Gotistobart Phase III data: a potentially best-in-class CTLA-4 mAb in squamous NSCLC and beyond

The release of Phase III Stage 1 data for gotistobart (BNT316/ONC-392) at NACLC 2025 marks one of the most significant developments in CTLA-4–targeted therapy in recent years. BioNTech (Nasdaq: BNTX) and OncoC4 presented results from the PRESERVE-003 trial, a registrational study designed to evaluate gotistobart in patients with squamous non-small cell lung cancer (sqNSCLC) who had progressed after PD-(L)1 inhibitor treatment. For a population long defined by limited therapeutic options and poor outcomes, the findings represent a genuine breakthrough.

Hints for a positive surprise had already emerged before the formal data release. BioNTech emphasized this program as a priority pipeline asset during its R&D Day last month after being somewhat silent on this asset for months since the PRESERVE-003 trial resumed in late 2024 after a temporary US Food and Drug Administration (FDA) hold in late 2024 prompted by differing outcomes between squamous and non-squamous patients. By the time of NACLC, anticipation was high, and the results did not disappoint.

The trial design incorporated two dosing regimens of gotistobart compared against docetaxel. The low-dose regimen (3 mg/kg Q3W) enrolled only ten patients and was discontinued in Stage 2. The high-dose regimen, however—two loading doses of 10 mg/kg followed by 6 mg/kg Q3W—was the centerpiece, enrolling 45 patients. The control arm included 42 patients treated with docetaxel. Importantly, the gotistobart cohort had a higher proportion of patients with brain and liver metastases, underscoring the robustness of the efficacy signal.

Survival outcomes were striking. At 12 months, overall survival was 63.1% with gotistobart compared to 30.3% with docetaxel. Median OS had not yet been reached in the gotistobart arm, while the control group showed a median of 9.95 months. The hazard ratio of 0.46 (95% CI: 0.25–0.84, p=0.0102) confirmed statistical significance. The survival curve displayed a classic tail effect, with over 60% of the patients in gotistobart high dose arm still alive at 15months, suggesting durable benefit. Safety was manageable, with grade ≥3 adverse events occurring at rates similar to docetaxel, although the specific toxicity profile for gotistobart showing classical CTLA-4 irAEs such as diarrhea and colitis.

For the field of sqNSCLC, these results carry profound implications. Approximately one-third of NSCLC cases are squamous, yet therapeutic innovation has lagged non-squamous disease. Second-line treatment after immunotherapy resistance has been a persistent challenge, with multiple investigational strategies—including VEGFR2/PD-1 combinations, Trop2 ADCs, and TKIs paired with PD-(L)1 inhibitors—failing to deliver meaningful survival benefit in randomized trials. Standard chemotherapy has remained the benchmark, with median OS hovering around nine months. Gotistobart’s data has the potential to break this bind, offering a survival advantage that is both statistically robust and clinically transformative.

Equally important is that this data demonstrates that next generation CTLA-4 antibody can have high market potential. Ipilimumab validated the target but was constrained by toxicity, limiting dosing to 1–3 mg/kg and often requiring PD-1 combinations for efficacy. Gotistobart, by contrast, selectively depletes Treg in the tumor microenvironment instead of completely blocking CTLA-4 signaling. It is the first CTLA-4 antibody to show positive monotherapy results in a high-difficulty indication, suggesting an effective approach to widen the therapeutic index for CTLA-4 target.

The implications of PRESERVE-003 trial data extend beyond just later line lung cancer. Gotistobart is being explored in ovarian cancer, prostate cancer, and other solid tumors, with a particularly innovative trial PRESERVE-006 combining the antibody with Lu-177 radioligand therapy in mCRPC, which is a far bigger market. Furthermore, BioNTech’s broader pipeline — including PD-L1/VEGF bispecific, ADCs, and mRNA therapeutics — offers fertile ground for rational combinations targeting earlier line patient populations in various disease areas. Pairing gotistobart with pumitamig, for example, could address lingering questions around OS benefit in PD-(L)1–VEGF strategies.

Taken together, the Phase III Stage 1 results from PRESERVE-003 establish Gotistobart as a clear leader in next-generation CTLA-4 therapy capable of overcoming the limitations of its predecessors. For immunotherapy-resistant sqNSCLC, the data represents a long-awaited breakthrough. For the CTLA-4 field, they signal a reinvention of the target’s role in oncology. And for BioNTech and OncoC4, they open the door to expanded indications, novel combinations, and significant commercial opportunities. The upcoming Stage 2 readout in 2026 will be pivotal, but the trajectory is clear: gotistobart is redefining the CTLA-4 landscape.