TRITON Study to Target Biomarkers for Patients With Select NSCLC Mutations

The phase 3b TRITON study (NCT06008093) will delve deeper into the effectiveness of a triplet regimen that encompasses immunotherapy of tremelimumab (anti–CTLA-4 and can block binding of CD80 and CD 86 to CD28) and durvalumab (anti–PD-L1 and can block binding of PD-L1 to PD-1 and CD80) plus standard-of-care (SOC) chemotherapy vs pembrolizumab and SOC chemotherapy for metastatic non–small lung cancer (NSCLC) harboring STK11 and/or KEAP1 and/or KRAS mutations.¹ The trial will build on results seen in the phase 3 POSEIDON trial (NCT03164616), which investigated this same regimen in the first line vs durvalumab with chemotherapy or chemotherapy alone²; findings from the trial led to the approval of tremelimumab and durvalumab plus chemotherapy for NSCLC.³

A subgroup analysis of patients from POSEIDON who harbored the 3 mutations showed they were likely to benefit from the triplet treatment, but the investigators noted the first trial was not powered to thoroughly investigate that outcome.³

These data were presented at the recent American Society of Clinical Oncology annual meeting, held May 31 to June 4 in Chicago.

The TRITON study stems from an exploratory analysis of the POSEIDON trial, which looked at how the presence of STK11 and/or KEAP1 and/or KRAS mutations may affect treatment for nonsquasmous NSCLC| Image Credit: photon_photo-stock.adobe.com

With a primary outcome of overall survival indicating treatment efficacy, and secondary outcomes that include safety/tolerability, time to first subsequent therapy or death, and overall survival (OS) at 12 and 24 months, patients in TRITON are being randomized 1:1 to either treatment group; inclusion criteria are age 18 years and older, diagnosis of nonsquamous NSCLC refractory to surgery or radiation, at least 1 lesion that has not been irradiated and fits RECIST v1.1 criteria, no systemic therapy for metastasis and no immunotherapy in the past 6 months, no EGFR or ALK mutations, an ECOG Performance Status score of 0 or 1, and confirmation of STK11 and/or KEAP1 and/or KRAS mutations or comutations.³

Treatment will initiate with induction of up to 4 cycles in each group. In the treatment group, the cycles will encompass 75-mg tremelimumab every 3 weeks, 1500-mg durvalumab every 3 weeks, and platinum chemotherapy (either carbopolatin AUC 5/6 or cisplatin 75 mg/m²) and pemetrexed 500mg/m² every 3 weeks, followed by maintenance of each regimen. In the pembrolizumab/chemotherapy group, induction will consist of 200-mg pembrolizumab every 3 weeks, 1500-mg durvalumab every 4 weeks, and platinum chemotherapy (either carbopolatin AUC 5/6 or cisplatin 75 mg/m²) and pemetrexed 500mg/m² every 3 weeks.

Maintenance treatment will follow, and in the treatment group this will consist of 75-mg tremelimumab and 1500-mg durvalumab every 4 weeks plus pemetrexed 500mg/m² every 4 weeks. In the pembrolizumab/chemotherapy group, maintenance will consist of 200-mg pembrolizumab every 3 weeks plus pemetrexed 500mg/m² every 3 weeks. Maintenance will be administered until disease progression, unacceptable toxicity, or consent withdrawal. The study investigators highlighted that additional doses of tremelimumab can be administered “at the investigator’s discretion” at week 16 after platinum treatment and at month 24.

In close to 20% and 15% of cases, respectively, individuals with nonsquamous NSCLC who have STK11 and KEAP1 mutations have a greater likelihood of poor outcomes, with previous research identifying correlations between these mutations and both low PD-L1 expression and T-cell activity.^4-7 This effect is amplified in the presence of a KRAS mutation.

Primary findings from POSEIDON show that among the 1013 patient population, median progression-free survival (PFS) was 6.2 months with tremelimumab/durvalumab/chemotherapy vs a PFS of 4.8 months with chemotherapy alone, for a 28% reduced risk of death (HR, 0.72; 95% CI, 0.60-0.86; P = .0003). OS was also superior with tremelimumab/durvalumab/chemotherapy, at 14 months vs 11.7 months with chemotherapy, for a 23% reduced risk of death (HR, 0.77; 95% CI, 0.65-0.92; P = .003).

The POSEIDON exploratory analysis that dovetailed into the TRITON investigation saw STK11 mutations in 14% of the patients with nonsquamous NSCLC (n = 87), KEAP1 mutations in 6% (n = 51), and KRAS mutations in 30% (n = 182). In this subanalysis, those with KRAS mutations had the longest median OS with tremelimumab/durvalumab/chemotherapy (25.7 months; 95% CI, 9.9-36.7), followed by patients with STK11 mutations (15.0 months; 95% CI, 8.2-23.8) and KEAP1 mutations (13.7 months; 955CI, 7.2-26.5). The corresponding OS measures for chemotherapy alone were 10.4 months (95% CI, 7.3-12.6), 10.7 months (95% CI, 6.0-14.9), and 13.7 months (95% CI, 7.2-26.5).

As with the overall POSEIDON investigation, the 5-year OS advantage in the exploratory analysis was clear for the combination compared with chemotherapy alone:

• KRAS subset: 21.7% vs 8.1%
• KEAP1 subset: 10% vs 0%
• STK11 subset: 12.9% vs 0%

The TRITON investigators are hoping for a patient population of 280; the estimated primary study completion date is August 17, 2027, and the estimated completion date is March 5, 2031.¹ Eleven states have active sites, 10 more sites are planned, and there will be up to 75 sites overall.

References

1. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic non-small cell lung cancer (NSCLC) patients (TRITON). ClinicalTrials.gov. Updated April 29, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT06008093

2. Study of durvalumab + tremelimumab with chemotherapy or durvalumab with chemotherapy or chemotherapy alone for patients with lung cancer (POSEIDON). (POSEIDON). ClinicalTrials.gov. Updated March 5, 2024. Accessed June 11, 2024. https://www.clinicaltrials.gov/study/NCT03164616

3. Skoulidis F, Borghaei H, Garon EB, et al. 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 STK11and/or KEAP1 and/or KRAS mutations. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Poster TPS8655.

4. Tanaka I, Koyama J, Itoigawa H, Haya S, Morise M. Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies. Front Oncol. 2023;13:1249237. doi:10.3389/fonc.2023.1249237

5. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol. 2015;16(7):e342-e351. doi:10.1016/S1470-2045(15)00077-7

6. Dabbous F, Wang CY, Simmons D, Huse S. Prevalence of STK11, KEAP1, and KRAS mutations/co-mutations and associated clinical outcomes for patients newly diagnosed with metastatic non-small cell lung cancer. J Clin Oncol. 2023;41(16_suppl):e21186. doi:10.1200/JCO.2023.41.16_suppl.e2118

7. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495-509. doi:10.1038/s41568-019-0179-8