An international phase III trial showed no significant benefit of pembrolizumab (Keytruda) plus intratumoral talimogene laherparepvec (T-VEC, Imlygic) compared with pembrolizumab alone Improve survival in unresectable melanoma.
Although the combination improved median progression-free survival (PFS) by nearly 6 months (14.3 months vs 8.5 months), the difference did not reach statistical significance (P=0.13). The median overall survival (OS) in the combination arm was 49.2 months compared to the median overall survival (OS) in the pembrolizumab and placebo arm (P=0.74).
Analyses involving three pre-specified subgroups – US patients, patients with low baseline lactate dehydrogenase (LDH), and patients with smaller baseline tumor volume – all support This combination, Jason A. Chesney, MD, PhD, Brown Cancer Center, University of Louisville, Kentucky, and colleagues write in the Journal of Clinical Oncology.
“Although the combination of T-VEC-pembrolizumab did not confer an OS benefit compared to placebo-pembrolizumab in first-line treatment of advanced melanoma, the combination Anti-PD-1 inhibitors are actively being studied in patients with melanoma and other tumor types,” the authors noted in their concluding remarks.
The MASTERKEY-265 trial included a Phase Ib single-arm study evaluating the pembrolizumab-T-VEC combination in 21 patients with advanced melanoma. The results showed an objective response rate (ORR) of 62%, including a complete response (CR) in 43% of patients. The results support the decision to proceed with a randomized phase III trial to compare pembrolizumab plus T-VEC with pembrolizumab and placebo.
MASTERKEY-265 may provide a patient population more similar to the real world, said Jeffrey Weber, MD, of NYU Langone Health in New York City, who was not involved in the study.
“As they say in the UK, ‘there’s a lot of people slipping on cups and lips” and the stage III population is a better assessment of the real world population, which may have higher disease burden, and therefore less chance of an inflamed tumor having an impact on the remaining disease,” Weber told Medicine Today Page via email.
Findings in low-risk patients – lower baseline LDH and disease burden – benefit more from a combination that supports the idea, he added. IIIB-IV M1c unresectable melanoma. Researchers in 21 countries put 692 Patients were randomized 1:1 to two treatment arms with balanced baseline characteristics.
The trial had dual primary endpoints of PFS and OS. Primary PFS The median follow-up for the analysis was 25.58 months, and the median follow-up for the primary OS analysis was 31 months.
The median PFS difference in favor of the combination was 5.8 months, reducing the 14% were at risk of progression or death (95% CI 0.71-1.04).
About 23% of patients in the US The combined risk (95% CI 0.37-0.92). The results also favored patients with a baseline LDH equal to or below the upper limit of normal (HR 0.76, 95% CI 0.59-0.99) and a baseline sum of target lesion longest diameter (SLD) equal to or below Combination of patients below median (HR 0.70, 95% CI 0.51-0.96).
The hazard ratio for combination versus placebo in OS analysis was 0.96 (95% CI 0.76 -1.22). In contrast to the PFS results, a pre-specified subgroup analysis did not show an improvement in OS with the combination.
Tumor response to treatment was a secondary endpoint. ORR, The CR and durable response rates were 48.6%, 17.9% and 42.2%, respectively, while the ORR, CR and durable response rates for pembrolizumab-placebo were 41.3%, 11.6% and 34.1%.
Adverse events were consistent with known side effects of T-VEC and pembrolizumab. Grade 3 or higher adverse events occurred in 20.7% of patients in the combination group and 19.5% in the placebo group.
In their Discussion, the authors review the lack of significant benefit of pembrolizumab-T-VEC. They argue that the pivotal trial leading to FDA approval of T-VEC may have included patients with less aggressive disease features. Furthermore, in MASTERKEY -265 Intermediate repair The T-VEC dosing schedule was modified to align with pembrolizumab dosing.
Differences in PFS in US-enrolled patients may reflect more LDH ≤ upper limit of normal and lower limit of SLD compared with non-US patients.
Lower incidence of false progression with MASTERKEY-265 compared to the pivotal trial leading to T-VEC agrees. The lower rate of pseudoprogression was close to that observed with single-agent pembrolizumab.
The authors also noted that the control group performed better compared to historical data for single-agent pembrolizumab. For example, in the KEYNOTE-006 and KEYNOTE-001 trials, the 2-year OS for pembrolizumab-placebo was 66% and 58% and 60%, respectively.
Results MASTERKEY-265 should be sufficient to conclude the evaluation of T-VEC versus immune checkpoint inhibitors, Weber said.
“I think this is a well-done study. They explicitly answer the question whether T-VEC increases the benefits of PD-1 blockade,” he said. “Not that it’s a limitation, but Pembroke is a very potent drug, so better do it to set a high bar.”
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DISCLOSURE
The study was supported by Amgen and Merck.
Chesney disclosed relationships with Amgen, Replimune, Iovance Biotherapeutics and Bristol Myers Squibb. Other co-authors have also been disclosed by reporters.
