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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)

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ClinicalTrials.gov Identifier: NCT06008093
Recruitment Status : Recruiting
First Posted : August 23, 2023
Last Update Posted : April 29, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: Durvalumab Drug: Tremelimumab Drug: Pemetrexed Drug: Pembrolizumab Drug: Carboplatin Drug: Cisplatin Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase IIIb 2-arm, parallel randomized open label multicenter study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IIIb, Randomized, Multicenter, Open-label Study to Assess the Efficacy of Durvalumab Plus Tremelimumab Versus Pembrolizumab in Combination With Platinum-Based Chemotherapy for First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients With Non-Squamous Histology Who Have Mutations and/or Co-mutations in STK11, KEAP1, or KRAS (TRITON).
Actual Study Start Date : April 4, 2024
Estimated Primary Completion Date : August 17, 2027
Estimated Study Completion Date : March 5, 2031

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
Participants will receive durvalumab plus tremelimumab q3w for four 21-day cycles in combination with chemotherapy followed by maintenance therapy (durvalumab plus pemetrexed maintenance) every 4 weeks (q4w) until disease progression or unacceptable toxicity or treatment discontinuation. During the maintenance therapy phase, participants will receive an additional cycle of durvalumab plus tremelimumab (plus pemetrexed, where applicable) at Week 16.
 Drug: Durvalumab
Participants will receive intravenous (IV) Durvalumab q3w for four 21-day cycles. Durvalumab will also be given during the maintenance phase q4w until disease progression or unacceptable toxicity and at week 16.

Drug: Tremelimumab
Participants will receive IV Tremelimumab q3w for four 21-day cycles. Tremelimumab will also be given during the maintenance therapy phase at week 16.

Drug: Pemetrexed
Participants will receive IV pemetrexed q3w for four 21-day cycles and q4w until disease progression or unacceptable toxicity. During the maintenance therapy phase, participants may receive an additional cycle of pemetrexed, where applicable, at Week 16.
Other Name: Background Platinum-based Chemotherapy

Drug: Carboplatin
Participants will receive IV Carboplatin on Day 1 of each 21-day cycle for 4 cycles.
Other Name: Background Platinum-based Chemotherapy

Drug: Cisplatin
Participants will receive IV Cisplatin on Day 1 of each 21-day cycle for 4 cycles.
Other Name: Background Platinum-based Chemotherapy
Experimental: Arm B: Pembrolizumab + Platinum-based Chemotherapy
Participants will receive pembrolizumab regimen q3w for four 21-day cycles in combination with chemotherapy followed by maintenance therapy (pembrolizumab plus pemetrexed maintenance) q3w until disease progression or unacceptable toxicity for up to 24 months or treatment discontinuation.
 Drug: Pembrolizumab
Participants will receive IV pembrolizumab q3w for four 21-day cycles and q3w until disease progression or unacceptable toxicity for up to 24 months.

Drug: Carboplatin
Participants will receive IV Carboplatin on Day 1 of each 21-day cycle for 4 cycles.
Other Name: Background Platinum-based Chemotherapy

Drug: Cisplatin
Participants will receive IV Cisplatin on Day 1 of each 21-day cycle for 4 cycles.
Other Name: Background Platinum-based Chemotherapy

Drug: Pemetrexed
Participants will receive IV pemetrexed q3w for four 21-day cycles and q3w until disease progression or unacceptable toxicity for up to 24 months.
Other Name: Background Platinum-based Chemotherapy


Outcome Measures
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Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months) ]
    OS is defined as the time from randomization until death due to any cause in all participants.

  2. OS in subset of randomized participants with STK11 or KEAP1 mutations and/or co-mutations [ Time Frame: From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months) ]
    OS is defined as the time from randomization until death due to any cause in participants with STK11 or KEAP1 mutations and/or co-mutations.


Secondary Outcome Measures :
  1. Overall survival at 12 months [ Time Frame: At 12 months ]
    OS is defined as the time from randomization until death due to any cause in all participants. The measure of interest is survival rate with corresponding 95% CI at 12 months landmark.

  2. Overall survival at 24 months [ Time Frame: At 24 months ]
    OS is defined as the time from randomization until death due to any cause in all participants. The measure of interest is survival rate with corresponding 95% CI at 24 months landmark.

  3. Overall survival at 12 months in subset of randomized participants with STK11 or KEAP1 mutation and/or co mutations. [ Time Frame: At 12 months ]
    OS is defined as the time from randomization until death due to any cause. The measure of interest is survival rate with corresponding 95% CI at 12 months landmark.

  4. Overall survival at 24 months in subset of randomized participants with STK11 or KEAP1 mutation and/or co mutations. [ Time Frame: At 24 months ]
    OS is defined as the time from randomization until death due to any cause. The measure of interest is survival rate with corresponding 95% CI at 24 months landmark.

  5. Overall survival in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1% [ Time Frame: From randomization until death, withdrawal of consent, or the end of the study (approximately 48 months) ]
    OS is defined as the time from randomization until death due to any cause.

  6. Overall survival at 12 months in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1% [ Time Frame: At 12 months ]
    OS is defined as the time from randomization until death due to any cause. The measure of interest is survival rate with corresponding 95% CI at 12 months landmark.

  7. Overall survival at 24 months in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1% [ Time Frame: At 24 months ]
    OS is defined as the time from randomization until death due to any cause. The measure of interest is survival rate with corresponding 95% CI at 24 months landmark.

  8. Progression-free survival (PFS) [ Time Frame: From randomization until disease progression, death, withdrawal of consent, or end of study (approximately 48 months) ]
    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 (in the absence of progression) in all participants.

  9. Objective response rate (ORR) [ Time Frame: From randomization until disease progression, or the last evaluable assessment in the absence of progression (approximately 48 months) ]
    ORR is defined as the proportion of participants with a confirmed objective tumour response (complete response [CR] or partial response [PR]) as determined by the investigator per RECIST 1.1 in all participants who have measurable disease at baseline.

  10. Duration of response (DOR) [ Time Frame: From first documented response until documented progression (approximately 48 months) ]
    DOR is defined as the time from the date of first documented confirmed response until the date of documented progression (per RECIST 1.1, as assessed by the Investigator) or death due to any cause (in the absence of disease progression) in all participants who have confirmed objective response.

  11. Time to First Subsequent Therapy (TFST) [ Time Frame: From randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized study intervention or death [approx. up to 48 months] ]
    TFST is defined as the time from randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized study intervention, or death due to any cause in all participants.

  12. Number of participants with adverse events (AEs) and serious adverse events (SAEs). [ Time Frame: From screening until the follow-up period is completed [approx. up to 48 months] ]
    To assess the safety and tolerability of durvalumab plus tremelimumab plus chemotherapy compared with pembrolizumab plus chemotherapy in participants with non-squamous histology who have metastatic NSCLC with mutations and/or co-mutations in STK11, KEAP1, or KRAS.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 12 months to 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

Exclusion Criteria:

  • 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).
  • Spinal cord compression unless asymptomatic and stable.

  • Participant meets the following:

    - Symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended.

  • Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
  • No radiation therapy is allowed, unless it is 1) definitive radiation that had been administered at least 6 months prior, 2) palliative radiation to brain, with associated criteria for stability or lack of symptoms, or 3) palliative radiation to painful bony lesions (this must comprise less than 30% of the bone marrow)

  • Patients with suspected brain metastases at screening should have an intravenous (IV) contrast-enhanced MRI (preferred) or IV contrast-enhanced CT/CT-PET of the brain prior to study entry. If brain metastases are detected patients must be treated before randomization. Randomization is only permitted if patients with brain metastases have:

    • Confirmed stable condition
    • Returned neurologically to baseline Brain metastases will not be recorded as RECIST target lesions at baseline.
  • History of leptomeningeal carcinomatosis.
  • Known to have tested positive for active tuberculosis infection

  • Known active hepatitis infection, positive HCV antibody, HBsAg, or anti-HBc, at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA); AND

    • HCV positive (presence of anti-HCV antibodies); OR
    • HDV positive (presence of anti-HDV antibodies).
  • Known human immunodeficiency virus (HIV) infection that is not well controlled.

  • Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
    • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication, premedication for chemotherapy) or a single dose for palliative purpose (eg, pain control).
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
  • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
  • Participants with a known hypersensitivity to any of the study interventions or any of the excipients of the products.
  • For females only: Currently pregnant (confirmed with positive pregnancy test) or breast-feeding, or who are planning to become pregnant.

Female participants should refrain from breastfeeding from enrolment throughout the study and until up to 14 months after the last dose of cisplatin or 180 days after pemetrexed or 90 days after tremelimumab or durvalumab or pembrolizumab, whichever is longer; and during treatment with carboplatin.

Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06008093


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
More Information
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT06008093    
Other Study ID Numbers: D419ML00003
First Posted: August 23, 2023    Key Record Dates
Last Update Posted: April 29, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.
Supporting Materials: Study Protocol
Statistical Analysis Plan (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.
URL: https://vivli.org/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by AstraZeneca:
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)
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carboplatin
 Pembrolizumab
Pemetrexed
Durvalumab
Tremelimumab
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors