Pembrolizumab Shows Long-Term Benefit in Advanced Melanoma Subgroups

A retrospective 10-year analysis of 3 randomized clinical trials explored the question of whether BRAF V600E/K mutations or previous use of a BRAF inhibitor with or without a MEK inhibitor in patients with metastatic disease impacted patient response to pembrolizumab (Keytruda).¹

“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, the first author of the analysis, director of Early Phase Clinical Trials and chief of melanoma at Roswell Park Comprehensive Cancer Center, said in a statement. “Coupled with what we know from separate studies about nivolumab, we see a clear picture of the benefits immune checkpoint inhibitors have had for thousands of people with advanced melanoma over the last decade.”²

The pooled findings from KEYNOTE-001 (NCT01295827), KEYNOTE-002 (NCT01704287), and KEYNOTE-006 (NCT01866319) support the use of pembrolizumab for the treatment of this patient population. These findings included the objective response rates (ORRs), the 4-year progression-free survival (PFS) rates by RECIST version 1.1, and overall survival (OS) rates in 1558 patients.

In the overall study population, the ORR was 38.3%. Patients who were BRAF wild-type had an ORR of 39.8% (n = 447/1124) and those who with BRAF V600E/K-mutant melanoma had an ORR of 34.3% (n =149/434). For those with BRAF V600E/K mutations who had received a BRAF inhibitor with or without a MEK inhibitor had an ORR of 28.4% (n = 77/271) and those who had received previous treatment with BRAF inhibitors had an ORR of 44.2% (n = 72/163).

The 4-year PFS rate and OR rate was 22.0% and 36.9% for the overall group, respectively. In the wild-type population, it was 22.9% and 37.5%. The patients with BRAF V600E/K had a 4-year PFS and OS rate of 19.8% and 35.1%. Those with BRAF V600E/K who received a BRAF inhibitor had 4-year rates of 15.2% and 26.9% of PFS and OS, respectively; those who did not had rates of 27.8% and 49.3%.

Across the multiple subgroups, the treatment-related adverse events of any-grrade appeared similar, and occurred in 71.6% to 84.7% of patients. The safety profile observed with pembrolizumab in this analysis was also similar for all subgroups despite difference in BRAF V600E/K mutation status or treatment with a BRAF inhibitor with or without a MEK inhibitor.

“Our long-term view provides evidence to support giving immunotherapy early in a patient’s treatment, before turning to targeted therapies. This course of treatment is now the standard of care, but this is an important affirmation for this approach, which was not standard at the time these patients were treated,” Puzanov stated in a press release.

The subgroups of patients involved were patients who were BRAF wild-type versus those with BRAF V600E/K mutations and BRAF V600E/K mutations with versus without previous treatment with a BRAF inhibitor with or without MEK inhibitor therapy.

In the 3 trials, pembrolizumab was investigated at different dosages for patients. For KEYNOTE-001, it was either 2 mg/kg every 3 weeks, or 10 mg/kg every 2 or 3 weeks. KEYNOTE-002 gave patients 2 mg/kg or 10 mg/kg every 3 weeks. Lastly, in KEYNOTE-006, patients received 10 mg/kg of pembrolizumab every 2 weeks or every 3 weeks. The drug was given intravenously in all of these trials.

For the overall population in this pooled analysis, 60.6% were men and 39.4% were women. The mean age was 60 years old.

_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: pooled analysis of 3 clinical trials. 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 [press release]. Roswell Park. Published July 16, 2020. Accessed July 17, 2020. https://bit.ly/395PTTu}