In advanced melanoma, PD-1 blockade with pembrolizumab (Keytruda) was effective regardless of patients’ BRAF mutation status, retrospective data from three KEYNOTE trials indicated.
Among more than 1,500 patients in the post hoc analysis, overall response rates (ORRs) with the immune checkpoint inhibitor were 39.8% for the group with BRAF wild-type tumors and 34.3% for those with BRAF V600E/K-mutant tumors, which included patients with prior exposure to BRAF and MEK inhibitors, reported Igor Puzanov, MD, MSCI, of Roswell Park Cancer Institute in Buffalo, New York, and colleagues.
As described in JAMA Oncology, the progression-free survival (PFS) rate at 4 years was 22.9% in the wild-type group and 19.8% in the BRAF-mutant group, with a 4-year overall survival (OS) of 37.5% and 35.1%, respectively.
“Our findings confirmed the long-term, lasting benefits of pembrolizumab for patients with unresectable advanced melanoma and show that the effect is seen regardless of BRAF mutation status — and regardless of earlier treatment with a BRAF-targeting therapy,” Puzanov said in a statement.
In the BRAF-mutant population, responses were higher for patients without prior exposure to BRAF inhibitors (44.2%), either with or without MEK inhibition, compared to those who first received a targeted agent (28.4%), though the latter had worse baseline characteristics.
Similarly, survival outcomes in the BRAF-mutant group were inferior among patients who previously were treated with targeted therapy, with PFS and OS rates of 15.2% and 26.9%, respectively, at 4 years. Among the group without a history of BRAF/MEK inhibitor treatment, the 4-year PFS and OS rates were 27.8% and 49.3%.
“Coupled with what we know from separate studies about nivolumab [Opdivo], we see a clear picture of the benefits immune checkpoint inhibitors have had for thousands of people with advanced melanoma over the last decade,” said Puzanov. “Our long-term view provides evidence to support giving immunotherapy early in a patient’s treatment, before turning to targeted therapies.”
Roughly 40% of patients with advanced melanoma have BRAF mutations, with 90% being V600E/K mutations, and the sequencing of immunotherapy versus targeted agents has been unclear, though a number of ongoing trials are attempting to answer this very question. Trials combining the two approaches in first-line have shown benefit, but at the expense of increased toxicity.
For their study, Puzanov’s team pooled data from KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006, which included 1,558 patients with advanced melanoma and BRAF wild-type tumors (n=1,124) or BRAF V600E/K-mutant tumors (n=447). In the BRAF-mutant population, 62.4% of patients had received targeted therapy prior to immunotherapy. Overall, the average patient age was 60 years and about 60% were men.
For the overall population, 38.3% responded to treatment with pembrolizumab and the 4-year PFS and OS rates were 22.0% and 36.9%, respectively.
“The study reinforces the fact that immunotherapy can significantly extend the life of patients with melanoma and even lead to cures,” Puzanov said. “But importantly, we also still see a role for targeted therapies. Having both of these treatment options at our disposal has helped to drive incredible progress against a cancer type that was almost universally fatal a decade ago.”
Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.
Puzanov disclosed fees from Amgen, Bristol-Myers Squibb, Oncorus, and Synthorx. Co-authors reported various relationships with industry, including Merck Sharp & Dohme.
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