Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

Abstract

Background: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma.

Methods: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks.

Results: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months.

Conclusions: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).

Figure 1. Antitumor Activity of Lambrolizumab

Data on the antitumor activity of lambrolizumab, as assessed by independent, central radiologic review, is shown for the patients who could be evaluated. Panel A shows a waterfall plot of the best objective response according to prior treatment with ipilimumab, measured as the maximum change from baseline in the sum of the longest diameter of each target lesion. A total of 10 of 103 patients with radiographically measurable disease at baseline and at least one evaluation after treatment had a 100% reduction in target lesions. Panel B shows the time to response and the duration of study treatment. A total of 42 of the 52 patients who had a response were still receiving the study treatment at the time of the current analysis. Of the 10 patients who discontinued therapy, 5 discontinued owing to toxic effects, and 2 of these patients showed improvement in their response after discontinuation (denoted by the two triangles that are outside the bar of the on-treatment period).

Figure 2. Tumor Responses with Lambrolizumab

Shown are examples of tumor responses in patients treated with lambrolizumab. Panel A shows images obtained from a patient with BRAF nonmutant metastatic melanoma who had symptomatic progression after biochemotherapy and treatment with high-dose interleukin-2 and ipilimumab; the patient had rapid resolution of symptoms and showed a partial response with lambrolizumab at the initial imaging on day 90. Arrows point to sites of melanoma metastases in the lung and liver. Immunohistochemical staining of biopsied specimens obtained before and after treatment show an increased CD8 T-cell infiltrate after treatment. Panel B shows the resolution of a local relapse of desmoplastic melanoma in a patient who had not received prior treatment with ipilimumab; an additional tumor response was observed in nodal and lung metastases (not shown). CD8 immunohistochemical staining of biopsy specimens obtained before and after treatment shows increased CD8 T-cell infiltrate. Panel C shows images from a patient without prior treatment with ipilimumab who had metastatic mucosal melanoma with significant progression at the initial 12-week imaging (red boxes), at which time lambrolizumab was discontinued. Without receiving any other therapy, the patient went on to have a nearly complete response that is ongoing more than 1 year after the start of the study. Panel D is a plot of the change in tumor burden (assessed as the longest dimension of the lesion) over time in patients with melanoma who had not received prior treatment with ipilimumab and who received lambrolizumab at a dose of 10 mg per kilogram of body weight every 2 weeks. In most patients who had an objective response, the responses were durable and were evident at the initial evaluation (12 weeks). Tumor regression followed both conventional and immune-related patterns of response, such as a prolonged reduction in the tumor burden in the presence of new lesions.