Pembrolizumab Improves PFS, ORR Versus Chemotherapy in Phase II Melanoma Study

Eric Rubin, MD

The PD-1 inhibitor pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) by over 43% compared with chemotherapy as a treatment for patients with metastatic melanoma who were refractory to ipilimumab (Yervoy), according to findings from the KEYNOTE-002 study presented at the 2014 Society of Melanoma Research (SMR) Congress.

In the 3-arm phase II study, patients received pembrolizumab at 2 mg/kg (n = 180), 10 mg/kg (n = 181), or chemotherapy (n = 179). At six months, the PFS rates were 34% and 38% for the 2-mg/kg and 10-mg/kg doses, respectively. Compared with chemotherapy, the lower dose demonstrated a 43% improvement in PFS and the 10-mg/kg dose showed a 50% improvement. The study was designed with coprimary endpoints to assess PFS and overall survival (OS). OS data are anticipated in 2015. 

“These findings demonstrate pembrolizumab was superior to chemotherapy in helping more patients with ipilimumab-refractory advanced melanoma achieve progression-free survival,” Eric Rubin, MD, vice president, global clinical development for oncology, Merck Research Laboratories, said in a statement. “The comparative efficacy and safety data from the pivotal KEYNOTE-002 study validate and extend the findings from our earlier study in these difficult-to-treat patients, and we look forward to sharing data on overall survival at a future congress.”

In early September, the FDA approved pembrolizumab as a treatment for patients with metastatic melanoma following progression on prior therapies. The accelerated approval was based on response rates demonstrated in the 173-patient phase Ib KEYNOTE-001 study. At the recommended dose for pembrolizumab of 2 mg/kg, the ORR was 24%, with a response duration lasting from 1.4 to 8.5 months.

The KEYNOTE-002 study enrolled 540 patients with ipilimumab-refractory advanced melanoma. The chemotherapy utilized was investigator's choice and consisted primary of paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide. Pembrolizumab was administered every 3 weeks.

A majority of patients enrolled (83%) had M1c disease and 73% had received at least 2 prior systemic therapies. The secondary endpoints of the study focused on overall response rate (ORR), duration of response (DOR), and safety, with responses assessed using RECIST 1.1 criteria.

At a median follow-up of 10 months, no significant differences were observed between pembrolizumab doses (HR = 0.91; CI, 0.71-1.16; P <.44). At the 2-mg/kg dose, the ORR with pembrolizumab was 21% with a median DOR not yet reached. At the analysis, 92% of responses were ongoing. In the 10-mg/kg arm, the ORR was 25% and 87% of patients remained in response. A statistical different in DOR was not seen between pembrolizumab arms (P = .21).

Both pembrolizumab arms were shown be significantly superior to chemotherapy (P <.0001). The ORR in the chemotherapy arm was 4%, the median DOR was 37 weeks, and 63% of responses were ongoing at the time of the analysis.

An exploratory analysis showed that patients treated with pembrolizumab experienced fewer declines in health-related quality of life. At 12 weeks from baseline, the mean change was 6.52-6.57 for pembrolizumab versus chemotherapy.

Treatment-related grade 3/5 adverse events occurred in 11% of patients treated with the 2-mg/kg dose, 14% with 10-mg/kg, and 26% with chemotherapy. The rates of serious adverse events were 8%, 11%, and 10%, respectively. Treatment discontinuation as a result of adverse events occurred in 3% of patients treated with the 2-mg/kg dose, 7% with 10-mg/kg, and 6% in those receiving chemotherapy. One treatment-related death was reported in the pembrolizumab arm compared with none with chemotherapy.

“Our focus on evaluating Keytruda as a monotherapy is enabling Merck to rapidly advance the clinical development of our anti-PD-1 therapy,” Roy D. Baynes, MD, PhD, senior vice president, Global Clinical Development, Merck Research Laboratories, said in a press release. "We continue to expand our immuno-oncology clinical program with Keytruda both as monotherapy and in combination with other agents.”

Pembrolizumab is a highly selective humanized monoclonal IgG4 antibody directed against the PD-1 receptor on the cell surface. The drug blocks the PD-1 receptor, preventing binding and activation of PD-L1 and PD-L2. This mechanism causes the activation of T-cell mediated immune responses against tumor cells.

Multiple clinical trials are currently underway exploring pembrolizumab across a variety of tumor types, including a phase II and III study investigating the agent for advanced melanoma. At this point, over 30 studies are exploring the drug.