As reported in the Journal of Clinical Oncology by Chesney et al, the phase III MASTERKEY-265 trial has shown no significant improvement in progression-free survival or overall survival with the addition of talimogene laherparepvec (T-VEC) to pembrolizumab in patients with advanced melanoma.

Study Details

The double-blind trial included 692 patients from sites in 21 countries with stage IIIB to IVM1c unresectable melanoma who had not received prior anti–PD-1 treatment. They were randomly assigned between March 2016 and April 2018 to receive T-VEC plus pembrolizumab (n = 346) or placebo plus pembrolizumab (n = 346). T-VEC was given at ≤ 4 x 10⁶ plaque-forming units (PFU) followed by ≤ 4 x 10⁸ PFU 3 weeks later, once every 2 weeks until dose 5, and once every 3 weeks thereafter. Pembrolizumab was given at 200 mg once every 3 weeks.

The dual primary endpoints were progression-free survival using modified Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review and overall survival.

Progression-Free and Overall Survival

Median follow-up for the primary progression-free survival analysis was 25.6 months (range = 0.3–45.8 months). Median progression-free survival was 14.3 months (95% confidence interval [CI] = 10.3–22.1 months) in the T-VEC/pembrolizumab group vs 8.5 months (95% CI = 5.7–13.5 months) in the pembrolizumab-alone group (hazard ratio [HR] = 0.86, 95% CI = 0.71–1.04, P = .13). Hazard ratios favored the combination group in three predefined subgroups: patients enrolled in the United States (0.59, 95% CI = 0.37–0.92); patients with baseline lactate dehydrogenase ≤ upper limit of normal (0.76, 95% CI = 0.59–0.99); and patients with baseline sum of the longest diameters of target lesions ≤ median (0.70, 95% CI = 0.51–0.96).  

At the second interim analysis for overall survival, the data monitoring committee indicated that the futility boundary had been crossed. Median follow-up was 31.0 months (range = 0.3–53.0 months). Median overall survival was not estimable in the T-VEC/pembrolizumab group vs 49.2 months (95% CI = 40.6 months–not estimable) in the pembrolizumab-alone group (HR = 0.96, 95% CI = 0.76–1.22, P = .74).

Objective response rates were 48.6% (complete response in 17.9%) vs 41.3% (complete response in 11.6%), durable response rates were 42.2% vs 34.1%, and median duration of response was 43.7 months (95% CI could not be estimated) vs not estimable.

Adverse Events

Treatment-related adverse events of any grade occurred in 88.4% of patients in the T-VEC/pembrolizumab group vs 74.6% of the pembrolizumab group, with the most common in the combination group being pyrexia (35.1% vs  5.0%) and fatigue (31.3% vs 22.2%). Grade ≥ 3 treatment-related adverse events occurred in 20.7% of the T-VEC/pembrolizumab group (most commonly, fatigue and diarrhea [in 5 patients each]) vs 19.5% of the pembrolizumab group (most commonly, increased aspartate aminotransferase [in 5 patients] and fatigue [in 4 patients]). Adverse events led to death in 13.1% vs 12.2% of patients and were considered related to treatment in four patients (1.2%) vs one patient (0.3%).

The investigators concluded, “T-VEC/pembrolizumab did not significantly improve progression-free survival or overall survival compared with placebo/pembrolizumab. Safety results of the T-VEC/pembrolizumab combination were consistent with the safety profiles of each agent alone.”

Jason A. Chesney, MD, PhD, of UofL Health-Brown Cancer Center, University of Louisville, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Amgen Inc and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.