TRITON: Phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with <i>STK11</i>and/or <i>KEAP1</i> and/or <i>KRAS</i> mutations.
Authors: Ferdinandos Skoulidis, Hossein Borghaei, Edward B. Garon, Ticiana Leal, Stephen V. Liu, Eric S. Nadler, Sandip Pravin Patel, Vamsidhar Velcheti, Ashish Gautam, Ugochinyere Emeribe, Luisa Luciani-Silverman, John Heymach
Journal: Journal of Clinical Oncology (2024)

TPS8655 Background: Mutations in STK11 and KEAP1, present in approximately 20% and 15% of patients (pts) respectively with NSQ mNSCLC, lead to an immunosuppressive tumor microenvironment and are associated with inferior clinical outcomes with anti-PD-(L)1 based chemo-immunotherapy, especially when co-mutated with KRAS. Pts with tumors bearing STK11, KEAP1and/or KRAS mutations may benefit from combinations with CTLA-4 inhibitors, aimed at increasing immune responses. In the phase 3 POSEIDON trial (NCT03164616), first-line (1L) T+D+CT significantly improved overall survival (OS; HR 0.77 [95% CI 0.65–0.92]; P=0.0030) vs CT. These results were maintained after a median follow-up of &gt;5 years. Subgroup analyses showed sustained OS improvement with T+D+CT vs CT in pts with mNSCLC with STK11 (NSQ), KEAP1(all histologies, due to small sample size), and KRAS (NSQ) mutations (HR [95% CI] 0.57 [0.32–1.04), 0.43 [0.16–1.25], and 0.55 [0.36–0.83], respectively). The TRITON study will further investigate the signal of efficacy observed in the POSEIDON subgroup analysis. The study will compare T+D+CT vs P+CT (a standard treatment for NSQ mNSCLC) in pts with STK11 and/or KEAP1 and/or KRASmutations. The results will help to inform clinical practice and to establish a biomarker-driven treatment strategy for these difficult-to-treat pts. Methods: TRITON (NCT06008093) is a phase 3b, multicenter, open-label, 2-arm parallel randomized study. Eligible pts, aged ≥18 years, must have NSQ mNSCLC (no EGFR or ALK alterations), with STK11, KEAP1, or KRAS mutations/co-mutations, no prior systemic therapy for mNSCLC, and ECOG performance status of 0/1. Approximately 280 pts will be randomized 1:1 to receive either T+D+CT or P+CT. In the T+D+CT arm, pts will receive T (75 mg) + D (1500 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m 2 ) + pemetrexed (500 mg/m 2 ) every 3 weeks (Q3W) for 4 cycles (a fifth dose of T [75 mg] will be given in combination with D, post-platinum at week 16), followed by maintenance D (1500 mg) + pemetrexed (500 mg/m 2 ) Q4W until disease progression (PD). In the P+CT arm, pts will receive P (200 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m 2 ) + pemetrexed (500 mg/m 2 ) Q3W for 4 cycles, followed by maintenance P (200 mg) + pemetrexed (500 mg/m 2 ) Q3W until PD, for up to 24 months. Randomization is stratified by mutation type ( KRAS [without STK11 or KEAP1] mutations are capped at 33% of the total sample) and tumor PD-L1 expression (≥1% vs &lt;1%). Primary endpoints are OS in all pts and in the subset with STK11 or KEAP1 mutations/co-mutations. Key secondary endpoints include OS rates at 12 and 24 months, progression-free survival, objective response rate, duration of response (all RECIST v1.1; investigator-assessed) and safety/tolerability (CTCAE v5.0). Enrollment is ongoing. Clinical trial information: NCT06008093 .