Relatlimab/Nivolumab Combo Active in Melanoma After PD-1/PD-L1 Therapy

Author(s):

Half of patients with melanoma who progressed on anti-PD-1/PD-L1 therapy benefited from the combination of nivolumab and the LAG-3 inhibitor relatlimab.

Paolo A. Ascierto, MD

Half of patients with melanoma who progressed on anti—PD-1/PD-L1 therapy benefited from the combination of nivolumab (Opdivo) and the LAG-3 inhibitor relatlimab (BMS-986016), data from a dose-expansion study showed.

The combination led to objective responses in 7 of 61 evaluable patients, increasing to 18% in a subgroup of patients LAG-3—positive tumors. Half of all patients treated and two-thirds of those patients with LAG-3–positive tumors derived clinical benefit, as reported at the 2017 ESMO Congress.

“With additional follow-up, clinically meaningful antitumor activity with relatlimab and nivolumab was observed in a heavily pretreated population of patients with melanoma who had progressed during prior anti—PD-1/PD-L1 therapy,” said Paolo A. Ascierto, MD, vice-chair of the Melanoma Unit at the National Cancer Institute Foundation G. Pascale in Naples, Italy.

“Responses were more likely in patients with LAG-3 expression greater than or equal to 1%, while PD-L1 expression did not appear to enrich for response. The combination is well tolerated, with a safety profile similar to that of nivolumab monotherapy. Further investigations of the combination of relatlimab and nivolumab are ongoing in melanoma and other tumor types, in both immune-oncology—naïve and immune-oncology– experienced patients.

The rationale for combining a LAG-3 inhibitor and an anti—PD-1/PD-L1 agent came from evidence suggesting that LAG-3 has a potential role in T-cell expression and anti–PD-1 resistance. LAG-3 regulates a checkpoint pathway that limits the activity of T cells, said Ascierto. Both LAG-3 and PD-1 receptors are overexpressed and/or co-expressed on tumor-infiltrating lymphocytes in melanoma.

The combination of relatlimab and nivolumab demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity in a small dose-escalation study involving patients with advanced solid tumors. The preliminary findings led to a dose-expansion study involving 262 patients with various solid tumors. Ascierto reported efficacy findings for a subgroup of 68 patients with melanoma who progressed during prior immunotherapy, as well as updated safety data for the entire expansion cohort.

The median age of the 68 patients is 60, 65% had ECOG performance status of 0, 68% had stage M1C disease without brain metastases, and 63% had BRAF-negative primary tumors. Almost half the patients had received 3 or more prior systemic regimens. All the patients had exposure to anti—PD-1/PD-L1 therapy, and a majority also had received anti–CTLA-4 therapy. Ascierto said 46% of the patients had progressive disease as a best response to a PD-1/PD-L1 inhibitor.

The overall response rate was 11.5%. Among 61 patients evaluable for response, 1 achieved a complete response (CR) to the combination of relatlimab/nivolumab and 6 others had partial responses (PRs). An additional 23 patients had stable disease (SD), resulting in a disease control rate (DCR) of 49%.

An analysis of 33 patients with LAG-3 expression ≥1% showed 1 CR, 5 PRs, and 15 patients with stable disease, resulting in a disease control rate of 64%.

Analyses by baseline LAG-3 expression showed no significant difference in the efficacy of the combination among patients with PD-L1 expression <1% or ≥1% expression. In the subgroup of 27 patients with LAG-3 expression ≥1 and known PD-L1 expression status, the response rate of 6.3% in patients with PD-L1 expression ≥1% and 27% in those with PD-L1 expression <1%. PD-L1 expression status also did not influence response in 17 patients with LAG-3 expression <1%.

Patients without BRAF mutations had higher responses than those with mutations, and patients without BRAF mutations were more likely to respond if they had LAG-3 expression ≥1% (24% vs 9.1% for LAG-3 <1%). Patients with prior anti—CTLA-4 therapy and LAG-3 expression ≥1% had a higher response rate (24% vs 8.3% no prior anti–CTLA-4 therapy and LAG-3 expression <1%).

At data cutoff, 21 of 61 (34%) patients remained progression free, including 18 of 33 (55%) patients with LAG-3 expression ≥1%, 1 of 20 with LAG-3 expression <1%, and 2 of 8 (25%) patients with LAG-3 status unknown.

The safety profile of the combination was similar for the subgroup of patients with prior PD-1/PD-L1 exposure and the overall expansion cohort, Ascierto reported. Grade 3/4 adverse events were uncommon, consisting of 3 cases each of diarrhea and colitis, and 2 cases of pneumonitis.

Ascierto PA, Bono P, Bhatia S, et al. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA18.