Final 5-year results of the phase II, multicenter, randomized, open-label trial of talimogene laherparepvec (T-VEC) neoadjuvant treatment (Tx) plus surgery vs immediate surgery in patients (pts) with resectable stage IIIB-IVM1a melanoma (MEL)

The risk of recurrence after resection remains high for pts with advanced MEL. Neoadjuvant therapies before surgery shrink tumors, reduce recurrence risks, and potentially improve long-term outcomes. T-VEC, an intralesional oncolytic viral immunotherapy, selectively replicates in MELs and enhances the antitumor immune response. The primary analysis (NCT02211131) reported a 2-y recurrence-free survival (RFS) of 29.5% for T-VEC + surgery and 16.5% for surgery alone (overall HR 0.75; 80% CI 0.58-0.96) in pts with resectable stage IIIB-IVM1a MEL, persisting at 3 y (overall HR 0.74; 80% CI 0.57-0.95) (Dummer Nat Med 2021). Here, we report the final 5-y analysis. Pts with resectable stage IIIB-IVM1a MEL and ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions were randomized 1:1 to six doses of neoadjuvant T-VEC, then surgery (Arm 1) or immediate surgery alone (Arm 2). T-VEC was administered at standard doses until surgery, no remaining injectable tumors, or intolerance. The investigator’s choice adjuvant Tx was allowed and used similarly in both arms. The final RFS was analyzed 5 y after randomization. As of May 30, 2022, the median follow-up for all 150 pts was 63.3 mo (range 0.1-86.8). For Arm 1 vs Arm 2, the 5-y KM estimates of RFS were 22.3% and 15.2% (HR 0.76, 80% CI 0.60-0.97), the 5-y KM estimates of EFS were 43.7% and 27.4% (HR 0.57, 80% CI 0.43-0.76), and the 5-y KM estimates of OS were 77.3% and 62.7% (HR 0.54, 80% CI 0.36-0.81). HRs for local RFS, regional RFS, and distant metastases-free survival (DMFS) were 0.82 (80% CI 0.64-1.06), 0.81 (80% CI 0.62-1.05), and 0.73 (80% CI 0.57-0.94), respectively. No new safety signals were detected. In the final readout of the largest randomized trial of neoadjuvant Tx in pts with resectable stage IIIB-IVM1a MEL, we report durable improvements in RFS, EFS, DMFS, and OS at 5 y with neoadjuvant T-VEC + surgery vs standard surgery. These results provide proof of concept that an intratumorally administered oncolytic agent can elicit a meaningful long-term systemic effect and support the use of neoadjuvant T-VEC + surgery in this pt population.