Pembrolizumab Provides Long-Term Benefit in Melanoma, Regardless of BRAF+ Status or Prior Targeted Therapy

Igor Puzanov, MD, MSci, FACP

Pembrolizumab (Keytruda) was found to prolong survival in patients with advanced melanoma, regardless of BRAF V600E/K mutation status or prior administration of a BRAF inhibitor with or without a MEK inhibitor, according to results from a 10-year, post-hoc pooled subgroup analysis recently published in The Journal of the American Medical Association Oncology.¹

Data from 1,558 patients with known BRAF V600E mutation status were collected from 3 studies—KEYNOTE-001 (n = 647), KEYNOTE-002 (n = 361), and KEYNOTE-006 (n = 550)—and pooled for the subgroup analysis. Results showed an overall response rate (ORR) of 38.9% (n = 1558) with the PD-1 inhibitor. The 4-year progression-free survival (PFS) and overall survival (OS) rates were 22.0% and 38.3%, respectively.

Patients with a BRAF wild-type disease experienced a higher ORR than those with BRAF V600E/K–mutant melanoma, at 39.8% versus 34.3%, respectively (95% CI, 0.1-10.6), according to a univariate analysis. Moreover, these 2 subgroups experienced comparable 4-year PFS rates, at 22.9% versus 19.8%, respectively; however, median PFS was longer in patients with BRAF wild-type disease, at 7.9 months versus 5.6 months in those with BRAF V600E/K–mutant disease (HR, 0.84; 95% CI, 0.74-0.96). This also held true in terms of OS benefit. The 4-year OS rates in patients with BRAF wild-type disease and BRAF V600E/K–mutant disease were 37.5% versus 35.1%, respectively; the median OS was 23.0 months versus 21.8 months, respectively.

Investigators also examined the response to pembrolizumab in patients with BRAF V600E/K–mutant melanoma who specifically had and had not previously received a BRAF inhibitor with or without a MEK inhibitor. The ORR in patients with BRAF wild-type disease proved to be similar to that in those with BRAF V600E/K–mutant disease who had not received prior treatment with a BRAF inhibitor with or without a MEK inhibitor (39.8% vs 44.2%, respectively).

Patients who had received a BRAF inhibitor with or without a MEK inhibitor experienced a lower ORR with the immunotherapy than those who were BRAF inhibitor with or without a MEK inhibitor naïve, at 28.4% versus 44.2%, respectively. Patients who were previously treated with a BRAF inhibitor, with or without a MEK inhibitor, experienced lower 4-year PFS rates (15.2% vs 27.8%) and a numerically shorter median PFS versus patients who were BRAF inhibitor with our without MEK inhibitor therapy naïve (3.4 months vs 12.0 months, respectively); the former group also had lower 4-year OS rates (26.9% vs 49.3%, respectively) and a shorter median OS (13.8 months vs 45.4 months, 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,” Igor Puzanov, MD, MSci, FACP, a professor of medicine and director of the Early Phase Clinical Trials Program in the Department of Medicine at Roswell Park Comprehensive Cancer Center, stated in a press release.² “Coupled with what we know from separate studies about nivolumab (Opdivo), we see a clear picture of the benefits that immune checkpoint inhibitors have had for thousands of [patients] with advanced melanoma over the past decade.”

Of the 1,558 patients included in the analysis, 944 (60.6%) were men and 39.4% were women, with a mean age of 60 years. Of the total population, 72.1% had BRAF wild-type disease and 27.9% had BRAF V600E/K–mutant melanoma. Furthermore, 62.4% (n = 271) received previous treatment with a BRAF inhibitor with or without a MEK inhibitor, while 37.6% (n = 163) were naïve to BRAF inhibitor treatment with or without a MEK inhibitor therapy. Patients were treated with pembrolizumab in 1 of 3 regimens—either at a dose of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. A total of 29 patients (1.9%) were lost to follow-up.

Baseline characteristics were comparable between the BRAF wild-type subgroup and the BRAF V600E/K–mutant subgroup but some key differences existed. For one, the majority of patients in the mutant subgroup received prior BRAF inhibitor with or without MEK inhibitor therapy. Moreover, more patients with wild-type disease were older than those with mutant disease; more of these patients had also previously received treatment with ipilimumab (Yervoy).

Differences existed with regard to baseline characteristics in those with mutant disease previously treated with a BRAF inhibitor with or without MEK inhibitor therapy versus those who were naïve. Specifically, more patients in the former subgroup had a higher ECOG performance status, PD-L1–negative tumors, M1c disease, stable brain metastases, elevated serum LDH levels, had received more prior lines of treatment, had received prior ipilimumab, had larger tumors, and had lower albumin levels, compared with the latter group.

A subgroup analysis by baseline characteristics revealed a lower ORR with pembrolizumab in patients who were treated with BRAF inhibitor with or without MEK inhibitor therapy versus those who were naïve. The most notable differences existed with regard to age 65 years and older, PD-L1–positive status, metastatic stage, and elevated LDH level.

“Although many baseline characteristics were associated with worse overall response in subgroup analysis, multivariate analysis confirmed that PD-L1–negative tumors, elevated LDH levels, lower albumin levels, larger baseline tumors, and prior ipilimumab exposure were associated with worse overall response,” the study authors wrote.

Notably, baseline factors that were linked with worse PFS included PD-L1–negative tumors, elevated LDH levels, previous exposure to ipilimumab, larger baseline tumors, and previous exposure to BRAF inhibitor treatment.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were similar across all subgroups.

“The study reinforces the fact that immunotherapy can significantly extend the life of patients with melanoma and even lead to cures,” concluded Puzanov. “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.”

References

1. Puzanov I, Ribas A, Robert C, et al. Association of BRAF V600E/K mutation status and prior BRAF/MEK inhibition with pembrolizumab outcomes in advanced melanoma. JAMA Oncol. Published online July 16, 2020. doi:10.1001/jamaoncol.2020.2288

2. Use of pembrolizumab provided long-term benefits in patients with metastatic melanoma, 10-year look shows. News release. Roswell Park. July 16, 2020. Accessed July 17, 2020. https://bit.ly/2WOlEeI.