Rationale and Design for a Phase IIIb Trial of First-Line Tremelimumab Plus Durvalumab Versus Pembrolizumab, in Combination With Chemotherapy, in Patients With Non-squamous Metastatic Non-Small-Cell Lung Cancer and Mutations or Co-mutations in STK11, KEAP1, or KRAS: the TRITON Study

Authors

Ferdinandos Skoulidis
Hossein Borghaei
Edward B Garon
Ticiana A Leal
Jacob Kaufman
Stephen V Liu
Eric Nadler
Sandip Pravin Patel
Solange Peters
Biagio Ricciuti
Ashish Gautam
Ugochinyere Emeribe
Luisa Luciani-Silverman
John V Heymach

Language

English

Publication Date

1-1-2025

Journal

Therapeutic Advances in Medical Oncology

DOI

10.1177/17588359251386611

PMID

41209621

PMCID

PMC12592654

PubMedCentral® Posted Date

11-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Metastatic non-small-cell lung cancers (mNSCLC) harboring mutations in STK11 or KEAP1 are associated with an immunosuppressive tumor microenvironment and reduced responsiveness to PD-(L)1 inhibitor-based therapy, which is particularly notable when these genes are co-mutated with each other or with KRAS. Patients with these mNSCLC subtypes may benefit from combinations including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, aimed at enhancing immune responses.

Objectives: TRITON is an ongoing study comparing tremelimumab plus durvalumab and chemotherapy with pembrolizumab plus chemotherapy as first-line treatment for patients with non-squamous mNSCLC and mutations or co-mutations in STK11, KEAP1, or KRAS.

Design: Phase IIIb, multicenter, open-label, two-arm parallel randomized trial.

Methods and analysis: Approximately 280 eligible patients, aged ⩾18 years, will be randomized 1:1 to receive tremelimumab 75 mg plus durvalumab 1500 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles, followed by maintenance durvalumab 1500 mg plus pemetrexed 500 mg/m2 Q4W, with an additional dose of tremelimumab 75 mg at week 16 and optional further dose at month 24; or pembrolizumab 200 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W for four cycles, followed by maintenance pembrolizumab 200 mg plus pemetrexed 500 mg/m2 Q3W. Dual primary endpoints are overall survival (OS) in all randomized patients and OS in patients with STK11 or KEAP1 mutations or co-mutations. Key secondary endpoints include 12- and 24-month OS rates, progression-free survival, objective response rate, and safety. Enrollment is ongoing.

Ethics: TRITON will be approved by the independent ethics committee or institutional review board at each study site. All participants will provide written informed consent.

Discussion: Results will help to inform clinical practice and establish a biomarker-driven treatment strategy for these subtypes of mNSCLC with high unmet need.

Keywords

CTLA-4, durvalumab, immunotherapy, metastatic non-small-cell lung cancer, PD-L1, tremelimumab

Comments

Trial registration: ClinicalTrials.gov identifier: NCT06008093 (registration date: August 17, 2023).

Published Open-Access

yes

Recommended Citation

Skoulidis, Ferdinandos; Borghaei, Hossein; Garon, Edward B; et al., "Rationale and Design for a Phase IIIb Trial of First-Line Tremelimumab Plus Durvalumab Versus Pembrolizumab, in Combination With Chemotherapy, in Patients With Non-squamous Metastatic Non-Small-Cell Lung Cancer and Mutations or Co-mutations in STK11, KEAP1, or KRAS: the TRITON Study" (2025). Faculty, Staff and Student Publications. 5829.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5829