January 2016, Vol. 3, No. 1

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Pembrolizumab Combination Shows Robust Antitumor Activity

Christine Anderson


In 3 phase 1 and 2 studies, improved overall response rates (ORRs) were shown in patients with metastatic melanoma taking pembrolizumab (Keytruda) in combination with 3 other immunotherapies, including epa­cadostat, talimogene laherparepvec (Imlygic), and ipi­limumab (Yervoy). All 3 studies demonstrated significant antitumor activity. In addition, long-term follow-up data in a phase 3 study indicated improved ORR and progression-free survival (PFS) in pembrolizumab compared with ipilimumab.

The KEYNOTE-037 trial is an ongoing, phase 1/2 study evaluating pembrolizumab (2 mg/kg or 200 mg every 3 weeks) plus epacadostat (25, 50, 100, or 300 mg twice daily) in patients with advanced cancers. Early data showed that in 19 patients, this combination therapy demonstrated an ORR of 53%; there were 3 complete responses (CRs) and 7 partial responses (PRs). Grade 3 treatment-related adverse events included rash (8%), arthralgia (2%), aspartate aminotransferase (AST) increase (2%), mucosal inflammation (2%), and nervous system disorder (2%). No grade 4 adverse events or deaths were observed.

Another ongoing phase 1b study, MASTERKEY-265, is assessing the safety, efficacy, and tolerability of pembrolizumab plus talimogene laherparepvec—a herpes simplex virus-1–based oncolytic immunotherapy—in patients with previously untreated and unresected advanced melanoma. In the 16 patients evaluated, pembrolizumab (200 mg every 2 weeks) plus talimogene laherparepvec (up to 4 mL of 106 PFU/mL, followed by 108 PFU/mL every 2 weeks) resulted in an unverified ORR of 56.3% (95% confidence interval [CI], 19.8-70.1), with 2 CRs and 7 PRs. The most common adverse events of any grade were fatigue (52%), pyrexia (48%), chills (43%), rash (38%), headache (33%), and nausea (33%); grade 3 adverse events included headache (5%) and diarrhea (5%).

The third study, KEYNOTE-029, is an ongoing phase 1/2 study of patients with advanced melanoma receiving pembrolizumab plus low-dose ipilimumab. Researchers are investigating whether lower doses of ipilimumab improve patients’ tolerance of this combination. Of the 72 evaluable patients, pembrolizumab (2 mg/kg every 3 weeks) plus low-dose ipilimumab (1 mg/kg every 3 weeks for 4 doses) exhibited an ORR of 56% (95% CI, 43-67), with 3 CRs and 37 PRs. Grades 3 and 4 treatment-related adverse events were observed in 36% of patients, including lipase increase (8%), amylase increase (6%), alanine transferase increase (6%), AST increase (4%), rash (3%), and diarrhea (1%). Grades 3 and 4 immune-mediated adverse events included thyroiditis, hypophysitis, type 1 diabetes mellitus, pneumonitis, colitis, hepatitis, pancreatitis, severe skin reactions, and renal events.

Phase 3 trials are planned for each of these studies based on these results. In addition, recent data from KEYNOTE-006, an open-label, randomized, phase 3 study of patients with unresectable stage 3 or 4 advanced melanoma, showed that patients receiving pembrolizumab as a single agent experienced improved ORR and PFS compared with ipilimumab in ipilimumab-naïve patients. These findings are based on 6 additional months of follow-up. PFS rates for pembrolizumab at 12 months were 37.7% in the cohort receiving the drug every 2 weeks, and 36.3% in the cohort receiving pembrolizumab every 3 weeks, compared with 17.2% in patients receiving ipi­limumab (hazard ratio [HR], 0.60 [95% CI, 0.49-0.74] and HR, 0.59 [95% CI, 0.48-0.73], respectively). The ORR was 36.2% and 36.1% in patients receiving pembrolizumab every 2 weeks or every 3 weeks, respectively (95% CI, 30.6-42.1 and 95% CI, 30.4-42.1, respectively), compared with 12.9% for ipilimumab (95% CI, 9.2-17.5).

New patient-reported, health-related, quality-of-life outcomes showed that physical, emotional, cognitive, and social functioning were better maintained in patients receiving pembrolizumab than in patients receiving ipilimumab. In addition, baseline fatigue, pain, dyspnea, appetite loss, and diarrhea worsened to a lesser degree in patients receiving pembrolizumab than in patients receiving ipilimumab.

Merck & Co. Inc. Merck announces initial results for Keytruda® (pembrolizumab) with novel immunotherapy combinations from 3 investigational studies presented at the Society for Melanoma Research International Congress. www.mercknewsroom.com/news-release/prescription-medicine-news/merck-announces-initial-results-keytruda-pembrolizumab-novel. Published November 21, 2015. Accessed December 2, 2015.
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