T-VEC Plus Pembrolizumab Generates Promising Responses, Safety in PD-1–Refractory Advanced Melanoma

Adding talimogene laherparepvec (T-VEC) to pembrolizumab (Keytruda) led to encouraging responses with a manageable safety profile in patients with advanced melanoma who progressed on prior anti–PD-1 therapy, most notably in the adjuvant setting, according to primary findings from the phase 2 MASTERKEY-115 trial (NCT04068181).

In data presented at the 2022 ASCO Annual Meeting, patients who received anti–PD-1 therapy in a locally recurrent or metastatic setting and had progressive disease (PD) within 12 weeks of the last anti–PD-1 dose had an objective response rate (ORR) of 3.8% (95% CI, 0.1%-19.6%) in cohort 1 (n = 27) and 6.7% (95% CI, 0.2%-32.0%) in cohort 2 (n = 15). Cohort 1 included patients with primary resistance while cohort 2 consisted of those acquired resistance.

In cohorts 3 (n = 15) and 4 (n = 15), which included patients who received adjuvant anti–PD-1 therapy and were disease-free for fewer than 6 months or at least 6 months prior to confirmed PD, respectively, the ORRs were 40% (95% CI, 16.3%-67.7%) and 46.7% (95% CI, 21.3%-73.4%), respectively.

“T-VEC plus pembrolizumab treatment showed ORRs of 40.0% to 46.7% in patients with advanced melanoma who progressed on prior anti–PD-1 in the adjuvant setting, while ORRs of 0% to 6.7% were observed in patients who progressed on prior PD-1 in the locally recurrent or metastatic setting,” senior study author Jason Chesney, MD, PhD, director of the J. Graham Brown Cancer Center at the University of Louisville, said in a presentation of the data. “Safety results were consistent with the patients’ underlying disease and the known safety profiles of either agent alone, as well as the combination.”

An unmet need exists for patients with advanced or metastatic melanoma who progress on immunotherapy despite advances that have been with anti–PD-1-based therapy. Although the population of patients with recurrent disease who have received prior adjuvant anti–PD-1 is growing, limited trials are available for this population.

T-VEC is an oncolytic viral intratumoral therapy designed to produce granulocyte-macrophage colony-stimulating factor. When paired with the PD-1 inhibitor pembrolizumab, T-VEC may overcome immunotherapy failure.

The phase 2, open-label, multicenter trial enrolled 71 patients across 26 international sites from January 2020 to February 2021. The median patient age was 65 years (range, 33-89).

Eligible patients were at least 18 years of age and had histologically confirmed, unresectable, or metastatic stage IIIB through IV M1d melanoma that was measurable and injectable; an ECOG performance status of 0 or 1; and progressed on anti–PD-1 therapy directly before enrollment. Prior anti–PD-1 therapy must have been given for at least 2 to 3 consecutive cycles within an 8-week period.

Patients received T-VEC at standard dose and pembrolizumab at 200 mg intravenously every 3 weeks.

The primary end point was ORR per modified RECIST v1.1 criteria. Key secondary end points were immune complete response (iCR) rate, immune progression-free survival (iPFS), and safety. Treatment decisions were made based on modified immune-related response criteria.

Of the 71 evaluable patients, 37 (52.1%) had stage IVM1b through IVM1d disease, 30 (42.3%) had confirmed PD-L1–positive tumors (combined positive score ≥ 1%), 20 (28.2%) had a BRAF V600 mutation, and 21 (29.6%) had lactate dehydrogenase levels above 1 upper limit of normal.

The primary analysis was performed 24 weeks after the last patient was enrolled. As of the data cutoff of August 19, 2021, 47 (65.3%) patients remained on study.

Additional results demonstrated a median iPFS of 5.5 months (95% CI, 2.8-not evaluable [NE]) and 8.2 months (95% CI, 2.7-15.0) in cohorts 1 and 2, respectively. The median PFS was not evaluable in cohorts 3 and 4.

The iCR rates were 0% in cohorts 1 and 2 and 13.3% each in cohorts 3 (95% CI, 1.7%-40.5%) and 4 (95% CI, 1.7%-40.5%).

Fifty-four (76.1%) patients experienced any-grade treatment-related adverse effects (TRAEs); the most common were pyrexia (29.6%), and fatigue and influenza-like illness (15.5% each). Nine (12.7%) patients experienced 3 grade 3 or greater TRAEs.

“Further studies with a larger sample size are needed to determine the potential role for the T-VEC plus pembrolizumab combination strategy in patients with advanced melanoma who have progressed on or after treatment with anti–PD-1 inhibitors,” Chesney concluded.

Reference

Gastman B, Robert C, Gogas H, et al. Primary analysis of a phase 2, open-label, multicenter trial of talimogene laherparepvec (T-VEC) plus pembrolizumab (pembro) for the treatment (Tx) of patients (pts) with advanced melanoma (MEL) who progressed on prior anti–PD-1 therapy: MASTERKEY-115. J Clin Oncol. 2022;40(suppl 16):9518. doi:10.1200/JCO.2022.40.16_suppl.9518