Antagonists of PD-1 and PD-L1 in Cancer Treatment

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Abstract


The PD-1 pathway, comprising the immune cell co-receptor Programmed Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates local immunosuppression in the tumor microenvironment. Drugs designed to block PD-1 or PD-L1 “release the brakes” on anti-tumor immunity and have demonstrated clinical activity in several types of advanced cancers, validating this pathway as a target for cancer therapy. Two such drugs have recently been approved to treat refractory advanced melanoma, and regulatory approvals in first- and second-line settings for additional cancer types are anticipated. The manageable safety profile of PD-1/PD-L1 blocking drugs identifies them as suitable for outpatient administration and the development of combinatorial therapies. Ongoing studies aim to identify biomarkers to guide patient selection, which would further improve the risk:benefit ratio for these drugs.

What was impressive to me*

MELANOMA

The annual incidence of melanoma continues to rise worldwide, and despite recent regulatory approvals for ipilimumab and several kinase inhibitors, more effective treatment options for patients with advanced disease are needed. Clinical experience with agents blocking PD-1 and its ligands in melanoma began in 2006 with the first-in-human trial of nivolumab (Opdivo, BMS-936558, MDX-1106, ONO-4538; Bristol-Myers Squibb, Princeton, NJ) involving 39 patients with various advanced, treatment-refractory malignancies.1 Nivolumab had an acceptable safety profile, and anti-tumor activity was seen not only in patients with melanoma, but also in those with colorectal cancer (CRC) and renal cell carcinoma (RCC), and transiently in non-small-cell lung cancer (NSCLC). Long-term follow-up revealed that tumor regressions were durable. One patient with melanoma achieved a partial response (PR) lasting 16 months after discontinuing nivolumab; at subsequent tumor progression, she was re-treated with nivolumab, resulting in a second PR.2 Furthermore, one patient each with RCC and CRC remained in complete response (CR) >3 years after completing therapy. Nivolumab was subsequently administered to 107 previously-treated, anti-CTLA-4-naïve patients with melanoma as part of a 306-patient phase I trial with cohort expansion; it was given every 2 weeks for up to 96 weeks.3–5 An objective response rate (ORR, PR+CR) of 32% (34/107), evaluated by conventional Response Evaluation Criteria in Solid Tumors (RECIST), was observed. Median response duration was 23 months. Among 21 patients with ORs who discontinued nivolumab for reasons other than progressive disease (PD), 11 (52%) maintained their responses for ≥24 weeks. One-, 2- and 3-year OS rates were 63%, 48% and 41%, respectively, comparing favorably to literature reports of similar patient populations. Fifty-eight patients (54%) experienced a treatment-related immune-mediated adverse event (irAE) of any grade. Of those, only 5 (5%) were grade 3





https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555873/