ONC-392

Shows activity

Also known as:

gotistobart

Cancer types include:

non-small cell lung cancer prostate cancer small cell lung cancer

HealthScout AI Analysis

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Overview

ONC-392 (gotistobart; also BNT316) is a humanized IgG1 monoclonal antibody targeting CTLA‑4 being co‑developed by OncoC4 and BioNTech. Early clinical data in PD-(L)1–resistant metastatic non–small cell lung cancer (NSCLC) show antitumor activity with a manageable safety profile, and a global, two‑stage, randomized Phase 3 trial (PRESERVE‑003; NCT05671510) is ongoing with Stage 2 focused on squamous NSCLC after a 2024 FDA partial hold was lifted in December 2024. (drugs.ncats.io)

Mechanism of action

Target: CTLA‑4 (CD152). Gotistobart is a pH‑sensitive anti‑CTLA‑4 antibody engineered to dissociate from CTLA‑4 in acidic endosomes, allowing CTLA‑4 to recycle to the cell surface rather than undergo lysosomal degradation. This design aims to preserve peripheral immune tolerance while enhancing intratumoral regulatory T‑cell (Treg) depletion via Fc‑dependent mechanisms. (mycancergenome.org)
Antibody class: humanized IgG1. (drugs.ncats.io)

Efficacy

NSCLC (PD-(L)1–resistant), monotherapy (Phase 1/2, PRESERVE‑001; ASCO 2023 poster discussion): - Evaluable patients: 27 at 10 mg/kg (then 6 mg/kg) Q3W. - Overall response rate (ORR): 29.6%. - Disease control rate (DCR): 70.4%. - Responses included 1 complete response and 7 partial responses. (ascopubs.org)

Note: These results are from an ongoing study and are preliminary. A randomized Phase 3 trial comparing gotistobart with docetaxel is underway; Stage 2 now randomizes only squamous NSCLC based on Stage 1 findings. The primary endpoint is overall survival. (ascopubs.org)

Safety

In the PD-(L)1–resistant NSCLC Phase 1/2 cohort above, immune‑related adverse events (irAEs) grade 3–4 were reported in 30% of patients in the treated cohort, described as lower than rates historically reported for other anti‑CTLA‑4 antibodies. (oncoc4.com)
A partial FDA clinical hold was placed on the Phase 3 trial in October 2024 due to disparate results between squamous and non‑squamous NSCLC cohorts; the hold was lifted in December 2024 with enrollment limited to squamous NSCLC. Already‑enrolled patients continued treatment; other gotistobart studies were unaffected. (cancernetwork.com)

(Comprehensive safety characterization will depend on mature randomized data.)

Clinical development (selected, as of October 7, 2025)

PRESERVE‑001 (NCT04140526): First‑in‑human Phase 1/2 evaluating monotherapy and combinations; ASCO abstracts report RP2D selection and activity in PD-(L)1–resistant NSCLC. (ascopubs.org)
PRESERVE‑003 (NCT05671510): Two‑stage, randomized Phase 3 vs docetaxel; Stage 2 proceeding in squamous NSCLC at 6 mg/kg Q3W with two 10 mg/kg loading doses. Trial design updates were slated for presentation at WCLC 2025. (oncoc4.com)
Additional studies: Combination trials in other tumor types (e.g., prostate cancer in combination with 177Lu‑PSMA‑617) are ongoing. (oncoc4.com)

Active trials using ONC-392

Found 4 active trials using this drug:

Randomized Study of ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Progressed on Androgen Receptor (AR) Pathway Inhibition

Sponsor: OncoC4, Inc. (industry) Phase: 1/2 Start date: Dec. 11, 2023

HealthScout AI summary: Adults with PSMA-positive metastatic castration-resistant prostate adenocarcinoma after progression on at least one AR-targeted agent (and up to two prior taxanes or taxane-ineligible) are randomized to lutetium Lu 177 vipivotide tetraxetan alone versus in combination with ONC-392 (gotistobart), an investigational anti-CTLA-4 antibody designed to preserve CTLA-4 recycling and selectively deplete intratumoral Tregs to potentially reduce immune toxicity. Requires ECOG 0–1, castrate testosterone, evidence of progression, and no prior PSMA radioligand therapy or active autoimmune disease.

ClinicalTrials.gov ID: NCT05682443

Phase 3, Two-stage, Randomized Study of ONC-392 Versus Docetaxel in Metastatic Non-Small Cell Lung Cancers That Progressed on PD-1/PD-L1 Inhibitors

Sponsor: OncoC4, Inc. (industry) Phase: 3 Start date: June 28, 2023

HealthScout AI summary: This trial enrolls adults with metastatic squamous NSCLC, ECOG 0-1, who have progressed after at least 12 weeks of PD-1/PD-L1 inhibitor and platinum-based chemotherapy, randomizing them to docetaxel or gotistobart (ONC-392), a next-generation anti-CTLA-4 antibody designed to selectively deplete intratumoral regulatory T cells while sparing peripheral Tregs. Key exclusions include actionable oncogenic drivers (except KRAS), symptomatic brain metastases, and significant comorbidities.

ClinicalTrials.gov ID: NCT05671510

LuCa-MERIT-1: First-in-human, Open Label, Phase I Dose Confirmation Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

Sponsor: BioNTech SE (industry) Phase: 1 Start date: June 17, 2022

HealthScout AI summary: This trial enrolls adults with advanced or metastatic NSCLC—including those post standard therapies, unresectable stage III after chemoradiotherapy, and resectable stage II/III eligible for perioperative treatment—and investigates BNT116, an mRNA cancer vaccine targeting six NSCLC antigens, as monotherapy or combined with standard chemotherapy, PD-1/CTLA-4 inhibition (cemiplimab, BNT316), and antibody–drug conjugates. Eligibility generally excludes patients with targetable mutations for which approved therapies exist.

ClinicalTrials.gov ID: NCT05142189

Safety, Pharmacokinetics (PK), and Efficacy of ONC-392 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumors and NSCLC: An Open Label Phase IA/IB Study. Preserve CTLA4 Checkpoint Function (PRESERVE-001)

Sponsor: OncoC4, Inc. (industry) Phase: 1/2 Start date: Sept. 16, 2020

HealthScout AI summary: This trial involves patients aged 18 and older with advanced solid tumors, including NSCLC, melanoma, pancreatic, and ovarian cancers, who have progressed after standard treatments or are treatment-naïve. It evaluates the safety and efficacy of ONC-392, an anti-CTLA-4 monoclonal antibody, alone and combined with pembrolizumab to determine appropriate dosing for future studies.

ClinicalTrials.gov ID: NCT04140526