T-VEC/Pembrolizumab Combination Misses Primary End Point in Unresectable Melanoma


The results of the phase 3 MASTERKEY-265 trial show that there is still an unmet need for patients who are refractory to pembrolizumab and anti–PD-1 inhibitors.

The addition of talimogene laherparepvec (T-VEC) to pembrolizumab (Keytruda) did not statistically improve progression-free survival (PFS) or overall survival (OS) in patients with advanced melanoma, according to phase 3 findings from the MASTERKEY-265 trial (NCT02263508).1 However, the combination demonstrated a viable safety profile and is still under active investigation in other settings.

Overall, T-VEC was not linked to significant improvements in PFS (HR, 0.86; 95% CI, 0.71-1.04; P = .13) or OS (HR, 0.96; 95% CI, 0.76-1.22; P = .74). It was associated with numerical improvements in secondary end points including objective response rate (ORR) and durable response rate (DRR). The ORR between the 2 arms was 48.6% vs 41.3%; the DRR was 42.2% vs 34.1%, respectively. These improvements were not deemed significant.

Moreover, grade 3 or greater adverse events were reported in 0.7% of patients in the T-VEC/pembrolizumab arm and in 19.5% of patients in the placebo/pembrolizumab arm, indicating that the combination’s safety profile was comparable to that of each agent alone.

“The combination of T-VEC-pembrolizumab did not statistically improve PFS or OS relative to placebo/pembrolizumab,” Gary K. Schwartz, MD, of Columbia Medical School, stated in a responding editorial.1 “However, T-VEC-pembrolizumab demonstrated a numerical progression-free survival improvement and safety was consistent with the known safety profiles of each agent.”

Immune checkpoint inhibitors have greatly advanced the quality of care available to patients with advanced melanoma. However, resistant to this treatment modality is still common. Agents designed to increase T-cell infiltration, such as T-VEC, are thought to represent a potential way to mitigate resistance and increase immune responses.

Based on positive complete response rates with the combination in a phase 1b trial, a multicenter, double-blind, placebo-controlled, randomized phase 3 study was designed.

The MASTERKEY-265 trial enrolled 692 patients with stage IIIB-IVM1c unresectable melanoma. They were randomly assigned 1:1 to receive either T-VEC-pembrolizumab (n = 346) or placebo-pembrolizumab (n = 346). In both arms, pembrolizumab was administered intravenously every 3 weeks at 200 mg. In the experimental arm, patients received T-VEC at a dose of at most 4 × 106 plaque-forming unit (PFU) followed by no more than 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter.

Study authors concluded by acknowledging that there is still a need for combination strategies to improve the efficacy of already approved therapies without compounding toxicities—especially with patients whose disease is refractory to anti–PD-1 inhibition.

T-VEC is currently under investigation in several other combination trials across different disease types, and in patients with unresectable, metastatic or recurrent HER2-negative breast cancer, high-risk and treatment naïve melanoma, non-melanoma skin cancers, locally advanced or metastatic sarcoma, soft-tissue sarcomas, advanced pancreatic cancer, squamous cell cancer, and peritoneal surface malignancies.2


  1. Chesney JA, Ribas A, Long GV, et al. Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. Published online ahead of print. J Clin Oncol. 2022;JCO2200343. doi:10.1200/JCO.22.00343
  2. Clinical trials using talimogene laherparepvec. National Cancer Institute. Accessed September 6, 2022. https://bit.ly/3AUXJNV
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