FDA Grants Orphan Drug Designation for Gotistobart in Squamous NSCLC

The FDA has granted orphan drug designation (ODD) to gotistobart (BNT316/ONC-392) for the treatment of patients with squamous non–small cell lung cancer (NSCLC). The announcement, made by BioNTech SE and OncoC4, Inc, highlights the investigational anti–CTLA-4 monoclonal antibody’s potential in treating an aggressive subset of lung cancer that has historically seen limited therapeutic breakthroughs following the failure of first-line immunotherapy.¹

The designation follows a previous fast track designation for metastatic NSCLC and comes on the heels of robust phase 3 data demonstrating a significant survival benefit for gotistobart monotherapy compared with standard-of-care chemotherapy. The ODD program provides various development incentives, including tax credits for qualified clinical testing and potential 7-year marketing exclusivity upon approval, intended to support the development of therapies for rare diseases or specific high-need patient populations.

Phase 3 PRESERVE-003 Efficacy Data

The regulatory decision is supported by results from the ongoing PRESERVE-003 trial (NCT05671510), a global, randomized phase 3 study.² In the nonpivotal dose-confirmation stage of the trial, gotistobart demonstrated a clinically meaningful improvement in overall survival (OS) compared with docetaxel in patients with metastatic squamous NSCLC whose disease had progressed following anti–PD-(L)1 therapy.

Data presented at the IASLC 2025 North America Conference on Lung Cancer revealed that at a median follow-up of 14.5 months, the median OS for the gotistobart arm had not yet been reached, whereas the docetaxel arm achieved a median OS of 10.0 months.³ The 12-month OS rate was 63.1% for patients treated with gotistobart, significantly higher than the 30.3% observed in the docetaxel group. The gotistobart treatment arm showed a 54% reduction in the risk of death (HR, 0.46; 95% CI: 0.25–0.84; P =.0102).

Safety and Clinical Unmet Need

In the PRESERVE-003 study, the safety profile of gotistobart remained manageable and consistent with earlier findings. Grade 3 or higher treatment-related adverse events (AEs) were reported in 42.2% of patients in the gotistobart arm compared with 48.8% in the docetaxel arm.

These findings suggest a favorable safety-to-efficacy ratio for a monotherapy approach in a population that currently relies on cytotoxic chemotherapy with high toxicity and modest benefit.

Squamous NSCLC accounts for approximately 25% to 30% of all lung cancer cases. For patients who progress on frontline platinum-based chemotherapy and PD-1/PD-L1 inhibitors, the prognosis is often poor, with limited targeted therapy options available compared to the nonsquamous adenocarcinoma subtype.

Next-Generation Mechanism: CTLA-4 Recycling

Gotistobart is a next-generation, pH-sensitive monoclonal antibody designed to selectively deplete regulatory T cells (Tregs) within the tumor microenvironment (TME) while preserving CTLA-4 expression in peripheral tissues.¹ Unlike first-generation CTLA-4 inhibitors, which typically lead to the lysosomal degradation of the CTLA-4 receptor, gotistobart enables the recycling of the protein back to the cell surface.

This mechanism aims to maintain the immunosuppressive function of Tregs in healthy organs, potentially mitigating the high rates of immune-related AEs that have historically limited the clinical utility of CTLA-4 blockade. By refining the therapeutic index, gotistobart may allow for more sustained dosing regimens in second-line settings where patients are often heavily pre-treated and fragile.

Future Outlook

The pivotal stage of the PRESERVE-003 trial plans to enroll about 600 patients at 160 clinical sites globally.² BioNTech and OncoC4 are also evaluating gotistobart in various other solid tumors, including platinum-resistant ovarian cancer (PRESERVE-004; NCT05446298).¹

REFERENCES

1. BioNTech and OncoC4 Receive FDA Orphan Drug Designation for Gotistobart in Squamous Non-Small Cell Lung Cancer. News release. BioNTech. January 12, 2026. Accessed January 13, 2026. https://tinyurl.com/4747bfbd

2. ONC-392 Versus Docetaxel in Metastatic NSCLC That Progressed on PD-1/​PD-L1 Inhibitors (PRESERVE-003). ClinicalTrials.gov. Updated June 29, 2025. Accessed January 13, 2026. https://clinicaltrials.gov/study/NCT05671510

3. BioNTech and OncoC4 Announce Clinically Meaningful Overall Survival Benefit for Selective Treg Modulator Gotistobart in Patients with Previously Treated Squamous Non-Small Cell Lung Cancer. News release. BioNTech. December 6, 2025. Accessed January 13, 2026. https://tinyurl.com/y5cbd33u