Background
Patients with advanced melanoma progressing on anti–PD-1 therapy have limited and toxic treatment options. RP1 (vusolimogene oderparepvec) is an HSV-1–based oncolytic immunotherapy expressing GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). The registration-intended cohort from the IGNYTE trial tested RP1 combined with nivolumab in melanoma patients with confirmed progression while being treated with anti–PD-1 mono- or combination therapy.
Methods
Melanoma patients with confirmed progressive disease during anti–PD-1 ± anti–CTLA-4 for ≥8 weeks as the last prior treatment were enrolled (NCT03767348). RP1 was given intratumorally at 1x106 PFU/mL, then Q2W (1x107 PFU/mL; ≤7 doses) with IV nivolumab (240mg); nivolumab was then given alone (240mg Q2W or 480mg Q4W) for ≤2 years, with further RP1 allowed if indicated. The primary endpoint was ORR by independent review (IR) using modified RECIST (mRECIST v1.1); responses were also assessed by RECIST v1.1. Tumor biopsies were collected at screening and D43; IHC was performed for CD8+ T-cells and PD-L1.
Results
Of the 140 enrolled patients, 48.6% had stage IVb/c/d disease, 65.7% had primary anti–PD-1 resistance, 56.4% were PD-L1 negative, and 43.6% had prior anti–PD-1 + anti–CTLA-4. Confirmed ORR by IR was 33.6% (15.0% CR) by mRECIST v1.1 (32.9% by RECIST v1.1). Responses were of both injected and non-injected, including visceral, lesions, with similar frequency, depth, and kinetics. Among responders, 98.7% of injected (n=79) and 98.4% of non-injected lesions (n=123) had reductions, with 93.7% and 79.7%, respectively, reduced by ≥30%. The median DOR (range) was 21.6 months (1.2–43.5 months). ORR was 35.9% in patients with primary anti–PD-1 resistance, 27.7% in patients who received prior anti–PD-1 + anti–CTLA-4, 52.3% in PD-L1 positive and 25.3% in PD-L1 negative patients. One- and two-year OS rates (95% CI) were 75.3% (66.9–81.9) and 63.3% (53.6–71.5); median not reached. Most treatment-related AEs were grade 1–2 (grade 3–4; 12.8%). Biomarker assessment showed immune activation as measured by increased CD8+ T-cell infiltration (20/50) and PD-L1 levels (CPS; 26/49) vs baseline in available biopsies, with additional biomarker analyses to be presented.
Conclusions
RP1 + nivolumab was well tolerated and provided durable, clinically meaningful antitumor activity in patients with advanced melanoma and confirmed disease progression during prior anti–PD-1 treatment. This included a 35.9% ORR in patients with primary refractory disease. Biomarker data demonstrated that RP1 + nivolumab increased immune activation markers consistent with the ability to treat primary refractory disease.
Trial Registration
NCT03767348.
Ethics Approval
The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the institutional review board/ethics committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.