Frontline Pembrolizumab Bests Ipilimumab in Phase III Melanoma Trial

Roger M. Perlmutter, MD, PhD

A trial comparing frontline pembrolizumab (Keytruda) with ipilimumab (Yervoy) for the treatment of advanced melanoma has met its progression-free survival (PFS) and overall survival (OS) endpoints, according to Merck, the company developing pembrolizumab. The trial will be stopped early, based on a recommendation from an independent data monitoring committee.

In this phase III trial, named KEYNOTE-006, pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in PFS and OS over ipilimumab in this patient population. Results will be presented at the upcoming AACR Annual Meeting in April.

“Evidence from our clinical program for Keytruda will help to define the appropriate treatment of advanced melanoma,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement.

Patients enrolled on KEYNOTE-006 had unresectable stage III or IV advanced melanoma and received no more than one prior systemic therapy. The primary endpoints of KEYNOTE-006 were focused on PFS and OS, with secondary endpoints focused on overall response rate (ORR), duration of response, and safety. Response was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. In total, 834 patients were randomized to receive 10 mg/kg of pembrolizumab every 3 weeks, 10 mg/kg of pembrolizumab every 2 weeks (higher than the FDA-approved dosage), or four cycles of ipilimumab 3 mg/kg every 3 weeks (the approved dosage).

In KEYNOTE-001, the trial that led to the 2014 approval of pembrolizumab, patients were treated with 2 mg/kg or 10 mg/kg of the agent. ORR (32% vs 27%) and 12-month OS rates were higher (63% vs 58%) with the 10-mg/kg dose compared with the 2 mg/kg dose, respectively, though PFS at 24 weeks (37% vs 44%) and median OS were shorter (18 months vs not reached at data cutoff). The FDA-recommended dosing regimen of pembrolizumab is 2 mg/kg given every 3 weeks.

In the trial of 173 patients, pembrolizumab demonstrated an ORR of 24% at the recommended dose of 2 mg/kg, with responses lasting 1.4 to 8.5 months. The most common side effects associated with pembrolizumab (occurring in ≥20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Ipilimumab was approved much earlier, in 2011, for the treatment of patients with unresectable or metastatic disease. The CTLA-4 inhibitor was approved based on a 676-patient study comparing the agent with or without the gp100 vaccine and the vaccine alone. In the trial, patients on either arm receiving ipilimumab experienced an OS of approximately 10 months, compared with 6.5 months with the vaccine alone. The most common side effects (≥5%) associated with the agent are fatigue, diarrhea, pruritus, rash, and colitis.

Outside of KEYNOTE-006, pembrolizumab and ipilimumab seem headed down different paths.

Ipilimumab has continued to show long-term benefit and is now moving into later lines of therapy. According to Clinicaltrials.gov, there are 76 open studies looking at the agent in melanoma.

Conversely, pembrolizumab is being examined in 18 open melanoma studies — further indicating its expansion into other tumor types.

Pembrolizumab has demonstrated activity and acceptable safety in separate phase Ib studies of metastatic triple-negative breast cancer and classical Hodgkin lymphoma. These studies were presented at the 2014 SABCS and ASH meetings, respectively.