Gotistobart monotherapy elicits an improved and durable antitumour response with a meaningful survival benefit relative to docetaxel in patients with metastatic squamous nonsmall cell lung cancer (sqNSCLC) who experience disease progression on or after anti-PD-(L)1 treatment, as shown by the results of the stage 1 PRESERVE-003 phase III trial.
“PRESERVE-003 stage 1 data highlight the potential of gotistobart as a chemotherapy-free option for patients with treatment-resistant sqNSCLC, a population with critical unmet need,” said study co-author Dr Kai He from the Ohio State University Comprehensive Cancer Center - James, Columbus, US.
He and his team enrolled 217 patients with sqNSCLC in stage 1 (as of 8 August 2025) and randomly allocated 87 participants to receive either gotistobart (6 mg/kg with two 10 mg/kg loading doses Q3W; n=45) or docetaxel (75 mg/m2 Q3W; n=42).
Overall survival was the primary endpoint, while objective response rate (ORR), progression-free survival (PFS), duration of response (DoR) assessed by investigators, and safety served as secondary endpoints.
Over a median follow-up of 14.5 months, the median OS was not reached in the gotistobart arm and 10 months in the docetaxel arm. Gotistobart monotherapy resulted in a 54-percent lower risk of mortality (hazard ratio [HR], 0.46, 95 percent confidence interval [CI], 0.25‒0.84; p=0.0102). [Ann Oncol 2026;11(suppl_3):1-97]
The median PFS was comparable between the two treatment arms (2.4 vs 2.6 months), but the PFS tail favoured gotistobart, with a 12-month rate of 25 percent as opposed to 0 percent for docetaxel (HR, 0.69, 95 percent CI, 0.42‒1.13 in favour of gotistobart). For the other secondary outcomes, the confirmed ORR was significantly higher for gotistobart (20 percent, 95 percent CI, 9.6‒34.6) than for docetaxel (4.8 percent, 95 percent CI, 0.6‒16.2), as was the median DoR (11 vs 3.8 months).
Adverse events
Safety was manageable, with similar rates of treatment-related adverse events (TRAEs) between the two treatment arms (84.4 percent vs 90.2 percent). The rates of grade ≥3 TRAEs also did not significantly differ between groups (42.2 percent vs 48.8 percent). The most common TRAEs were diarrhoea (28.9 percent) and increased alanine aminotransferase (ALT; 28.9 percent) with gotistobart and anaemia (36.6 percent) and decreased neutrophil count (24.4 percent) with docetaxel.
“The incidence of grade ≥3 TRAE events was consistent with the known safety profiles of both agents, with no unexpected toxicities observed in either treatment group,” He said.
“Mitigation strategies include close monitoring (particularly for events such as colitis and immune-mediated lung disease), dose interruptions, and management with corticosteroids and/or supportive care, according to American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines,” according to He and colleagues. [J Clin Oncol 2021;39:4073-4126; NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer Version 8]
Mechanism
In preclinical studies, gotistobart demonstrated greater antitumour activity and a lower risk of immune-related AE (irAE) than other anti-CTLA-4 antibodies tested due to its unique mechanism of action. [Cell Res 2019;29:609-627]
“Gotistobart binds well to CTLA-4 at pH 6.0 or above but disassociates from its target at pH 6.0 or lower,” He and colleagues said. “This pH dependency allows it to avoid antibody-induced lysosomal degradation of CTLA-4, the root cause of toxicity and reduced antitumour activities of other anti-CTLA-4 antibodies in preclinical models.”
Other studies showed how engineering acidic pH sensitivity into ipilimumab enhanced the antitumour activity in a preclinical tumour model while reducing the risk of irAEs. [Proc Natl Acad Sci USA 2025;122:e2422731122]
“The clinical data presented herein provide clinical proof of concept for preserving the CTLA-4 immune checkpoint to achieve safer and more effective therapeutic targeting of CTLA-4,” He and colleagues said. [Trends Pharmacol Sci 2020;41:4-12]
The second stage of PRESERVE-003 will evaluate patients with sqNSCLC globally, with enrolment nearing its completion, according to He.