Interim safety and efficacy of a randomized (1:1), open-label phase 2 study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected, stage IIIB-IV melanoma

Abstract

T is a herpes simplex virus 1‐based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM‐CSF and stimulate antitumor immune responses. I (anti‐CTLA‐4 Ab) blocks inhibition of antitumor T‐cells. Both T and I monotherapy are approved in the US and EU for the treatment of advanced melanoma. The primary endpoint for the phase 2 part was ORR by immunerelated response criteria. Key secondary endpoints are safety, progression‐free survival, time to response, duration of response, and survival. Key entry criteria are unresectable stage IIIB‐IV melanoma, with ≤2 prior tx, measurable/injectable tumor(s), and no symptomatic autoimmunity or clinically significant immunosuppression. T was given ≤4 ml x 106 plaque forming units (PFU)/ml on d1 w1; ≤4 ml x 108 PFU/ml d1 w4, then q2w in arm 1 until no injectable tumors, disease progression, or intolerance. I started with the 3rd dose of T in arm 1 or alone in arm 2 at 3 mg/kg IV q3w x 4. An interim analysis (IA) for efficacy was performed when 82 patients (pts) had ≥48 w of follow up. 173 pts were randomized: 88 T+I; 85 I. Characteristics for all pts were similar: 54% stage IIIB‐IVM1a, 45% IVM1b/c. Median follow up time for 82 pts in the efficacy set was 61.2 w (range: 0.14‐113.9). Confirmed ORR was 35.7% (T+I) and 17.5% (I); unconfirmed ORR was 50% (T+I) and 27.5% (I). Of 165 pts in the safety set (85 T+I, 80 I), most common adverse events (AEs) for T+I, I (%) were fatigue (52, 39), chills (51, 3), diarrhea (39, 34), pyrexia (39, 8), rash (39, 31) and pruritus (38, 35). 20% T+I and 18% I pts had grade 3/4 tx‐related AE. A grade 5 autoimmune hepatitis occurred in the T+I arm (investigator attributed to I). ORR was higher for T+I versus I alone at this IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T+I arm.