Novel Pembrolizumab Combos Show Promising Responses in Melanoma

Roger Dansey, MD

Two separate early phase clinical trials exploring pembrolizumab (Keytruda)-containing immunotherapy combinations have shown objective response rates (ORRs) of over 50% in patients with advanced melanoma, according to findings presented during the late-breaking abstract session at the 2015 Society for Melanoma Research (SMR) Congress.

In a phase I/II trial, the combination of the PD-1 inhibitor pembrolizumab and the IDO-1 inhibitor epacadostat showed an ORR of 53%. In a phase Ib trial, the ORR with pembrolizumab and the oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) was 56.3%.

“The combination data presented at SMR, including Keytruda combined with epacadostat or Imlygic, may further our goal of improving outcomes without substantial increased toxicity,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, the company developing pembrolizumab, said in a statement.

In the first ongoing study, labeled KEYNOTE-037, 60 patients with various advanced cancers received the combination of pembrolizumab and epacadostat. At the SMR analysis, data were available from 19 patients with advanced melanoma. Patients received pembrolizumab at 2 mg/kg or a fixed 200 mg dose every 3 weeks. Epacadostat was administered at four doses twice daily (20, 50, 100, or 300 mg).

In addition to responses in the trial, which included 3 complete responses, 21% of patients had stable disease (SD). The disease control rate (ORR plus SD) with the combination was 74%. Data for other efficacy endpoints were not yet available at the time of the analysis.

Treatment-related adverse events (AEs) were consistent with previous reports for pembrolizumab. Across all tumor types, grade 3 AEs were experienced by 15% of patients. The most common grade 3 AEs with the combination were rash (8%), arthralgia (2%), AST increased (2%), mucosal inflammation (2%), and nervous system disorder (2%).

Altogether, 3 patients discontinued treatment due to AEs (grade 3 arthralgia, AST increase, and grade 2 nervous system disorder). There were not any grade 4 treatment-related AEs or deaths with the combination.

Based on earlier assessments of the study, Incyte, which develops epacadostat, and Merck launched a phase III trial to explore the combination as a frontline therapy for patients with advanced melanoma. The study is expected to begin in the first half of 2016.

“The initiation of this large phase III study with Incyte in the first-line advanced melanoma treatment setting is an important addition to our robust immunotherapy clinical development program for Keytruda,” said Dansey.

In the second ongoing phase Ib study, efficacy data were analyzed from 16 evaluable patients with previously untreated, unresected advanced melanoma. Pembrolizumab was administered at 200 mg every 2 weeks while T-VEC was given at up to 4 mL of 10⁶ PFU/mL for the first dose followed by 10⁸ PFU/mL every two weeks.

On top of the responses, which consisted of partial responses and 2 complete responses, 12.5% of patients also had SD. The disease control rate was 68.8% (95% CI, 11-58.7). Other efficacy endpoints were not yet mature at the time of the analysis.

Grade 1/2 AEs occurred in all 21 patients who were evaluable for the safety analysis. The most frequent all-grade AEs were fatigue (52%), pyrexia (48%), chills (43%), rash (38%), headache (33%), and nausea (33%). Grade 3 AEs, regardless of cause, included headache (5%) and diarrhea (5%). No dose-limiting toxicities were reported.

“T-VEC plus pembrolizumab was well tolerated, and we observed no dose-limiting toxicity,” investigator Georgina V. Long, BSc, PhD, MBBS, associate professor at the University of Sydney in Australia, said when an initial analysis of safety was presented at the European Cancer Congress. “Treatment-related adverse events were mostly grade 1/2. The combination of T-VEC and pembrolizumab is feasible and warrants further investigation.”

Both T-VEC and pembrolizumab are approved as single-agents for patients with melanoma. T-VEC is approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Pembrolizumab is approved for patients with advanced or unresectable melanoma following progression on prior therapies.

Based on the findings from the phase Ib study, Merck and Amgen, the developer of T-VEC, are planning a phase III study for the combination in patients with regionally or distantly metastatic melanoma. Additionally, the companies announced plans to explore the combination in a phase I open-label trial for patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

"We believe that talimogene laherparepvec has potential in several cancer types based on its proposed mechanism of action to initiate tumor antigen release and presentation, important steps in activating a systemic anti-tumor immune response," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said when the collaboration was announced. "We will discuss the design of the phase III melanoma trial with global regulators and look forward to collaborating with Merck on this study."

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