In PD-1 inhibitor–resistant metastatic melanoma, NuCana’s NUC-7738 plus pembrolizumab produced two partial responses (one confirmed) and seven instances of stable disease among patients treated to date, including one ongoing stable disease converting to a complete metabolic response with no detectable active disease. No new safety signals were reported, and several patients remain on therapy with ongoing disease control. As of the latest cut, nine patients have been dosed in the Phase 2 expansion cohort, adding to 12 previously treated in the dose-confirmation cohort; enrollment is planned to reach up to 40 patients.
The update, presented at ESMO Immuno-Oncology 2025, reflects continued readout from NuTide:701, a Phase 1/2 study evaluating NUC-7738—a ProTide designed to disrupt RNA polyadenylation—in combination with pembrolizumab in cutaneous melanoma progressing after prior PD-1 therapy. The company is advancing an expansion cohort of up to 28 additional patients to refine response and durability estimates and to further characterize safety in a more homogenous, post–PD-1 setting. The dataset remains small and uncontrolled, but the signal is notable given that all enrolled patients had documented progression before study entry.
Strategically, NuCana is positioning NUC-7738 as an IO-sensitizing backbone in a salvage population where options are limited and where regulators have become less receptive to single-agent follow-ons that do not shift outcomes meaningfully. The choice to combine with pembrolizumab in patients already resistant to PD-1 inhibition reflects a hypothesis of immune re-priming via tumor and microenvironmental effects, aiming to restore responsiveness without the complexity of cell therapy or dual checkpoint intensification. The move also differentiates NUC-7738 from the company’s earlier ProTide programs by anchoring development to a clear, high-need niche rather than broad solid tumor exploration.
For sites and CROs, the operational footprint of an outpatient, small-molecule plus PD-1 regimen is straightforward relative to TIL therapy, potentially widening access beyond tertiary centers and easing scheduling, pharmacy, and inpatient resource burdens. That said, confirming benefit will require rigorous RECIST-based adjudication and longer follow-up for duration of response; the reported complete metabolic response underscores the importance of consistent imaging protocols, including PET, across participating centers. Sponsors watching this space will note that the efficacy bar in post–PD-1 melanoma has shifted with the availability of lifileucel and combination strategies, raising expectations for objective response and durability if a single-arm pathway is contemplated. Regulators are also likely to press for randomized evidence or, at minimum, robust durability in a well-defined, biomarker-agnostic population to support any accelerated route.
What comes next will determine whether this signal is hypothesis-generating or registration-worthy. The expansion cohort needs to clarify the true objective response rate, confirm responses on independent review, and deliver duration data beyond six to nine months. NuCana will also need to articulate a registrational strategy, including control selection in a post–PD-1 setting where physician’s choice now includes TILs at specialized centers, and to define consistent criteria for PD-1 resistance. Biomarker work—tumor-intrinsic or immune contexture—could help enrich for responders and streamline future trial design. Watch enrollment velocity, the confirmed response tally as the n approaches 40, and any movement toward U.S. or EU regulatory interactions that indicate whether the company is pursuing a single-arm accelerated filing or preparing for a randomized study. A partnership for drug supply, funding, and potential co-development would also signal intent and capacity to compete in a maturing salvage melanoma market.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
