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

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/m²and pemetrexed 500 mg/m²every 3 weeks (Q3W) for four cycles, followed by maintenance durvalumab 1500 mg plus pemetrexed 500 mg/m²Q4W, 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/m²and pemetrexed 500 mg/m²Q3W for four cycles, followed by maintenance pembrolizumab 200 mg plus pemetrexed 500 mg/m²Q3W. 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. Trial registration: ClinicalTrials.gov identifier: NCT06008093 (registration date: August 17, 2023).