COMMENTARY

NIVO + LAG-3 Antibody Succeeds in Advanced Melanoma

Jeffrey S. Weber, MD, PhD

Disclosures

July 01, 2021

This transcript has been edited for clarity.

Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City. Today I'll be commenting on two studies on melanoma treatment presented at the oral sessions of this year's American Society of Clinical Oncology (ASCO) meeting.

RELATIVITY-047 was a randomized study that included more than 700 patients with previously untreated melanoma. Patients were randomly assigned to receive either relatlimab (RELA), an antibody that blocks the lymphocyte activation gene 3 (LAG-3), plus nivolumab (NIVO) vs NIVO alone. The primary endpoint of this trial was investigator-called progression-free survival (PFS). The secondary endpoints were response rate and overall survival.

This was a well-conducted, well-balanced, randomized phase 3 trial. All of the usual prognostic factors were well matched, including gender, age, performance status, serum LDH, tumor burden, and LAG-3 expression. Previous trials of second-line treatment have shown that a high LAG-3 expression in the tumor was associated with a better response. Overall, 75% of the patients in this study had LAG-3 in more than 1% of the tumor, presumably mostly on infiltrating immune cells, with 25% having LAG-3 in less than 1%, probably meaning that they were essentially LAG-3 negative.

The median PFS in the RELA/NIVO combination arm was 10.1 months vs 4.6 months for NIVO alone, with a hazard ratio of 0.75 and a P value of .005. The 12-month PFS was 47% for the combo vs 36% for NIVO alone, clearly a winner for the combination.

Benefit was seen in patients who were LAG-3 positive and also in those who were LAG-3 negative, which frankly is surprising. If you look at the PFS curves for LAG-3 expression greater than 1%, the median PFS for the RELA/NIVO group was 12 months vs 4.7 months for NIVO alone. For the minority of patients with a LAG-3 of less than 1%, PFS was around 4.8 months vs 2.8 months for NIVO alone — not quite as good, meaning the patients who were LAG-3 negative clearly had less impressive, less immunogenic, less inflamed tumors. LAG-3 is another checkpoint like PD-1, so that antibody will do better in the more inflamed tumors.

The rate of grade 3/4 treatment-related, immune-related adverse events was about 18.9% for RELA/NIVO, compared with 9.7% for NIVO alone. There were three deaths in the RELA/NIVO group vs two deaths in the NIVO alone group. One death in the NIVO alone arm was related to myocarditis; three episodes of myocarditis, presumably not leading to death, occurred in the RELA/NIVO arm. The distribution of immune-related adverse events was typical, as you would expect with a slight increase in the combination arm, but again, I think quite tolerable.

Bottom line: RELATIVITY-047 was the first phase 3 study to validate dual LAG-3 and PD-1 inhibition, and I think this was a clear winner. This provided clear evidence of greater activity in the RELA/NIVO combination than in NIVO alone.

This presentation came right on the heels of another interesting study, presented by Rodabe Amaria, of neoadjuvant and adjuvant RELA/NIVO in patients with resectable stage III melanoma. A total of 30 patients received neoadjuvant RELA/NIVO, followed by resection, followed by adjuvant RELA/NIVO, something that has not been done before. The primary endpoints were the determination of the pathologic complete response (PCR) rate and the major pathologic response rates.

Most of the 30 participants had an ECOG performance status of zero; the majority had stage IIIB or IIIC disease, with a sprinkling of patients with stage IIID or IV. Twenty-nine patients underwent surgery; one could not because of toxicity.

The PCR rate was 59%, which is pretty darn impressive, with an additional 7% of patients at 90% PCR or better. A total of 66% of the patients had a major pathologic response rate. Those are impressive data. If you look at the overall radiographic response rate, it matches the PCR rate of 57%. I would agree with the investigator in that trial, however, that the radiologic response underestimates the pathologic response because the major response rate was 66%, but only 57% by radiologic assessment. Of the patients who had a major 90% or more pathologic complete response at 16 months of follow-up, no one has relapsed and the relapse rate in everyone else is a pretty healthy 60% at 16 months. Those are impressive data. In all, 26% of the patients had grade 3 immune-related adverse events in the adjuvant setting, with no significant dose-limiting toxicity in the patients who received two 4-week cycles of RELA/NIVO in the neoadjuvant setting.

This is impressive data that sets up RELA/NIVO as a favored neoadjuvant regimen. It could replace ipilimumab/NIVO as the favored neoadjuvant immunotherapy regimen.

This is Dr Jeffrey Weber. Please do contact me with questions or comments. Thank you for your attention.

Jeffrey Weber, MD, PhD, is deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its Melanoma Research Program. His research, which has been continuously funded by the NCI for more than 20 years, focuses on experimental therapeutics and drug development, particularly in immunotherapy.

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