Lambrolizumab Demonstrates Significant Antitumor Activity in Melanoma

Antoni Ribas, MD, PhD

The investigational antibody lambrolizumab (formerly known as MK-3475) demonstrated significant antitumor activity and good response rates as well as a tolerable toxicity profile in patients with melanoma, according to the results of an ongoing phase IB expansion study presented at the 2013 ASCO Annual Meeting.

The results of the trial were concurrently published in The New England Journal of Medicine.

“We’ve seen clinically meaningful activity in a substantial number of patients,” said Antoni Ribas, MD, PhD, director of the Tumor Immunology Program Area at UCLA’s Jonsson Comprehensive Cancer Center in Los Angeles, California, and lead author of the study. “We can start to get the sense of the response rate and the durability of that response.”

Lambrolizumab is an anti—PD-1 humanized IgG4 antibody. The agent received the FDA’s Breakthrough Therapy Designation for promising new drugs in April.

At last year’s ASCO meeting, initial results that included two patients with melanoma showed antitumor activity. The phase Ib trial presented at this year’s meeting focused on melanoma in 135 patients with advanced and unresectable melanoma, with 48 patients having been previously treated with ipilimumab. Patients received lambrolizumab in either a dosage of 10 mg/kg once every 2 or 3 weeks or 2 mg/kg once every 3 weeks. Treatment was continued until progressive disease or unacceptable toxicity.

The confirmed response rate across all dose cohorts was 38% (95% CI, 25-44), and the highest confirmed response rate was observed in patients receiving 10 mg/kg of lambrolizumab once every 2 weeks, the highest dosing cohort in this study, with a response rate of 52% (95% CI, 38-66). The response rate did not differ significantly based on whether patients had received prior ipilimumab (38%; 95% CI, 23-55) or had not received prior ipilimumab (37%; 95% CI, 26-49).

Therapy with lambrolizumab produced durable responses, and as of March 2013, 81% of patients who had a response (42 of 52) were still receiving the drug. The overall median progression-free survival among the patients enrolled in the trial was >7 months.

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Dr. Ribas on Anti-PD-1 Agent Lambrolizumab in Melanoma

Dr. Ribas on Anti-PD-1 Agent Lambrolizumab in Melanoma

The researchers found that adverse events (AEs) of grade 3 or 4 occurred in 12.6% of patients in the study (n = 17). The most common AEs observed were fatigue, rash, and an increase in the aspartate aminotransferase enzyme that can indicate an increased risk of liver disease, all of which Ribas said could be managed through dose interruptions or reductions, if necessary.

The highest incidence of grade 3/4 AEs occurred in patients who received 10 mg/kg of lambrolizumab once every 2 weeks, the highest dosing cohort in the study. However, those patients were followed up for the longest period of time at a median of 40.1 weeks and could have resulted in a higher number of reported AEs.

A global phase II study of lambrolizumab is currently open for enrollment. Patients will be randomized to one of two dosing regimens or investigator’s choice of chemotherapy with the ability to cross over. Additionally, a phase III study comparing two different dosing regimens of lambrolizumab with ipilimumab in patients who have not previously received ipilimumab is planned.

Ribas A, Robert C, Daud A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. J Clin Oncol. 2013;31 (suppl; abstr 9009).