FDA Grants Orphan Drug Designation to Gotistobart in Squamous NSCLC

The FDA has granted orphan drug designation to gotistobart, a novel tumor microenvironment–selective, regulatory T cell–depletion candidate targeting CTLA-4, for the treatment of patients with squamous non–small cell lung cancer (NSCLC).¹

The agent is being evaluated in the pivotal phase 3 PRESERVE-003 trial (NCT05671510) in patients with metastatic squamous NSCLC.²

Although PD-(L)1 inhibitors have led to improved outcomes for patients with metastatic NSCLC without oncogene-driven disease, their use is associated with temporary or no disease control in a substantial portion of patients. Moreover, CTLA-4, despite being a validated target for checkpoint inhibition, has not shown significant single-agent activity in patients with NSCLC.

What is gotistobart, and how does it work in NSCLC?

Gotistobart was designed to allow CTLA-4 protein recycling as a pH-sensitive monoclonal antibody. By binding to the CTLA-4 receptor on the cell surface, the complex is internalized. The change in pH triggers the antibody to unbind, enabling CTLA-4 to return to the surface and keep the immune checkpoint function intact at surrounding organs while boosting antitumor immunity in the tumor microenvironment.

What have early data shown with respect to gotistobart’s activity in NSCLC?

Prior data from the first-in-human, phase 1/2 PRESERVE-001 trial (NCT04140526) demonstrated an encouraging safety profile and preliminary antitumor activity in patients with PD-(L)1–resistant metastatic NSCLC, with an objective response rate (ORR) of approximately 29.6% and disease control rate of 62.9%.

What other regulatory milestones has gotistobart achieved?

In 2022, the FDA granted fast track designation to gotistobart for the treatment of patients with metastatic NSCLC whose disease progressed on prior anti–PD-(L)1 therapy.¹ In 2025, gotistobart also received breakthrough therapy designation from China’s National Medical Products Administration for patients with squamous NSCLC following progression on standard immuno-oncology (IO) treatments.³

What do I need to know about the design and eligibility criteria for the PRESERVE-003 trial?

PRESERVE-003 is a two-stage, randomized, open-label, active-controlled, phase 3 trial evaluating the safety and efficacy of single-agent gotistobart vs docetaxel in patients with metastatic NSCLC following progression on PD-(L)1 inhibition with or without platinum-based chemotherapy.²

The study was designed with a non-pivotal stage, which enrolled all-comers with NSCLC. In this stage, 217 patients were randomly assigned to receive 6 mg/kg of gotistobart with 2 loading doses of 10 mg/kg every 3 weeks (Q3W; n = 103), 3 mg/kg of gotistobart Q3W (n = 10), or 75 mg/kg of docetaxel Q3W (n = 104). Data presented at the IASLC ASCO 2025 North America Conference on Lung Cancer revealed that the agent led to a clinically meaningful improvement in overall survival (OS) vs docetaxel and a manageable safety profile in patients with squamous NSCLC whose disease had progressed on chemoimmunotherapy.¹

The ongoing pivotal stage is now only enrolling patients with squamous histology.² In this stage, 478 patients will be randomly assigned to receive 6 mg/kg of gotistobart with 2 loading doses of 10 mg/kg Q3W (n = 239) or 75 mg/kg of docetaxel Q3W (n = 239).

The primary end point of the pivotal stage is OS. Secondary end points include ORR and progression-free survival by blinded independent central review per RECIST 1.1 criteria, as well as the incidence of treatment-emergent adverse effects (AEs), treatment-related AEs, immune-related AEs, and AEs leading to treatment discontinuation.

Eligible patients had to be at least 18 years old with histologically or cytologically confirmed stage IV, metastatic NSCLC, with measurable metastasis in regional lymph nodes or distant organs per RECIST 1.1 criteria. Radiographic progression after the most recent line of therapy was required and was defined as at least 12 weeks of PD-(L)1 inhibition plus platinum-based chemotherapy, or at least 2 cycles of platinum-based chemotherapy, followed by at least 12 weeks of standard doses of PD-(L)1 inhibition.

An ECOG performance status of 0 or 1 was also required, as was adequate organ function, and life expectancy exceeding 3 months. Prior IO therapy was allowed.

References

1. BioNTech and OncoC4 receive FDA orphan drug designation for gotistobart in squamous non-small cell lung cancer. News release. BioNTech SE. January 12, 2026. Accessed January 23, 2026. https://investors.biontech.de/news-releases/news-release-details/biontech-and-oncoc4-receive-fda-orphan-drug-designation
2. Li T, Wu T, Cho BC, et al. PRESERVE-003: a phase 3 study of gotistobart versus docetaxel in metastatic NSCLC after progression on PD-(L)1 inhibitors. J Thorac Oncol. 2025;20(suppl 1):S562. doi:10.1016/j.jtho.2025.09.1054
3. China’s NMPA grants breakthrough therapy designation for anti-CTLA-4 antibody candidate gotistobart (BNT316/ONC-392). News release. OncoC4. October 27, 2025. Accessed January 23, 2026. https://oncoc4.com/press-releases/chinas-nmpa-grants-breakthrough-therapy-designation-for-anti-ctla-4-antibody-candidate-gotistobart-bnt316-onc-392/