LAG-3 Antibody Combo Active in Patients With Immunotherapy-Treated Melanoma

Paolo Ascierto, MD

More than half of patients with immunotherapy-relapsed/refractory melanoma benefited from treatment with nivolumab and an anti-lymphocyte activation gene-3 (LAG-3) antibody, according to data from an early clinical study.

The addition of BMS-986016 to the PD-1 inhibitor nivolumab (Opdivo) led to partial responses in 6 of 48 evaluable patients (2 unconfirmed responses), and stable disease in another 20. Response to the combination in all but 1 of the responses occurred in LAG-3—positive tumors (≥1% expression by immunohistochemistry), whereas PD-L1 expression did not appear to influence responsiveness.

The combination was generally well tolerated, as 3 of 55 evaluable patients developed grade 3/4 treatment-emergent adverse events (TRAEs), as reported at the 2017 American Society of Clinical Oncology meeting in Chicago.

“The combination of BMSl-986016 and nivolumab resulted in clinically meaningful antitumor activity in a heavily pretreated, anti-PD-1 refractory/relapsed melanoma population,” Paolo Ascierto, MD, a medical oncologist in the Melanoma Unit at the National Cancer Institute in Naples, Italy, and colleagues concluded in a poster presentation. “We observed enrichment of antitumor activity in patients who express LAG-3 on tumor-associated immune cells. The safety profile was comparable to that of nivolumab alone.”

LAG-3 regulates a checkpoint pathway that limits T-cell activity. In patients with melanoma, exposure to PD-L1 blockade may increase LAG-3 expression, leading to T-cell exhaustion, anti—PD-1 drug resistance, and tumor escape. Preliminary clinical investigation of simultaneous blockade of LAG-3 and PD-1 yielded evidence of tolerability, peripheral T-cell activation.

Ascierto and colleagues reported preliminary efficacy data from a dose-expansion cohort (n = 55) treated with BMS-986016 and nivolumab for advanced melanoma that progressed on prior anti—PD-1/PD-L1 therapy. They also reported updated safety data for all patients treated at the expansion dose (n = 212).

The melanoma cohort had a median age of 59 years. All had ECOG performance status of 0 to 1, two-thirds had stage M1C disease without brain metastases, about 70% had normal to <2 times the upper limit of normal lactose dehydrogenase levels, 80% did not have visceral metastases, and about 40% hadBRAF-mutant disease.

The overall response rate in the patients with immunotherapy-treated melanoma was 13%. Ascierto reported that 15 patients had reductions in tumor burden from baseline, including reductions >30% in 7 patients. An additional 20 patients had stable disease, resulting in a disease control rate of 54%.

Further analyses showed that 5 of 6 partial responses occurred in patients who had LAG-3 expression &ge;1%, a subgroup of patients who accounted for two-thirds of the disease control benefit (16 of 26). The investigators found that patients with LAG-3-positive tumors had deeper and longer-lasting responses to the combination therapy.

Several different analyses of PD-L1 expression showed no association with the clinical efficacy of BMS-986016 and nivolumab. Overall, 2 of 16 patients with PD-L1 expression achieved partial responses compared with 4 of 19 patients who had lower levels of PD-L1 expression.

Four of the 6 objective responses occurred in patients with M1C disease without brain metastases, 5 responding patients had no liver metastases, and all 6 responses occurred in patients withoutBRAFmutations.

The safety data showed that the most common adverse events (all grades) were fatigue (9.0%), diarrhea (6.1%), pruritus (6.1%), and infusion-related reaction (5.2%). The most frequent grade 3/4 adverse events were elevated lipase (1.9%) and elevated liver enzymes (AST, 1.4%).

In the subgroup of patients with previously treated melanoma, diarrhea and nausea occurred most often (5.5% each), followed by pruritus, arthralgia, pyrexia, and dry mouth (3.6% each). Grade &ge;3 TRAEs consisted of 1 case each of diarrhea, elevated lipase, and colitis associated with elevated lipase.

Reference:

Ascierto PA, Melero I, Bhatia S, et al. Initial efficacy of anti-lymphocyte activation gene-3 (anti—LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti&ndash;PD-1/PD-L1 therapy.J Clin Oncol.2017;35 (suppl; abstr 9520).