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

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.

Trial registration:

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

Plain language summary

TRITON: a clinical trial designed to compare the effectiveness and safety of tremelimumab plus durvalumab and chemotherapy with pembrolizumab plus chemotherapy as a first treatment for patients with non-squamous metastatic non-small-cell lung cancer (NSCLC) whose tumors have mutations or co-mutations in the STK11, KEAP1, or KRAS genes

Tremelimumab and durvalumab are two different types of immunotherapy; they work by blocking two different proteins (called CTLA-4 and PD-L1, respectively) that prevent the body’s immune system from attacking and killing cancer cells. The combination of tremelimumab plus durvalumab and chemotherapy is approved as a first treatment for patients with NSCLC that has spread from its original site to other parts of the body (metastatic disease). This approval was based on the results of the phase III POSEIDON clinical study.

In some types of metastatic NSCLC, the tumor cells contain DNA mutations in STK11 and/or KEAP1 (genes that control cell growth and division). Patients with these tumors tend not to live as long as other patients when treated with immunotherapy that blocks PD-L1 (or a related protein called PD-1) with or without chemotherapy. This is especially true when the tumor cells also contain mutations in the KRAS gene. Mutations in the STK11 and/or KEAP1 and/or KRAS genes are more common in non-squamous NSCLC (a type of NSCLC that begins in the thin, flat cells lining the airways) than in other types of NSCLC.

The results of an exploratory analysis of POSEIDON suggested that patients with tumors carrying STK11 and/or KEAP1 and/or KRAS mutations, which can make their disease harder to treat, might particularly benefit from treatment with tremelimumab plus durvalumab and chemotherapy. However, the POSEIDON study was not designed to answer this question. The TRITON study includes only patients with tumors carrying these types of mutations, to show specifically whether tremelimumab plus durvalumab and chemotherapy may be useful for these patients.

To be eligible to participate in the TRITON study, patients must have:

• Non-squamous metastatic NSCLC carrying mutations in the STK11 and/or KEAP1 and/or KRAS genes;

• Not received any systemic therapy (treatment that affects the whole body) for metastatic NSCLC, or any immunotherapy in the previous 6 months;

• No mutations in the EGFR or ALK genes.

Approximately 280 eligible patients will be randomly assigned in equal numbers to one of two treatment groups:

• Tremelimumab plus durvalumab and chemotherapy;

• Pembrolizumab plus chemotherapy (a different standard treatment for non-squamous metastatic NSCLC).

The TRITON study will compare the length of time that participants remain alive after starting treatment (overall survival) in the two treatment groups. The study will also compare other measures of how well each treatment works and will describe their side effects.

Keywords

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

Introduction

The introduction of therapies targeting programmed cell death-1 (PD-1) or its ligand programmed cell death ligand-1 (PD-L1), given either as monotherapy or in combination with chemotherapy, has transformed the first-line therapy of metastatic non-small-cell lung cancer (mNSCLC), leading to major improvements in patient survival and quality of life.^1,2 However, not all patients’ disease responds well to treatment with anti-PD-(L)1-based regimens.^3,4 Comparatively poor outcomes may be explained in part by the presence of inactivating mutations in the tumor suppressor genes STK11 and KEAP1, which occur in approximately 20% and 15% of patients with non-squamous mNSCLC, respectively, with greater frequency in PD-L1-negative tumors.^4–6

STK11 and KEAP1 mutations are major drivers of an immunologically inert or “cold” tumor microenvironment in non-small-cell lung cancer (NSCLC), characterized by relatively few infiltrating CD3+, CD4+, and CD8+ T-lymphocytes and low tumor cell PD-L1 expression, as well as a comparatively high median tumor mutational burden (TMB).^4,7–10 STK11 mutations promote an immunosuppressive microenvironment via multiple mechanisms, including increased lactate production suppressing T-cell function and driving M2 macrophage polarization,¹¹ suppressed STING signaling,¹² and increased production of immunosuppressive cytokines including IL-6.^13,14 KEAP1 mutations (commonly loss-of-function mutations) disrupt KEAP1 binding to NRF2, leading to constitutive activation of NRF2-regulated pathways,^15–18 which, in turn, results in enhanced growth and survival of tumor cells, and enables immune evasion.^16,17,19

Mutations in STK11 and KEAP1 are negatively prognostic; NSCLC with STK11 and/or KEAP1 mutations is one of the most aggressive malignancies, and is commonly resistant both to standard cytotoxic chemotherapy and to radiotherapy.^4,20–25 The efficacy of immunotherapy (PD-(L)1 inhibitors) against these types of tumors is also relatively limited, irrespective of the level of PD-L1 expression and TMB status.^{4,8,9,25–27} A retrospective analysis in patients with KRAS^G12C-mutant mNSCLC suggests that the role of STK11 mutations in NSCLC may not be purely prognostic, as co-mutations in STK11 did not impact outcomes to treatment with KRAS G12C inhibitors, while KEAP1 mutations appear to be strongly prognostic across treatment types.²⁸

Activating KRAS mutations are the most frequent oncogenic driver in early-stage NSCLC and mNSCLC, occurring in up to a third of tumors.⁹ Standard-of-care immunotherapy (with or without chemotherapy) has demonstrated efficacy in mNSCLC with KRAS mutations^4,29,30; however, there is substantial variability in reported outcomes. Some of this variability may be explained by the presence of co-mutations in STK11 and KEAP1, which significantly co-occur with mutant KRAS as well as with each other.^5,7 The reduced efficacy of anti-PD-(L)1-based therapy in patients with mNSCLC is especially notable with co-mutations of STK11 and KEAP1, or when either of these genes is co-mutated with KRAS.^25,31–33 There is a clear need for effective therapeutic strategies for patients with poor-prognosis NSCLC tumors that harbor these clinically relevant mutations and co-mutations; recent evidence suggests that such patients may benefit from the incorporation of anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents into their treatment regimen, to enhance the immune response.

In the open-label, phase III POSEIDON study (NCT03164616) in patients (n = 1,013) with EGFR/ALK wild-type mNSCLC, a limited course of first-line tremelimumab (anti-CTLA-4) added to durvalumab (anti-PD-L1; treatment until disease progression) and four cycles of chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone, without a meaningful additional tolerability burden.³⁴ Median PFS was 6.2 months with tremelimumab plus durvalumab and chemotherapy and 4.8 months with chemotherapy (hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.60–0.86; p = 0.0003), while median OS was 14.0 months with tremelimumab plus durvalumab and chemotherapy versus 11.7 months with chemotherapy (HR 0.77; 95% CI 0.65–0.92; p = 0.0030). Although first-line durvalumab plus chemotherapy also significantly improved PFS compared with chemotherapy (HR 0.74; 95% CI 0.62–0.89; p = 0.0009), the difference in OS did not reach statistical significance (HR 0.86; 95% CI 0.72–1.02; p = 0.0758).³⁴ A prespecified updated analysis of OS after a median follow-up of over 5 years³⁵ confirmed that adding tremelimumab to durvalumab and chemotherapy provided a sustained improvement in OS compared with chemotherapy alone (HR 0.76; 95% CI 0.64–0.89); the 5-year OS rate with tremelimumab plus durvalumab and chemotherapy (15.7%) was more than twice that with chemotherapy (6.8%). The improvement in OS with tremelimumab plus durvalumab and chemotherapy versus chemotherapy was more marked in patients with non-squamous (HR 0.69; 95% CI 0.56–0.85) than squamous histology (HR 0.85; 95% CI 0.65–1.10).³⁵ Based on these findings, tremelimumab in combination with durvalumab and platinum-based chemotherapy was approved for first-line treatment of mNSCLC without sensitizing EGFR mutations and ALK genomic aberrations.^36,37

An exploratory analysis of POSEIDON with a median follow-up of more than 5 years compared survival outcomes between patients with and without mutations in KEAP1, STK11, and KRAS.³⁵ Mutation status was determined using tumor and plasma samples collected at baseline. Among 612 patients with non-squamous mNSCLC, 244 patients (39.9%) had at least one of these three mutations, including 14% who had STK11 mutations, 6% who had KEAP1 mutations, and 30% who had KRAS mutations.³⁵ The influence of STK11 and KRAS mutation status on treatment outcomes was evaluated in patients with non-squamous histology; due to the small sample size, the influence of KEAP1 mutation status was evaluated irrespective of tumor histology. Greater relative OS benefit with tremelimumab plus durvalumab and chemotherapy versus chemotherapy was observed in subsets of patients with tumors bearing STK11 (HR 0.57; 95% CI 0.32–1.04), KEAP1 (HR 0.43; 95% CI 0.16–1.25), and KRAS mutations (HR 0.55; 95% CI 0.36–0.83).³⁵ In the non-squamous subset with STK11 mutations (n = 87 across the three treatment arms), median OS was 15.0 months (95% CI 8.2–23.8) with tremelimumab plus durvalumab and chemotherapy versus 10.7 months (95% CI 6.0–14.9) with chemotherapy alone; the 5-year OS rates were 12.9% versus 0%. In the subset with KEAP1 mutations (n = 51 across the three arms), median OS was 13.7 months (95% CI 7.2–26.5) with tremelimumab plus durvalumab and chemotherapy versus 8.7 months (95% CI 5.1–not estimable) with chemotherapy alone, and the 5-year OS rates were 10.0% versus 0%. In this subset, 95% CIs for both HR and median OS were relatively wide due to the small sample size. Lastly, in the non-squamous subset with KRAS mutations (n = 182 across the three arms), median OS with tremelimumab plus durvalumab and chemotherapy versus chemotherapy was 25.7 months (95% CI 9.9–36.7) versus 10.4 months (95% CI 7.3–12.6), with 5-year OS rates of 21.7% versus 8.1%. In all three mutation subsets, the magnitude of OS benefit with tremelimumab plus durvalumab and chemotherapy compared with chemotherapy alone was numerically greater than that with durvalumab plus chemotherapy versus chemotherapy, for which HRs in the subsets with STK11, KEAP1, and KRAS mutations were 1.02 (95% CI 0.59–1.80), 0.77 (95% CI 0.31–2.15), and 0.74 (95% CI 0.50–1.09), respectively. Similar trends were observed for PFS and objective response by STK11, KEAP1, and KRAS mutation status at an earlier data cutoff.^10,38 Although these findings were derived from subgroup analyses, the signals of efficacy were promising, suggesting that treatment regimens incorporating CTLA-4 inhibitors plus PD-(L)1 inhibitors plus chemotherapy may provide effective first-line treatment options for patients with this type of less responsive disease.³⁵ It is notable that most patients (~90%) in this analysis had evaluable circulating tumor DNA (ctDNA) samples^35,38; ctDNA shedding is associated with worse prognosis in a number of cancer types, including advanced NSCLC.³⁹

Post hoc exploratory analyses of other phase III trials in treatment-naïve patients with EGFR and ALK wild-type mNSCLC have also investigated the impact of STK11, KEAP1, and KRAS mutation status on outcomes with immune checkpoint inhibitors, given with or without chemotherapy. For example, the KEYNOTE-189 trial showed that pembrolizumab (anti-PD-1) plus platinum-based chemotherapy improved OS and PFS in the overall study population compared with chemotherapy alone in patients with non-squamous mNSCLC⁴⁰; these benefits were achieved regardless of STK11, KEAP1, or KRAS mutation status, although less pronounced in mutation versus wild-type subgroups.⁴¹ In CheckMate 227 and CheckMate 9LA, treatment with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) or with nivolumab plus ipilimumab plus chemotherapy, respectively, also demonstrated improvements in OS versus chemotherapy in the overall study populations as well as in patients with STK11, KEAP1, or KRAS mutations.^42,43 Furthermore, in CheckMate 227, CheckMate 9LA, and POSEIDON, the benefit of treatment with dual immunotherapy (with or without chemotherapy) was seen regardless of PD-L1 expression level.^34,42,44 Given the association of STK11 mutations in particular with low PD-L1 expression,^10,32,45 and also in some studies an association of KEAP1 with low PD-L1 expression,^32,45 these data support the use of dual immunotherapy in patients with tumors harboring these mutations.

To date, no randomized phase III trial has prospectively assessed outcomes with immunotherapy (including the combination of a PD-(L)1 inhibitor plus a CTLA-4 inhibitor) in these subsets of patients with mNSCLC that have a suboptimal response to immunotherapy and chemotherapy. Building on the signals of efficacy observed in POSEIDON in patients with STK11, KEAP1, and KRAS mutations, the phase IIIb TRITON trial (NCT06008093) is prospectively investigating treatment with tremelimumab plus durvalumab in combination with platinum-based chemotherapy in patients with non-squamous mNSCLC and mutations or co-mutations in STK11, KEAP1, or KRAS. In this population, the efficacy of tremelimumab plus durvalumab and chemotherapy will be compared with that of pembrolizumab plus platinum-based chemotherapy, which became a standard-of-care first-line treatment for patients with non-squamous mNSCLC and no targetable EGFR or ALK genomic aberrations, independent of tumor PD-L1 expression, based on the KEYNOTE-189 and -021 clinical trial results.^40,46 Here, we describe the design of the TRITON trial.

Methods

Study design

TRITON (NCT06008093) is a phase IIIb, multicenter, open-label, two-arm parallel randomized trial comparing the efficacy of tremelimumab plus durvalumab and chemotherapy with pembrolizumab plus chemotherapy, in patients with non-squamous mNSCLC with mutations or co-mutations in STK11, KEAP1, or KRAS (Figure 1). Eligible patients enrolled from up to 75 sites across the United States (see https://www.clinicaltrials.gov/study/NCT06008093#contacts-and-locations) will be randomized 1:1 to receive either tremelimumab plus durvalumab and platinum-based doublet chemotherapy (Arm 1) or pembrolizumab plus platinum-based doublet chemotherapy (Arm 2).

Figure 1.

Study design.

Randomization will be stratified by mutation status and by tumor cell (TC) PD-L1 expression (TC <1% vs TC ⩾1%) as determined by the VENTANA PD-L1 (SP263) immunohistochemistry (IHC) assay (VENTANA Medical Systems, Tucson, AZ, USA) or PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA, USA; Table 1). The strata based on mutation status will comprise the following: patients with STK11 mutation, with or without KRAS mutation (the STK11 stratum); patients with KEAP1 mutation, with or without mutations in either STK11 or KRAS or STK11 plus KRAS (the KEAP1 stratum); and patients with KRAS mutation, without mutations in either STK11 or KEAP1 (the KRAS stratum). Randomization into the STK11 and KEAP1 strata will be based on all comers; randomization into the KRAS stratum will be capped at 33% of the total sample size.

Table 1.

Stratification factors for randomization.

Eligible patients	First stratification	Second stratification	Randomization
Treatment-naïve non-squamous metastatic NSCLC with STK11m and/or KEAP1m and/or KRASm	STK11 stratum STK11m only STK11m + KRASm	PD-L1 TC <1%	Each subgroup was randomized 1:1 to: Tremelimumab + durvalumab + platinum + pemetrexed OR Pembrolizumab + platinum + pemetrexed
	STK11 stratum STK11m only STK11m + KRASm	PD-L1 TC ⩾1%
	KEAP1 stratum KEAP1m only KEAP1m + STK11m KEAP1m + KRASm KEAP1m + STK11m + KRASm	PD-L1 TC <1%PD-L1 TC ⩾1%
	KRAS stratum KRASm only (capped at 33% of the total sample size)	PD-L1 TC <1%PD-L1 TC ⩾1%

m, mutation; NSCLC, non-small-cell lung cancer; PD-L1, programmed cell death ligand-1; TC, tumor cell.

In Arm 1, patients will receive intravenous tremelimumab 75 mg plus durvalumab 1500 mg plus either carboplatin area under the curve (AUC) 5 or 6 (at the discretion of the treating physician) or cisplatin 75 mg/m² and pemetrexed 500 mg/m² every 3 weeks (Q3W) for four cycles, followed by maintenance treatment with durvalumab 1500 mg plus pemetrexed 500 mg/m² every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. During the maintenance period, an additional dose of tremelimumab 75 mg will be given post-platinum at week 16, with an optional further dose at month 24 (at the investigator’s discretion), in combination with durvalumab and pemetrexed. In Arm 2, patients will receive intravenous pembrolizumab 200 mg plus either carboplatin AUC 5 or 6 (at the discretion of the treating physician) or cisplatin 75 mg/m² and pemetrexed 500 mg/m² Q3W for four cycles, followed by maintenance treatment with pembrolizumab 200 mg (for up to 24 months) plus pemetrexed 500 mg/m² Q3W until disease progression, unacceptable toxicity, or withdrawal of consent.

The reporting of this study conforms to the SPIRIT 2025 statement⁴⁷ (Supplemental File).

Key eligibility criteria

To be eligible, patients must be aged ⩾18 years and have histologically or cytologically documented metastatic (stage IV) non-squamous NSCLC, Eastern Cooperative Oncology Group performance status 0/1 at enrollment and randomization, and at least one lesion that has not previously been irradiated and qualifies as a Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) target lesion at baseline, with the longest diameter ⩾10 mm. In addition, patients must not have received any systemic therapy for mNSCLC or any immune-mediated therapies in the 6 months before randomization. Tumors must carry STK11, KEAP1, or KRAS mutations or co-mutations, identified before randomization; activating EGFR mutations and ALK fusions must be absent. Pre-existing mutation test results using local testing via next-generation sequencing (NGS) or non-NGS tests are acceptable. A formalin-fixed paraffin-embedded tumor tissue sample (or, if not available, unstained tissue sections) for NGS of tumor DNA, as well as a pre-treatment blood sample for ctDNA analysis, must be provided at screening to confirm the presence of functional mutations in STK11, KEAP1, or KRAS.

Patients are excluded if they have acute or uncontrolled disease, a history of allogeneic organ transplantation or another primary malignancy, or documented prior or active autoimmune or inflammatory disorders. Patients with suspected brain metastases should have intravenous contrast-enhanced magnetic resonance imaging (preferred) or computed tomography of the brain before study entry. Detected brain metastases must be treated before randomization, which is permitted if patients are in a confirmed stable condition and have returned neurologically to baseline. Further details of the study inclusion and exclusion criteria are shown in Table 2.

Table 2.

Key inclusion and exclusion criteria.

Inclusion criteria
• Age ⩾18 years • Histologically or cytologically documented stage IV non-squamous NSCLC, not amenable to curative surgery or radiation • Tumors bearing STK11, KEAP1, or KRAS mutations or co-mutations • No activating EGFR mutations or ALK fusions • ECOG performance status 0 or 1 at enrollment and randomization • At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 target lesion, with the longest diameter ⩾10 mm at baseline, and suitable for accurate repeated measurements per RECIST v1.1 • No prior chemotherapy or other systemic therapy for metastatic NSCLC. Prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy for advanced disease is allowed if progression occurred >6 months from the end of the last therapy • No prior immune-mediated therapy (excluding therapeutic anti-cancer vaccines) in the 6 months before randomization • Adequate organ and bone marrow function • Life expectancy ⩾12 weeks at randomization • Body weight >30 kg • Capable of giving signed informed consent
Exclusion criteria
• Mixed SCLC and NSCLC histology • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, autoimmune pneumonitis, and autoimmune myocarditis) • Evidence of acute or uncontrolled disease, or history of allogeneic organ transplantation, which in the investigator’s opinion makes it undesirable for the patient to participate in the study, or that would jeopardize compliance with the protocol • Major surgical procedure (as defined by the investigator) within 28 days before first dose of study treatment • Medical contraindication to treatment with platinum-based doublet chemotherapy • History of another primary malignancy, except: ○ Malignancy treated with curative intent with no known active disease ⩾2 years before first dose of study drugs and of low risk of recurrence ○ Adequately resected non-melanoma skin cancer and curatively treated in situ disease • History of leptomeningeal carcinomatosis • Spinal cord compression, unless asymptomatic and stable • Patients with suspected brain metastases should have a brain MRI or CT/CT-PET scan before study entry; detected brain metastases must be treated before randomization, which is permitted if patients are stable and have returned neurologically to baseline • Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment • Persistent toxicity NCI CTCAE grade ⩾2 from previous anticancer therapy ○ Patients with irreversible toxicity not reasonably expected to be exacerbated by study treatment, in the opinion of the investigator, may be included • Immunosuppressive medication or live attenuated vaccine within 14 and 30 days, respectively, before the first dose of study drugs • Radiation therapy, except (1) definitive radiation ⩾6 months prior, (2) palliative brain radiation, with associated criteria for stability or lack of symptoms, or (3) palliative radiation to painful bony lesions (must occupy <30% of the bone marrow) • Positive test for active tuberculosis infection • Active hepatitis infection, positive HCV antibody, HBsAg, or anti-HBc at screening • HIV infection that is not well controlled

Anti-HBc, hepatitis B core antibody; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; NCI, National Cancer Institute; NSCLC, non-small-cell lung cancer; PET, positron emission tomography; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SCLC, small-cell lung cancer.

Study endpoints

The dual primary endpoints are OS in all randomized patients (intention-to-treat population), and OS in patients with STK11 or KEAP1 mutations or co-mutations, excluding patients with KRAS mutation alone (the STK11m/KEAP1m subset).

Secondary endpoints include the OS rate at 12 and 24 months in the intention-to-treat population and the STK11m/KEAP1m subset; OS and the OS rate at 12 and 24 months in the PD-L1 TC <1% subset; PFS (defined as the time from randomization until progression or death from any cause), objective response rate (defined as the proportion of patients with confirmed complete response or partial response), and duration of response (defined as the time from the date of first documented confirmed response until the date of documented progression or death from any cause), all as assessed by the investigator per RECIST v1.1; time to first subsequent treatment or death (defined as the time from randomization until the start date of the first subsequent anti-cancer therapy after discontinuing randomized study intervention, or death from any cause); and safety and tolerability.

Study assessments

Tumor assessments by computed tomography (preferred) or magnetic resonance imaging (per RECIST v1.1) will be performed every 6 weeks until week 12 after randomization, then every 9 weeks until week 48, and every 12 weeks thereafter, until RECIST v1.1-defined radiological progression, withdrawal of consent, or death. Following confirmed disease progression or treatment discontinuation, patients will be followed for survival at months 2, 3, and 4, and then every 8 weeks until the end of the study. Safety will be monitored throughout the study, and adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. An independent data monitoring committee will conduct an interim analysis of objective response rate and may also assess safety data on an ad hoc basis.

Statistical analysis

Approximately 330 patients will be screened to achieve approximately 280 patients randomized to study treatment. No statistical hypotheses are planned to be tested in this study, which is sized to characterize trends in OS in the intention-to-treat population and the STK11m/KEAP1m subset using a non-hypothesis testing approach. The primary OS endpoints will be assessed via HRs and corresponding nominal two-sided 95% CIs using a Cox proportional hazards model adjusted for stratification factors at randomization. Median OS and OS rates at 12 and 24 months will be assessed using Kaplan–Meier methods. Safety will be summarized descriptively in all patients who received at least one dose of study treatment.

Discussion

A combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody plus chemotherapy may help to improve outcomes in subgroups of patients with mutations in STK11 and/or KEAP1, with or without co-mutations in KRAS. To our knowledge, TRITON is the first randomized phase III study to prospectively evaluate immune checkpoint inhibitors in a mNSCLC population with mutations or co-mutations in STK11, KEAP1, or KRAS. The results of the TRITON study will help to inform clinical practice and to establish a more personalized, biomarker-driven first-line paradigm for patients with these poor-prognosis subtypes of mNSCLC, for whom the only biomarker currently used to guide some (although not all) immunotherapy-based regimens is PD-L1 expression. The first patient was enrolled in April 2024, and recruitment is ongoing. Primary completion is anticipated in August 2027, and full study completion is estimated to be in March 2031.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251386611 – Supplemental material for 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

Supplemental material, sj-docx-1-tam-10.1177_17588359251386611 for 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 by 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 and John V. Heymach in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors would like to thank the patients, their families and caregivers, and all investigators involved in the study. Medical writing support for the development and submission of this article, under the direction of the authors, was provided by Jean Scott, PhD, and Michael Simpson, PhD, of Ashfield MedComms (Manchester, UK), an Inizio company, and was funded by AstraZeneca.

Declarations

ORCID iD

Ferdinandos Skoulidis

Supplemental material

Supplemental material for this article is available online.

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