In a phase II trial reported in the Journal of Clinical Oncology, Robert H.I. Andtbacka, MD, and colleagues found that intratumoral injection of the oncolytic RNA virus Coxsackievirus A21 (V937) was well tolerated and produced responses in some patients with unresectable stage III or stage IV melanoma.
Robert H.I. Andtbacka, MD
Study Details
In the U.S. multicenter trial—conducted between December 2011 (first patient visit) to January 2015 (last patient discontinued)—57 patients received a total V937 dose of up to of 3 x 108 TCID-50 (50% tissue culture infectious dose) in a maximum 4.0 mL volume by intratumoral injection. Ten V937 injections were to be administered between days 1 and 127. Response and disease progression were determined using contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and categorized according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Overall, 61% of patients had stage IV disease. The primary endpoint was 6-month progression-free survival.
Key Findings
Overall, 57 patients received one or more V937 treatments; 40 (70.2%) received ≥ 80% and 17 (29.8%) received < 80% of planned injections.
Progression-free survival at 6 months on irRECIST was 38.6% (95% confidence interval [CI] = 26.0%–52.4%). Median progression-free survival was 5.7 months (95% CI = 2.8–11.1 months); Kaplan-Meier estimated rates at 6, 9, and 12 months were 46.1%, 43.9%, and 32.9%, respectively.
Median overall survival was 25.6 months (95% CI = 16.7–33.7 months), including 26.6 months (95% CI = 25.6 months–not reached) among patients with stage IIIC or IVM1a disease vs 16.1 months (95% CI = 9.5–17.3 months) among those with stage IVM1b or M1c disease. Overall survival at 12 months was 75.4% (95% CI = 62.1%–84.7%).
Complete or partial response was observed in 22 (38.6%) of patients including unconfirmed responses, with confirmed response in 16 (28.1%); responses lasted for ≥ 6 months in 12 responding patients (54.5%).
KEY POINTS
- Progression-free survival at 6 months on irRECIST was 38.6%. Median progression-free survival was 5.7 months; Kaplan-Meier estimated rates at 6, 9, and 12 months were 46.1%, 43.9%, and 32.9%, respectively.
- No treatment-related grade ≥ 3 adverse events were observed. The most common grade 1 or 2 treatment-related adverse events were injection site pain, fatigue, and chills.
Regression of melanoma was observed in both injected and noninjected target lesions. A reduction in lesion size of ≥ 30% from baseline was observed in 43 (49.4%) of 87 target injected lesions and in 8 (26.7%) of 30 target noninjected lesions.
Viral RNA was detected in serum within 30 minutes of injection. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, with no effect on clinical or immunologic response being observed.
No treatment-related grade ≥ 3 adverse events were observed. The most common grade 1 (64.9% of patients) or 2 (14.0% of patients) treatment-related adverse events were injection site pain (31.6%), fatigue (29.8%), and chills (26.3%). Treatment was discontinued due to non–treatment-related adverse events in three patients: one who died from sepsis and cardiogenic shock, one with grade 2 fatigue and grade 3 motor dysfunction, and one with grade 4 pulmonary embolism.
The investigators concluded, “V937 was well tolerated and warrants further investigation for [the] treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing.”
Dr. Andtbacka, of Huntsman Cancer Institute, University of Utah, Salt Lake City, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Viralytics Limited, a wholly owned subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.
