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 and improves overall survival (OS) in advanced melanoma. This phase 1b/2 study of T + I evaluates safety and efficacy in unresected stage IIIB-IV melanoma.
The 1° endpoint for phase 2 is ORR by immune-related response criteria. Key 2° endpoints are safety, progression-free survival, time to response, duration of response, and OS. Key eligibility criteria are unresectable stage IIIB-IV melanoma, ≤1 prior treatment (tx) if BRAF WT or 2 prior tx if BRAF MT, measurable/injectable tumor(s), and no symptomatic autoimmunity or clinically significant immunosuppression. T was given ≤4x106 plaque forming units (PFU) on d1, w1; ≤4x108 PFU 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 ORR interim analysis (IA) 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 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; table). 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 AEs. A grade 5 autoimmune hepatitis occurred in the T + I arm (attributed to I per investigator).
|Confirmed* n (%)||Unconfirmed^ n (%)|
|T + I n = 42||I n = 40||T + I n = 42||I n = 40|
|ORR - n (%) (95% CI)||15 (35.7) (21.6, 52.0)||7 (17.5) (7.3, 32.8)||21 (50.0) (34.2, 65.8)||11 (27.5) (14.6, 43.9)|
|CR||4 (9.5)||4 (10.0)||6 (14.3)||7 (17.5)|
|PR||11 (26.2)||3 (7.5)||15 (35.7)||4 (10.0)|
|SD||13 (31.0)||11 (27.5)||7 (16.7)||7 (17.5)|
|PD||6 (14.3)||5 (12.5)||11 (26.2)||17 (42.5)|
|UE||5 (11.9)||13 (32.5)||0 (0.0)||1 (2.5)|
|DCR - n (%) (95% CI)||28 (66.7) (50.5, 80.4)||18 (45.0) (29.3, 61.5)||28 (66.7) (50.5, 80.4)||18 (45.0) (29.3, 61.5)|
*Confirmation of initial CR/PR/PD by subsequent assessment by ≥4 w apart. A CR/PR without confirmation is classified as SD and an unconfirmed PD is classified as UE.
^Unconfirmed is response or PD without confirmation requirement.
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; UE: unable to evaluate; DCR: disease control rate (SD or better).
ORR was higher for T + I vs I alone at this IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T + I arm.
Clinical trial identification
Legal entity responsible for the study
J. Chesney: Advisory Board: Amgen Inc. Institution receives funds for clinical trial costs from Amgen Inc. F. Collichio: Consultant for Amgen Inc. Institution receives funding for clinical trials from Amgen Inc. R.H.I. Andtbacka: Received honoraria from Amgen Inc., Merck, and Provectus. I. Puzanov: Consultant for Amgen Inc. M. Milhem: Advisory boards for EMD Serono, Genentech, Amgen Inc., and Novartis. O. Hamid: Consultant to Amgen Inc., Novartis, Roche, BMS, Merck. Speaker for BMS, Genentech, Novartis, Amgen, Inc. Research support from AstraZeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. Y. Saenger: Receive funding through a preclinical award from Amgen Inc. Recipient of an academic/industry paartnership award funded by Amgen Inc. and the Melanoma Research Alliance. Served on melanoma research advisory boards for Amgen Inc. more than 12 months ago. M. Ross: Research grants/support from GSK, Amgen Inc., Merck, and Provectus. Honoraria or consulting fees from Amgen Inc., GSK, and Merck. Speaker's bureaus for GSK and Merck. Compensated for travel expenses from GSK, Amgen Inc., Merck, Provectus, and Caladrius. L. Chen: Employee and stockholder of Amgen Inc. J.J. Kim: Employee of Amgen Inc. H.L. Kaufman: Advisory boards for Amgen Inc., EMD Serono, Merck, Prometheus, and Sanofi. Speaker's bureau for Merck but returns all honoraria to his institution. Research funding from Amgen Inc., BMS, EMD Serono, Merck, Prometheus, and Viralytics. All other authors have declared no conflicts of interest.
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