Gotistobart (ONC-392) monotherapy elicited improved and durable antitumor activity vs docetaxel and led to a clinically meaningful survival benefit in patients with squamous non–small cell lung cancer (NSCLC) following progression on anti–PD(L)1 therapy, according to data from stage 1 of the phase 3 PRESERVE-003 trial (NCT05671510) presented during the 2026 European Lung Cancer Congress.1
The objective response rate (ORR) in those who received gotistobart (n = 45) was 20.0%; this was comprised entirely of partial responses (PRs). A total of 15.6% of patients had stable disease (SD), 48.9% experienced disease progression (PD), 8.9% were not evaluable (NE), and this information was missing for 6.7% of patients. In comparison, docetaxel (n = 42) elicited an ORR of 4.8%, again comprised of PRs; 33.3% of patients had SD, 45.2% had PD, 2.4% were NE, and this information was missing for 14.3%. Moreover, responses proved to be durable, with a median duration of response (DOR) of 11.0 months (95% CI, 3.5-NE) with gotistobart vs 3.8 months (95% CI, 3.6-NE) with docetaxel.
The median progression-free survival (PFS) with gotistobart was 2.4 months (95% CI, 2.1-4.5) vs 2.6 months (95% CI, 2.1-3.9) with docetaxel (HR, 0.69; 95% CI, 0.42-1.13). In the gotistobart arm, the 3-, 6-, 9-, and 12-month PFS rates were 45.3%, 32.7%, 25.2%, and 25.2%, respectively; these respective rates were 41.3%, 12.9%, 3.2%, and 0% in the docetaxel arm. At a median duration of follow-up of 14.5 months (Q1 to Q3, 13.0-16.4) in the gotistobart arm and 15.2 months (Q1 to Q3, 11.5-16.0) in the docetaxel arm, the median overall survival (OS) was NE (95% CI, 9.33-NE) and 9.95 months (95% CI, 6.18-11.93), respectively (HR, 0.46; 95% CI, 0.25-0.84; nominal P = .0102).
“PRESERVE-003 stage 1 data highlight the potential of gotistobart as a chemotherapy-free option for patients with treatment-resistant squamous NSCLC, a population with critical unmet need,” lead study author Kai He, MD, PhD, shared in a presentation during the meeting. He is a medical oncologist and assistant professor of medicine in the Thoracic Oncology Program at The Ohio State University in Columbus.
Gotistobart Provides Clinical Benefits in Squamous NSCLC
- Gotistobart improved response rates vs docetaxel in previously treated squamous NSCLC, achieving an ORR of 20% vs 4.8%, respectively.
- The agent delivered a clinically meaningful overall survival benefit, with a median OS that was not reached vs 9.95 months with docetaxel in this population.
- The agent’s safety profile was consistent with prior data, with manageable immune-related toxicities and a distinct profile compared with chemotherapy.
What is the mechanism of action of gotistobart?
As a pH-sensitive anti–CTLA-4 monoclonal antibody with an optimized Fc domain, gotistobart “can promote regulatory T-cell depletion in the tumor microenvironment,” He noted. He explained that the antibody binds to the target, the complex dissociates inside the endosome, and CTLA-4 and gotistobart are recycled without degradation. This preserves high CTLA-4 density on tumor-infiltrating regulatory T cells. The agent enables effective depletion of those T cells via enhanced ADCC/ADCP in the tumor microenvironment with minimal peripheral immune activation, he added.
What was the design of the PRESERVE-003 study evaluating gotistobart?
The 2-stage, multicenter, international, randomized, phase 3 study enrolled patients with stage III and IV metastatic NSCLC who were at least 18 years of age and who had received prior PD-(L)1 therapy and platinum-based chemotherapy. Patients had measurable lesions by RECIST 1.1 criteria. Those with prior IO-IO exposure were permitted, He specified.
In stage 1, referred to as the non-pivotal part of the study, a total of 217 patients were randomized to receive gotistobart monotherapy at 3 mg/kg every 3 weeks (Q3W; n = 10), gotistobart at 6 mg/kg with 2 loading doses of 10 mg/kg Q3W (n = 103), or docetaxel at 75 mg/m2 Q3W (n = 104). Patients were stratified based on histology (squamous vs nonsquamous; stage 1 only), brain metastases (yes vs no), ECOG performance status (0 vs 1), and region (United States [US] vs ex-US). Enrollment was completed for this portion of the study, He noted.
Enrollment is ongoing for stage 2, which is referred to as the “pivotal part” of the research and will only include those with squamous NSCLC. Here, patients (n = 414) will be randomized 1:1 to receive gotistobart at 6 mg/kg with 2 loading doses of 10 mg/kg Q3W or docetaxel at 75 mg/m2 Q3W.
The primary end point of the study is OS. Secondary end points include ORR and PFS by investigator assessment and RECIST 1.1 criteria, as well as safety.
What should be known about the population of patients included in the current analysis?
The presentation shared during the congress focused on patients with squamous NSCLC who were enrolled in stage 1 (n = 87). Of the 87 patients, 45 received gotistobart and 42 were given docetaxel. In the gotistobart arm, 7 were still receiving treatment, 38 discontinued, 25 were still on study, and 20 had discontinued the study; these respective numbers were 0, 41, 10, and 32 in the docetaxel arm.
In terms of baseline characteristics, the median patient age was 64 years (range, 39-86) and 68.5 years (range, 43-84) in the gotistobart and docetaxel arms, respectively. Most patients were male (80.0%; 90.5%), Asian (71.1%; 71.4%), had an ECOG performance status of 1 (80.0%; 83.3%), were not from the United States (75.6%; 73.8%), were former smokers (75.6%; 64.3%), and had received 1 prior line of systemic therapy (66.7%; 71.4%). About one-third of patients had received 2 or more prior lines (33.3%; 28.6%). All patients had received prior chemotherapy and anti–PD(L)1 therapy; 6.7% of those in the gotistobart arm had prior exposure to an anti–CTLA-4 therapy.
In terms of PD-L1 expression, 31.1% of patients in the gotistobart had a tumor proportion score (TPS) below 1%, 17.8% had a score ranging from 1% to 49%, and 15.6% had a score of 50% or higher; this information was not known for 35.6% of patients. In the docetaxel arm, 26.2%, 7.1%, and 28.6% of patients had a TPS less than 1%, between 1% and 49%, and 50% or higher, respectively; this information was unknown for 38.1% of patients.
What was the toxicity profile of gotistobart in patients with squamous NSCLC?
Any-grade treatment-emergent adverse effects (TEAEs) were reported in all patients in the gotistobart arm vs 97.6% of those in the docetaxel arm; TEAEs were grade 3 or higher for 66.7% and 63.4% of patients, respectively. Serious TEAEs occurred in 75.6% and 39.0% of patients in the respective arms. In the gotistobart arm, 22.2% of patients experienced TEAEs that led to discontinuation of the agent; 2.2% of patients experienced TEAEs that resulted in death.
Moreover, treatment-related adverse effects (TRAEs) were reported in 84.4% of those given gotistobart and 90.2% of those treated with docetaxel; TRAEs were grade 3 or higher for 42.2% and 48.8% of patients, respectively, and serious for 42.2% and 29.3% of patients, respectively. TRAEs led to discontinuation for 13.3% of those in the gotistobart arm vs 4.9% of those in the docetaxel arm. He noted that 15.6% of patients had received gotistobart for at least 1 year.
The most common grade 3 or higher TRAEs reported in the gotistobart arm were colitis (8.9%), increased alanine aminotransferase level (6.7%), increased aspartate aminotransferase level (4.4%), diarrhea (4.4%), immune-mediated lung disease (4.4%), and pneumonia (4.4%). In the docetaxel arm, the most common TRAEs that were grade 3 or higher included decreased neutrophil count (24.4%), decreased white blood cell count (14.6%), febrile neutropenia (9.8%), neutropenia (4.9%), and pneumonia (2.4%).
“The observed safety profile of gotistobart aligns with its previously established safety profile,” He concluded, adding that gastrointestinal disorders, hepatic laboratory abnormalities, and infusion-related reactions were among the most common adverse effects observed with the agent.
Disclosures: Dr He disclosed serving as an advisory board participant for Amgen, AstraZeneca, Beigene, BioNTech, BMS, Iovance, Lyell, Mirati, Obsidian, Regeneron, and Sythekin; and being an invited speaker for Amgen, Beigene, BioNTech, BMS, Genentech, GSK, Iovance, Lyell, Mirati, Obsidian, OncoC4, Servier, and Sythekin.
References
- Anti-tumor activity of gotistobart compared to docetaxel in patients with metastatic squamous non-small cell lung cancer (sqNSCLC) progressing on PD-(L)1 inhibitors: Stage 1 PRESERVE-003 phase 3 trial. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 3O.
- ONC-392 versus docetaxel in metastatic NSCLC that progressed on PD-1/PD-L1 inhibitors (PRESERVE-003). ClinicalTrials.gov. Updated February 25, 2026. Accessed March 27, 2026. https://clinicaltrials.gov/study/NCT05671510
