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Pembrolizumab (Keytruda) plus intratumoral talimogene laherparepvec (T-VEC, Imlygic) did not significantly improve survival in unresectable melanoma as compared with pembrolizumab alone, an international phase III trial showed.

Although the combination improved median progression-free survival (PFS) by almost 6 months (14.3 vs 8.5 months), the difference did not achieve statistical significance (P=0.13). Median overall survival (OS) had yet to be reached in the combination arm as compared with a median of 49.2 months with pembrolizumab and placebo (P=0.74).

Analyses involving three prespecified subgroups -- U.S. patients, patients with lower baseline lactate dehydrogenase (LDH), and those with smaller baseline tumor volume -- all favored the combination, Jason A. Chesney, MD, PhD, of the University of Louisville Brown Cancer Center in Kentucky, and colleagues wrote in the .

"Although the combination of T-VEC-pembrolizumab did not result in OS benefit compared with placebo-pembrolizumab in the frontline treatment of advanced melanoma, this combination is still under active investigation in patients who are refractory to anti-PD-1 inhibitor therapy for melanoma and other tumor types," the authors noted in their concluding comments.

The trial included a that evaluated the pembrolizumab-T-VEC combination in 21 patients with advanced melanoma. The results showed an objective response rate (ORR) of 62%, including complete responses (CRs) in 43% of the patients. The results supported the decision to proceed with a phase III randomized trial to compare pembrolizumab plus T-VEC versus pembrolizumab and placebo.

MASTERKEY-265 probably provided a patient population more similar to real-world clinical practice, said Jeffrey Weber, MD, PhD, of NYU Langone Health in New York City, who wasn't involved with the study.

"As they say in the U.K., 'there's been many a slip twixt cup and lip,' and the phase III population was a better assessment of a real world population, in which there was likely a higher disease burden and thus less chance for an inflamed tumor to have an impact on the remaining disease," Weber told 番茄社区app via email.

The finding that lower-risk patients -- lower baseline LDH and disease burden -- benefited more from the combination support that viewpoint, he added.

The phase III trial limited enrollment to patients with previously untreated histologically confirmed stage IIIB-IV M1c unresectable melanoma. Investigators in 21 countries randomized 692 patients 1:1 to the two treatment arms, which had well-balanced baseline characteristics.

The trial had dual primary endpoints of PFS and OS. Median follow-up to the primary PFS analysis was 25.58 months and 31 months for the primary OS analysis.

The 5.8-month difference in median PFS in favor of the combination represented a 14% reduction in the risk for progression or death (95% CI 0.71-1.04).

About 23% of patients were enrolled in the U.S. A prespecified analysis of that subgroup revealed a 41% reduction in the hazard in favor of the combination (95% CI 0.37-0.92). Results also favored the combination for patients with baseline LDH at or below the upper limit of normal (HR 0.76, 95% CI 0.59-0.99) and patients with baseline sum of the longest diameters (SLD) of target lesions at or below the median value (HR 0.70, 95% CI 0.51-0.96).

The OS analysis yielded a hazard ratio of 0.96 for the combination versus placebo (95% CI 0.76-1.22). In contrast to the PFS results, analysis of the prespecified subgroups did not show improvement in OS with the combination.

Tumor response to treatment was a secondary endpoint. The ORR, CR, and durable response rate were 48.6%, 17.9%, and 42.2% with the combination, respectively, and 41.3%, 11.6%, and 34.1% with pembrolizumab-placebo.

Adverse events were consistent with the know side effects of T-VEC and pembrolizumab. Grade ≥3 adverse events occurred in 20.7% of patients in the combination arm and 19.5% of patients in the placebo group.

In their discussion, the authors reviewed several possible explanations for the lack of significant benefit with pembrolizumab-T-VEC. They suggested that the pivotal trial that led to FDA approval of T-VEC probably included patients with less aggressive disease characteristics. Additionally, the administration schedule for T-VEC was modified in MASTERKEY-265 to align with pembrolizumab dosing.

The difference in PFS among U.S.-enrolled patients probably reflected the larger number of U.S. patients with LDH ≤ the upper limit of normal and lower SLD as compared with non-U.S. patients.

MASTERKEY-265 had a low incidence of pseudoprogression as compared with the pivotal trial that led to T-VEC approval. The lower rate of pseudoprogression approximated the rate observed with single-agent pembrolizumab.

The authors also noted that the control arm performed better as compared with historical data with single-agent pembrolizumab. For example, the 2-year OS for pembrolizumab-placebo was 66% as compared with 58% and 60%, respectively, in the and trials.

The results of MASTERKEY-265 should be sufficient to end the evaluation of T-VEC with immune checkpoint inhibitors, said Weber.

"I thought it was a well done study. They definitively answered the question of whether T-VEC added to the benefit of PD-1 blockade," he said. "Not that it's a limitation, but pembro is a very effective drug, so doing better set a high bar."

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