Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma

By O. Hamid, C. Robert, A. Daud, F. Hodi, W. Hwu, R. Kefford, J. Wolchok, P. Hersey, R. Joseph, J. Weber and 16 more. New England Journal of Medicine, 2013

3,338 citations recorded by the source corpus.

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.)

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/983457b188c687b550509bbcb7b027a43b57ef71

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Citations in the corpus

Overcoming T cell exhaustion in infection and cancer (2015, background): “the majority of patients still fail to achieve robust objective clinical responses [21-23, 25-32].”
PD-L1 expression in human cancers and its association with clinical outcomes (2016, neutral): “93 Other effective biomarkers such as gene marker or combined indexes and improved understanding of tumor microenvironment are needed to accurately determine which patients will benefit from PD-1/PD-L1 pathway blockade therapy and to avoid the unnecessary autoimmune side effects from overtreatment.”
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy (2018, background): “PD-L1–unselected B2 (n = 73) cohorts (40, 41) and patients with advanced melanoma from the pembrolizumab arms of the KEYNOTE-001 (n = 30 of 668 total enrolled patients) and KEYNOTE006 (n= 59 of 834 total enrolled patients) studies (26, 42).”
Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential (2015, background): “Recently, a large phase I clinical trial with an anti-PD-1 antibody known as MK-3475 showed response rates of 37%–38% in patients with advanced melanoma, including patients who had progressive disease after prior ipilimumab treatment (Hamid et al., 2013), triggering the approval of MK-3475 (pembrolu”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Phase I clinical trials have proven the safety and efficacy of pembrolizumab in treating melanoma, and phase II clinical trials have shown that pembrolizumab’s efficacy in treating advanced melanoma is significantly superior to that of ipilimumab (anti-CTLA-4 antibody) [322].”
Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance (2017, background): “Studies have also begun to uncover mechanisms of resistance, including expression of immune checkpoint molecules (10, 14–21), insufficient infiltration of CD8 T cells (9, 10), oncogenic pathways (22–24), transcriptomic resistance signatures (25), lack of sensitivity to interferon (IFN) signaling (26”
IFN-&ggr;–related mRNA profile predicts clinical response to PD-1 blockade (2017, background): “Results of recent clinical studies with anti–PD-1 monoclonal antibodies in patients with cancer have validated the concept that targeting the host immune checkpoint mechanism via PD-1 receptor blockade produces durable antitumor responses, resulting in improved progression-free survival (PFS) and ov”
The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints (2014, neutral): “Anti-PD-1 and anti-PD-L1 antibodies have been demonstrated to induce significant durable tumor regressions in patients with melanoma, renal cancer and non-small cell lung cancer (6-9).”