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)
Overview
- Phase
- Phase 3
- Intervention
- Durvalumab
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Sponsor
- AstraZeneca
- Enrollment
- 280
- Locations
- 1
- Primary Endpoint
- Overall survival (OS)
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
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.
Detailed Description
A trial to learn if durvalumab plus tremelimumab with chemotherapy is safe and how well it works compared to pembrolizumab with chemotherapy in participants with metastatic non-small cell lung cancer with certain genetic mutations. INFORMATION FOR TRIAL PARTICIPANTS: Researchers are looking for a better way to treat people who have metastatic NSCLC and tumors with STK11, KEAP1, or KRAS genetic mutations. Most people learn they have NSCLC after it has already become metastatic, and it can no longer be treated with surgery. Based on previous trials, researchers think durvalumab plus tremelimumab with chemotherapy could help participants more than the current standard treatment, which is pembrolizumab with chemotherapy. Durvalumab and tremelimumab are designed to work by helping the immune system recognize and kill cancer cells. In this trial, researchers want to learn more about how well durvalumab plus tremelimumab with chemotherapy works in people with metastatic NSCLC and genetic mutations that can cause the cancer to be less responsive to treatment. This trial is planned to have 280 participants. These participants will be randomly divided into one of two groups: * One group will receive durvalumab plus tremelimumab with standard of care chemotherapy * One group will receive pembrolizumab with standard of care chemotherapy Durvalumab, tremelimumab, pembrolizumab, and chemotherapy are given as an injection over time into a vein, also called an IV infusion. Chemotherapy will be one of the following regimens: pemetrexed plus cisplatin or pemetrexed plus carboplatin. This is an open-label trial. This means that each participant will know which trial treatment they receive, and the doctors and trial staff will also know. Researchers will measure and compare: * How long participants live during the trial * How long participants live during the trial without their cancer getting worse * How many participants' tumors respond to treatment * How long participants' tumor responses last * How long before participants need to start a different treatment type Researchers will also keep track of all the medical problems participants have during the trial and monitor their safety. Participants will stop receiving trial treatment if they no longer benefit from it or they stop participating for another reason. Participants will visit their trial site every 3 to 4 weeks. At most visits, participants will: * Have a physical exam and answer questions about any medications they are taking or any medical problems they have * Receive their trial treatment * Give blood and urine samples * Have pictures of their tumors taken using CT or MRI scans
Investigators
Eligibility 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 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
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.
Arms & Interventions
Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
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 disease progression or unacceptable toxicity or treatment discontinuation. 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.
Intervention: Durvalumab
Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
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 disease progression or unacceptable toxicity or treatment discontinuation. 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.
Intervention: Tremelimumab
Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
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 disease progression or unacceptable toxicity or treatment discontinuation. 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.
Intervention: Pemetrexed
Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
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 disease progression or unacceptable toxicity or treatment discontinuation. 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.
Intervention: Carboplatin
Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy
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 disease progression or unacceptable toxicity or treatment discontinuation. 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.
Intervention: Cisplatin
Arm B: Pembrolizumab + Platinum-based Chemotherapy
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 until disease progression or unacceptable toxicity or treatment discontinuation.
Intervention: Pemetrexed
Arm B: Pembrolizumab + Platinum-based Chemotherapy
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 until disease progression or unacceptable toxicity or treatment discontinuation.
Intervention: Pembrolizumab
Arm B: Pembrolizumab + Platinum-based Chemotherapy
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 until disease progression or unacceptable toxicity or treatment discontinuation.
Intervention: Carboplatin
Arm B: Pembrolizumab + Platinum-based Chemotherapy
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 until disease progression or unacceptable toxicity or treatment discontinuation.
Intervention: Cisplatin
Outcomes
Primary Outcomes
Overall survival (OS)
Time Frame: From randomization until death, withdrawal of consent, or the end of the study (approximately 84 months)
OS is defined as the time from randomization until death due to any cause in all participants. The measure of interest is the hazard ratio with corresponding 95% CI.
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 84 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. The measure of interest is the hazard ratio with corresponding 95% CI.
Secondary Outcomes
- Overall survival at 12 months(At 12 months)
- Overall survival at 24 months(At 24 months)
- Overall survival at 12 months in subset of randomized participants with STK11 or KEAP1 mutation and/or co mutations(At 12 months)
- Overall survival at 24 months in subset of randomized participants with STK11 or KEAP1 mutation and/or co mutations(At 24 months)
- Overall survival in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1%(From randomization until death, withdrawal of consent, or the end of the study (approximately 84 months))
- Overall survival at 12 months in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1%(At 12 months)
- Overall survival at 24 months in subset of randomized participants whose PD-L1 status is PD-L1 TC < 1%(At 24 months)
- Progression-free survival (PFS)(From randomization until disease progression, death, withdrawal of consent, or end of study (approximately 84 months))
- Objective response rate (ORR)(From randomization until disease progression, or the last evaluable assessment in the absence of progression (approximately 84 months))
- Duration of response (DOR)(From first documented response until documented progression (approximately 84 months))
- Time to First Subsequent Therapy (TFST)(From randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized study intervention or death [approx. up to 84 months])
- Number of participants with adverse events (AEs)(From screening until the follow-up period is completed [approx. up to 84 months])