Squamous NSCLC represents roughly 25–30% of lung cancer cases and, unlike adenocarcinoma, has fewer actionable driver alterations. After progression on frontline chemo-immunotherapy, many patients fall back on single-agent docetaxel, which offers modest benefit and meaningful toxicity—creating a clear unmet need for more effective second-line strategies.
What Is Gotistobart (BNT316/ONC-392)?
Gotistobart, also known by its research codes BNT316 or ONC-392, is a next-generation anti–CTLA-4 monoclonal antibody jointly developed by BioNTech SE and OncoC4 in late-stage clinical development across several solid tumor indications, including squamous non–small cell lung cancer (NSCLC) and others.
Unlike traditional CTLA-4 inhibitors, gotistobart is engineered to be pH-sensitive and to preserve CTLA-4 recycling. When it binds the CTLA-4 receptor on T cells, the antibody-receptor complex is internalized, but under acidic conditions found inside cells, the antibody dissociates rather than triggering lysosomal degradation of CTLA-4. This allows CTLA-4 to return to the cell surface and preserves its function outside the tumor microenvironment, while preferentially depleting immunosuppressive regulatory T cells (Tregs) within the tumor. This tumor-microenvironment-selective action is intended to enhance anti-tumor immunity while potentially limiting peripheral toxicity relative to conventional CTLA-4 blockade.
Gotistobart is being studied both as monotherapy and in combination with other immunotherapies, and has received regulatory designations—including FDA Fast Track and Orphan Drug status—reflecting its potential in hard-to-treat cancers such as squamous NSCLC.
Why Orphan Drug Designation matters
ODD is intended to accelerate development for therapies targeting rare/high-need populations, providing incentives such as tax credits for qualified clinical testing and (if approved) 7 years of marketing exclusivity in the U.S.
Study Design and Methods
The ODD announcement is supported by efficacy signals from the ongoing PRESERVE-003 trial (NCT05671510), a global, randomized phase 3 study evaluating gotistobart versus standard chemotherapy in metastatic squamous NSCLC after progression on anti–PD-(L)1 therapy.
Results
Phase 3 PRESERVE-003 (dose-confirmation stage; nonpivotal)
At a median follow-up of 14.5 months, gotistobart monotherapy showed a notable overall survival advantage versus docetaxel:
- Median OS: not reached (gotistobart) vs 10.0 months (docetaxel)
- 12-month OS: 63.1% vs 30.3%
- Risk of death: HR 0.46 (95% CI, 0.25–0.84), P = .0102
Safety
In the same dataset, treatment-related toxicity appeared comparable or slightly lower than chemotherapy:
- Grade ≥3 treatment-related AEs: 42.2% (gotistobart) vs 48.8% (docetaxel)
Insights
- If these OS findings hold in the pivotal stage, gotistobart could redefine expectations for post–PD-(L)1, second-line squamous NSCLC, where meaningful OS gains have been difficult to achieve with immunotherapy alone.
- The therapeutic-index engineering (CTLA-4 recycling concept) is the key scientific bet: maintaining anti-tumor CTLA-4 biology while improving tolerability may be what allows CTLA-4 blockade to succeed as monotherapy in a heavily pretreated population.
Key Takeaway Messages
- FDA ODD has been granted to gotistobart for squamous NSCLC.
- In PRESERVE-003 (dose-confirmation stage), gotistobart showed strong OS separation vs docetaxel (HR 0.46; 12-month OS 63.1% vs 30.3%).
- Safety appears manageable and at least comparable to chemotherapy in the reported dataset.
- The program’s differentiator is a pH-sensitive CTLA-4 approach designed around recycling and tumor-selective Treg depletion.
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