In the non-pivotal, dose-confirmation stage of the randomized Phase 3 PRESERVE-003 trial in metastatic squamous NSCLC after PD-(L)1 therapy and platinum chemotherapy, gotistobart (BNT316/ONC-392) reduced the risk of death by 54% versus docetaxel (HR 0.46; 95% CI 0.25–0.84; nominal p=0.0102). At 12 months, overall survival was 63.1% with gotistobart versus 30.3% with docetaxel. Median OS was not reached for gotistobart at a median follow-up of 14.5 months, compared with 10 months for docetaxel. Grade ≥3 treatment-related AEs occurred in 42.2% (19/45) on gotistobart and 48.8% (20/41) on docetaxel. The analysis included 45 patients on gotistobart monotherapy and 42 on docetaxel.
The core development is BioNTech and OncoC4’s disclosure of Stage 1 results from a two-stage, global Phase 3 program and the transition into the pivotal stage, now focused on squamous histology. The open-label trial compares gotistobart monotherapy to standard docetaxel, with overall survival as the primary endpoint. The pivotal stage is enrolling roughly 500 patients across more than 160 sites worldwide. The candidate, a pH-sensitive CTLA-4 antibody designed to selectively deplete Tregs in the tumor microenvironment while preserving peripheral checkpoint function, holds U.S. FDA Fast Track designation in post-IO NSCLC and Breakthrough Therapy designation in China.
Strategically, this is a focused bid to reopen CTLA-4’s clinical utility through engineering and to stake a chemo-free path in the post-immunotherapy, second-line sqNSCLC setting—a space where options remain thin and operationally straightforward monotherapies can gain traction. The two-stage Phase 3 architecture is a risk-managed bet: calibrate dose and signal in a smaller global cohort, then concentrate statistical power in a pivotal OS study confined to the histology with the clearest benefit. For BioNTech, it also widens its oncology footprint beyond mRNA while preserving optionality for combinations already in exploration.
The tension points are clear. The comparator is docetaxel monotherapy, while many centers use docetaxel with ramucirumab in this setting; that choice could shape payer and regional regulatory reception even if the pivotal study is positive. The stage-one dataset is small, open-label, and reports a nominal p-value without alpha control; the effect size is compelling but inherently unstable at this maturity, with median OS not yet reached. Translating this signal through an event-driven pivotal study—with consistent site-level conduct, balanced post-progression therapies, and clean handling of immune-related AEs—will determine credibility.
For sites, a chemotherapy-free regimen with a manageable high-grade AE rate may be attractive, particularly for community networks managing post-IO lung cancer. The loading-dose schedule (two 10 mg/kg doses before 6 mg/kg maintenance) will require infusion planning and robust irAE monitoring, but screening should be straightforward without biomarker gating, aiding accrual. CROs can expect heavy emphasis on survival event adjudication, immunotoxicity oversight, and long follow-up windows across a broad geographic footprint. Vendors supporting safety signal detection and decentralized AE management could see increased demand.
What to watch next is whether the pivotal stage sustains a hazard ratio near or below 0.6 with durable 12- and 18-month OS landmarks, without drift in immune toxicity as exposure scales. Subgroup consistency, prior-line balance, and clarity on real-world-comparable post-progression regimens will be scrutinized. Exploratory biomarkers tied to Treg modulation could sharpen positioning, particularly if combinations with BioNTech’s mRNA candidates advance. A confirmatory OS win could support accelerated pathways in multiple regions, but comparator context and operational execution—more than mechanism—will decide how quickly this moves from signal to standard.
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.
