrenal insufficiency in 23% of patients, with no patients recovering adrenal function to date. ⁽¹⁾

Findings from the present study were complementary to the RELATIVITY-047 study in patients with unresectable metastatic melanoma, ⁽²⁾ and added to a growing body of pooled analyses from neoadjuvant melanoma trials demonstrating the importance of pathologic response rates as an early predictor of favorable relapse-free survival following surgery. ⁽⁴⁾

Clinical Trials for Patients With Melanoma

MSK’s multidisciplinary Melanoma Disease Management Team consists of experts specializing in treating melanoma, including surgical oncologists, medical oncologists, dermatologic surgeons, radiation oncologists, head and neck surgeons, plastic and reconstructive surgeons, dermatopathologists, nurses, and social workers.

MSK investigators continue to investigate new treatment options to improve outcomes for patients with melanoma. MSK is currently conducting 35 clinical trials for patients with melanoma, evaluating novel immunotherapy and targeted therapy strategies.

Advancing Melanoma Research Through Multidisciplinary Collaboration

The study was a multidisciplinary collaboration among MSK experts as follows. From the Department of Pathology: Klaus Busam, MD. From the Department of Medicine: Allison Betof-Warner, MD, PhD; Alexander Shoushtari, MD; Margaret Callahan, MD, PhD; and Parisa Momtaz, MD. From the Department of Surgical Oncology: Daniel Coit, MD, FACS; Edmund Bartlett, MD; and Danielle Bello, MD.

This research was supported by the Melanoma Informatics, Tissue Resource, and Translational Pathology Core at the University of Texas MD Anderson Cancer Center and philanthropic contributions to the University of Texas MD Anderson Cancer Moon Shots Program. Drs. Postow and Ariyan are supported by a Cancer Center Support Grant (P30 CA08748) from the National Institutes of Health/National Cancer Institute. Dr. Ariyan is supported by a pilot grant from the Parker Institute for Cancer Immunotherapy at MSK.

Dr. Postow has received consulting fees from Bristol Myers Squibb, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai, and Pfizer and honoraria from Bristol Myers Squibb and Merck. He also receives institutional support from RGenix, Infinity, Bristol Myers Squibb, Merck, Array BioPharma, Novartis, and AstraZeneca. Dr. Ariyan has received a consulting fee from Iovance.