Does Tumor Shrinkage Mean a Systemic Effect? FDA Again Questions Evidence for RP1 in Melanoma

Can shrinkage of an injected tumor prove that a patient’s cancer is also being controlled throughout the body? This seemingly simple question is becoming central to whether Replimune’s melanoma therapy RP1 can clear the regulatory threshold. Ahead of an expert committee meeting on July 30, the U.S. Food and Drug Administration (FDA) released review documents that again questioned whether the existing data are sufficient to support the combination of RP1 and nivolumab (brand name Opdivo).

The application is based on the single-arm Phase I/II IGNYTE trial, which enrolled 140 patients with unresectable stage IIIB to IV cutaneous melanoma whose disease had progressed after anti-PD-1 therapy. Replimune reported an objective response rate of 33.6%, as assessed by an independent committee using RECIST 1.1 criteria, including 23 complete responses and 24 partial responses; the median duration of response was 24.8 months.

The first point of contention is “how responses are calculated.” RECIST 1.1 was originally used primarily to assess systemic therapies, and lesions that have received local treatment generally should not be directly included in response determinations; RP1, however, is an oncolytic immunotherapy injected into tumors. The FDA believes IGNYTE’s approach may have counted local shrinkage caused by the injection itself toward overall efficacy and may have been confounded by factors including lesion reinjection, surgery, or biopsy. After the FDA excluded responders whose target lesions had all been injected or who had no target lesions at baseline, the estimated response rate fell to 15.7%, and the median duration of response shortened to 14.1 months.

The second gap is the lack of a concurrent control group. Because patients received RP1 and nivolumab together, the single-arm trial cannot directly answer how much efficacy RP1 actually added. Replimune argues that randomly assigning patients who had clearly failed anti-PD-1 treatment to continue receiving the same class of drug as monotherapy would be difficult both operationally and ethically. Citing the literature, the company estimated that the response rate from restarting or continuing anti-PD-1 therapy would be no more than 5% to 7%, and argued that the IGNYTE results therefore demonstrated RP1’s additional contribution. The FDA, however, noted that patients’ disease courses, prior treatments, and disease burdens differed substantially across studies, and that no sufficiently reliable historical benchmark exists for comparison.

This also bears on whether RP1 has a systemic effect. Replimune presented analyses showing shrinkage of uninjected lesions, including visceral lesions, arguing that the immune effect was not limited to areas reached by the needle. The FDA, however, believes the existing assessments still make it difficult to separate local effects from genuine systemic disease modification, while the overall survival analysis is uninterpretable because of the single-arm design and follow-up issues. In other words, the dispute is not simply over whether tumors shrank, but whether that shrinkage can reliably predict clinical benefit.

Safety must likewise be weighed against the uncertain benefit. The FDA believes the combination’s overall safety profile is broadly consistent with the known risks of nivolumab, with the addition of injection-site reactions and systemic symptoms such as fever and chills; among the 140 patients, 31% experienced grade 3 or higher adverse events, and approximately 16% discontinued at least one treatment because of adverse events. These figures may not independently justify rejection, but they make clarifying RP1’s actual contribution more important.

Background

RP1’s application previously received an FDA complete response letter because of the trial design, patient heterogeneity, and the inability to distinguish the contributions of the combination’s components. After resubmission, it still relies primarily on the same single-arm study. The forthcoming Cellular, Tissue, and Gene Therapies Advisory Committee meeting will discuss the reliability and interpretability of these data. The committee’s opinion is not the FDA’s final decision, but it will test how high an evidentiary threshold locally injected cancer therapies must clear to claim systemic benefit.