A Study to Investigate the Efficacy of Durvalumab Plus Tremelimumab in Combination With Chemotherapy Compared With Pembrolizumab in Combination With Chemotherapy in Metastatic NSCLC Patients With Non-squamous Histology Who Have Mutations and/or Co-mutations in STK11, KEAP1, or KRAS

NCT06008093 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: D419ML00003
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 47

Brief Summary

The purpose of the study is to assess the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic NSCLC patients with non-squamous histology who have mutations and/or co-mutations in STK11, KEAP1, or KRAS.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

Mutation; Metastatic Non-Small Cell Lung Cancer; Kelch-Like ECH-Associated Protein 1 (KEAP1); Kirsten rat sarcoma virus (KRAS); Programmed death-ligand 1 (PD-L1); Serine/threonine kinase 11 (STK11)

Outcome Measures

Primary Outcomes (3)

• Progression-free survival (PFS) in randomized participants

  PFS is defined as the time from randomization until the date of confirmed PD (per Response Evaluation Criteria in Solid Tumours, Version 1.1 \[RECIST 1.1\] as assessed by the Investigator) or death due to any cause. The measure of interest is the hazard ratio (HR) and the corresponding 95% confidence interval (CI).

  From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months)

• PFS at 6 months

  PFS is defined as the time from randomization until the date of confirmed PD (per RECIST 1.1 as assessed by the Investigator) or death due to any cause. The measure of interest is the PFS rate and the corresponding 95% CI at 6 months.

  From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months)

• PFS at 12 months

  PFS is defined as the time from randomization until the date of confirmed PD (per RECIST 1.1 as assessed by the Investigator) or death due to any cause. The measure of interest is the PFS rate and the corresponding 95% CI at 12 months.

  From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months)

Secondary Outcomes (9)

• Overall survival (OS) at 12 months

  At 12 months

• OS at 24 months

  At 24 months

• OS at 12 months in subset of randomized participants with STK11, KEAP1 or KRAS mutation and/or co mutations

  At 12 months

• OS at 24 months in subset of randomized participants with STK11, KEAP1 or KRAS mutation and/or co mutations

  At 24 months

• OS in randomized participants

  From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months)

Study Arms (2)

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy

EXPERIMENTAL

Participants will receive durvalumab plus tremelimumab every 3 weeks (q3w) for four 21-day cycles in combination with chemotherapy followed by maintenance treatment period (durvalumab plus pemetrexed maintenance) every 4 weeks (q4w) until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first. During the maintenance treatment period, participants will receive additional doses of tremelimumab at Cycle 6 (Week 16) and Cycle 28 (Week 104 - at Investigator's discretion) along with durvalumab and pemetrexed.

Drug: Durvalumab; Drug: Tremelimumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Cisplatin

Arm B: Pembrolizumab + Platinum-based Chemotherapy

EXPERIMENTAL

Participants will receive pembrolizumab regimen q3w for four 21-day cycles in combination with chemotherapy as induction treatment followed by maintenance treatment (pembrolizumab plus pemetrexed maintenance) q3w for up to 24 months, until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first.

Drug: Pemetrexed; Drug: Pembrolizumab; Drug: Carboplatin; Drug: Cisplatin

Interventions

Durvalumab DRUG

Participants will receive intravenous (IV) Durvalumab q3w for four 21-day cycles as induction treatment. Durvalumab will also be given during the maintenance treatment period q4w until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first.

Also known as: MEDI4736 & IMFINZI®

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy

Tremelimumab DRUG

Participants will receive IV Tremelimumab q3w for four 21-days cycles as induction treatment. Tremelimumab will also be given during the maintenance therapy phase at week 16 and week 104 (at the investigators discretion).

Also known as: IMJUDO®

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy

Pembrolizumab DRUG

Participants will receive IV pembrolizumab q3w for four 21-days cycles as induction treatment. Pembrolizumab will also be given in the maintenance treatment phase q3w until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first.

Arm B: Pembrolizumab + Platinum-based Chemotherapy

Carboplatin DRUG

Participants will receive IV Carboplatin or IV Cisplatin on Day 1 of each 21-day cycle for 4 cycles as induction treatment.

Also known as: Background Platinum-based Chemotherapy

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy; Arm B: Pembrolizumab + Platinum-based Chemotherapy

Cisplatin DRUG

Participants will receive IV Carboplatin or IV Cisplatin on Day 1 of each 21-day cycle for 4 cycles as induction treatment.

Also known as: Background Platinum-based Chemotherapy

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy; Arm B: Pembrolizumab + Platinum-based Chemotherapy

Pemetrexed DRUG

Participants in Arm A and Arm B will receive IV pemetrexed q3w for four 21-day cycles as induction treatment. In the maintenance therapy phase, Treatment Arm A will receive Pemetrexed q4w, Treatment Arm B will receive Pemetrexed q3w until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first.

Also known as: Background Platinum-based Chemotherapy

Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy; Arm B: Pembrolizumab + Platinum-based Chemotherapy

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically documented Stage IV non-squamous NSCLC not amenable to curative surgery or radiation.
• Participants must have tumors with STK11 or KEAP1 or KRAS mutations. Co-mutations are also allowed.
• Participants must have tumors that lack activating epidermal growth factor receptor mutations and ALK fusions.
• No prior chemotherapy or any other systemic therapy for metastatic NSCLC. Participants who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred \> 6 months from end of last therapy.
• No prior exposure to immune-mediated therapy excluding therapeutic anti-cancer vaccines, within 6 months of randomization.
• WHO/ECOG performance status of 0 or 1 at enrollment and randomization.
• Minimum life expectancy ≥ 12 weeks at randomization.
• At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter with Computed Tomography (CT)/CT- Positron Emission Tomography or Magnetic Resonance Imaging and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines.
• Adequate organ and bone marrow function.
• Negative pregnancy test (urine or serum) for women of child-bearing potential
• Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control
• Male and Female participants and their partners must use an acceptable method of contraception.
• Body weight of \> 30 kg

You may not qualify if:

• Any evidence of acute or uncontrolled diseases or history of allogeneic organ transplant.
• Mixed small cell lung cancer and NSCLC histology.
• Major surgical procedure within 28 days prior to the first dose of the study intervention or an anticipated need for major surgery during the study.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis \[requiring immunosuppressive systemic therapy, eg, methotrexate, steroids\], hypophysitis, uveitis, etc), autoimmune pneumonitis and autoimmune myocarditis. The following are exceptions to this criterion:
• Participants with vitiligo or alopecia.
• Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
• Any chronic skin condition that does not require systemic therapy.
• Participants without active disease in the last 5 years may be included but only after consultation with the Study Clinical Lead.
• Participants with celiac disease controlled by diet alone.
• Medical contraindication to platinum-based doublet chemotherapy.
• History of another primary malignancy except:
• Malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence
• Adequately resected non-melanoma skin cancer and curatively treated in situ disease.
• Persistent toxicities (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade ≥ 2) caused by previous anti-cancer therapy, alopecia and vitiligo are excluded toxicities.
• Participants with Grade ≤ 2 neuropathy can be considered based on Investigator's judgement. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with study intervention in the opinion of the Investigator may be included (eg, hearing loss).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (47)

Research Site

Beverly Hills, California, 90211, United States

Location

Research Site

La Jolla, California, 92093, United States

Location

Research Site

Los Alamitos, California, 90720, United States

Location

Research Site

Los Angeles, California, 90034, United States

Location

Research Site

Santa Monica, California, 90404, United States

Location

Research Site

Washington D.C., District of Columbia, 20007, United States

Location

Research Site

Fort Lauderdale, Florida, 33308, United States

Location

Research Site

Jupiter, Florida, 33458, United States

Location

Research Site

Ocala, Florida, 34474, United States

Location

Research Site

Orlando, Florida, 32804, United States

Location

Research Site

St. Petersburg, Florida, 33705, United States

Location

Research Site

Atlanta, Georgia, 30318, United States

Location

Research Site

Atlanta, Georgia, 30322, United States

Location

Research Site

Honolulu, Hawaii, 96813, United States

Location

Research Site

Carterville, Illinois, 62918, United States

Location

Research Site

Urbana, Illinois, 61801, United States

Location

Research Site

Bethesda, Maryland, 20817, United States

Location

Research Site

Jamaica Plain, Massachusetts, 02130, United States

Location

Research Site

Saint Paul, Minnesota, 55101, United States

Location

Research Site

Kansas City, Missouri, 64132, United States

Location

Research Site

St Louis, Missouri, 63128, United States

Location

Research Site

Billings, Montana, 59102, United States

Location

Research Site

Grand Island, Nebraska, 68803, United States

Location

Research Site

Lincoln, Nebraska, 68506, United States

Location

Research Site

Albany, New York, 12206, United States

Location

Research Site

East Syracuse, New York, 13057, United States

Location

Research Site

New York, New York, 10032, United States

Location

Research Site

Shirley, New York, 11967, United States

Location

Research Site

Stony Brook, New York, 11790, United States

Location

Research Site

Syracuse, New York, 13210, United States

Location

Research Site

The Bronx, New York, 10461, United States

Location

Research Site

Cleveland, Ohio, 44111, United States

Location

Research Site

Cleveland, Ohio, 44124, United States

Location

Research Site

Cleveland, Ohio, 44195, United States

Location

Research Site

Columbus, Ohio, 43210, United States

Location

Research Site

Dayton, Ohio, 45459, United States

Location

Research Site

Norman, Oklahoma, 73072, United States

Location

Research Site

Pittsburgh, Pennsylvania, 15212, United States

Location

Research Site

Sioux Falls, South Dakota, 57105, United States

Location

Research Site

Memphis, Tennessee, 38120, United States

Location

Research Site

Dallas, Texas, 75246, United States

Location

Research Site

Denton, Texas, 76210, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Houston, Texas, 77090, United States

Location

Research Site

Kingwood, Texas, 77339, United States

Location

Research Site

Fairfax, Virginia, 22031, United States

Location

Research Site

Richmond, Virginia, 23298, United States

Location

Related Publications (1)

• Skoulidis F, Borghaei H, Garon EB, Leal TA, Kaufman J, Liu SV, Nadler E, Patel SP, Peters S, Ricciuti B, Gautam A, Emeribe U, Luciani-Silverman L, Heymach JV. 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. Ther Adv Med Oncol. 2025 Nov 6;17:17588359251386611. doi: 10.1177/17588359251386611. eCollection 2025.

  PMID: 41209621 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; tremelimumab; Pemetrexed; pembrolizumab; Carboplatin; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Coordination Complexes; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase IIb 2-arm, parallel randomized open label multicenter study

Study Record Dates

• First Submitted: August 17, 2023
• First Posted: August 23, 2023
• Study Start: April 4, 2024
• Primary Completion (Estimated): December 8, 2026
• Study Completion (Estimated): December 23, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Locations

US (47)