Durvalumab + Tremelimumab + Chemo vs Pembrolizumab + Chemo for Lung Cancer

(TRITON Trial)

Recruiting at 76 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants, others

Disqualifiers: Autoimmune disorders, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

280 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different treatment combinations for individuals with advanced non-squamous lung cancer that surgery or radiation cannot cure. It compares the effectiveness of durvalumab and tremelimumab (both immunotherapies) with chemotherapy against another combination using pembrolizumab (an immunotherapy) with chemotherapy. The study targets patients whose tumors have specific genetic mutations, namely STK11, KEAP1, or KRAS, but not certain other mutations. Suitable candidates have advanced lung cancer with these mutations and have not received previous treatments for metastatic disease. As a Phase 3 trial, this study serves as the final step before FDA approval, offering patients access to potentially groundbreaking treatments.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but it does mention that you cannot use immunosuppressive medications within 14 days before starting the study. It's best to discuss your current medications with the study team to see if they might affect your eligibility.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining durvalumab and tremelimumab with chemotherapy is generally safe, with many cancer patients tolerating the combination well. However, about 3.5% of patients experienced side effects like lung inflammation, known as immune-mediated pneumonitis, which can be severe in rare cases.

For pembrolizumab with chemotherapy, research also indicates safety. It has been used in many patients with various types of cancer, including lung cancer. Common side effects include tiredness and nausea, while serious side effects are less common.

Both treatments have undergone testing in several studies, providing a good understanding of their safety. While side effects can occur, these treatments are generally considered safe with careful monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine immunotherapy with chemotherapy to tackle lung cancer more effectively. Durvalumab and tremelimumab, used in Arm A, work together to supercharge the immune system by blocking proteins that prevent immune cells from attacking tumors. This dual immunotherapy approach is unique and may enhance the body's natural cancer-fighting abilities beyond what traditional chemo alone can achieve. Arm B pairs pembrolizumab, another powerful immune checkpoint inhibitor, with chemo, aiming to boost immune response and directly target cancer cells. These combinations offer new hope by potentially improving outcomes for lung cancer patients compared to standard treatments.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research has shown that combining the drugs durvalumab and tremelimumab with chemotherapy, which participants in this trial may receive, can effectively treat advanced non-small cell lung cancer (NSCLC). The POSEIDON study found that this combination helped patients live longer and delayed cancer progression.

Similarly, pembrolizumab, another treatment option in this trial, works well with chemotherapy for advanced NSCLC. The KEYNOTE-189 study demonstrated that this combination can lead to a five-year survival rate of about 19.4%, surpassing the results of chemotherapy alone. Both treatment options in this trial aim to extend the lives of patients with certain genetic changes in their lung cancer. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with Stage IV non-squamous NSCLC who haven't had systemic therapy for metastatic disease. They must have specific mutations (STK11, KEAP1, or KRAS), good organ function, and no history of certain cancers or immune disorders. Participants need a life expectancy over 12 weeks, be able to use contraception, and not be pregnant or breastfeeding.

Inclusion Criteria

My tumor has STK11, KEAP1, or KRAS mutations.

I haven't had immune therapy, except cancer vaccines, in the last year.

I haven't had systemic therapy for advanced lung cancer, but past treatments were over 6 months ago.

Exclusion Criteria

I have or had an autoimmune or inflammatory disorder.

I do not have uncontrolled heart problems or symptoms like chest pain or irregular heartbeat.

I have lasting side effects from cancer treatment, but not hair loss or skin color changes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab plus tremelimumab or pembrolizumab with chemotherapy for four 21-day cycles, followed by maintenance therapy

12 weeks

Every 3 weeks

Maintenance Therapy

Participants continue with maintenance therapy until disease progression or unacceptable toxicity

Up to 24 months

Every 3-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Durvalumab
• Pembrolizumab
• Pemetrexed
• Tremelimumab

Trial Overview The study compares the effectiveness of two treatments: Durvalumab plus Tremelimumab with chemotherapy versus Pembrolizumab with chemotherapy in patients whose tumors have specific genetic changes. The goal is to see which combination works better for this type of lung cancer.

How Is the Trial Designed?

Group I: Arm B: Pembrolizumab + Platinum-based Chemotherapy Experimental Treatment 4 Interventions

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.

Group II: Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy Experimental Treatment 5 Interventions

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.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

In the phase III KEYNOTE-189 study, pembrolizumab combined with pemetrexed and platinum-based chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in patients with untreated metastatic nonsquamous non-small-cell lung cancer, with a hazard ratio of 0.56 for OS and 0.49 for PFS after a median follow-up of 31 months.

The treatment was associated with a high objective response rate (ORR) of 48.3% compared to 19.9% for the placebo group, and among patients who completed 35 cycles of pembrolizumab, the ORR was even higher at 85.7%, indicating strong efficacy with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Rodríguez-Abreu, D., Powell, SF., Hochmair, MJ., et al.[2022]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

In the phase III POSEIDON study, the combination of tremelimumab, an anti-CTLA-4 antibody, with durvalumab and chemotherapy showed increased antitumor activity and improved long-term survival in patients with first-line metastatic non-small cell lung cancer (mNSCLC).

Higher exposure to tremelimumab was associated with better progression-free survival (PFS) and overall survival (OS), but further analyses suggested that this relationship might be confounded, and no significant safety concerns were linked to tremelimumab exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study. He, JZ., Duval, V., Jauslin, P., et al.[2023]

In the CASPIAN study involving 805 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of durvalumab and platinum-etoposide significantly improved overall survival compared to platinum-etoposide alone, with a median survival of 12.9 months versus 10.5 months.

However, adding tremelimumab to durvalumab and platinum-etoposide did not provide a significant survival benefit, indicating that durvalumab plus platinum-etoposide should be considered the new standard of care for first-line treatment of ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Goldman, JW., Dvorkin, M., Chen, Y., et al.[2021]

In the KEYNOTE-189 study, first-line treatment with pembrolizumab combined with pemetrexed-platinum significantly improved overall survival (OS) to a median of 22.0 months compared to 10.7 months for the placebo group, indicating a strong efficacy in treating metastatic nonsquamous non-small-cell lung cancer (NSCLC).

The combination therapy also resulted in a median progression-free survival (PFS) of 9.0 months versus 4.9 months for placebo, with benefits observed regardless of tumor PD-L1 expression or the presence of liver/brain metastases, while maintaining a similar incidence of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. Gadgeel, S., Rodríguez-Abreu, D., Speranza, G., et al.[2021]

Pemetrexed, when combined with cisplatin, significantly improves median survival in patients with malignant pleural mesothelioma, with a median survival of 12.1 months compared to 9.3 months for cisplatin alone, based on a phase III trial involving 448 patients.

The drug works by inhibiting key enzymes involved in DNA synthesis, but it can cause side effects like myelosuppression, neutropenia, and fatigue, necessitating supportive care with folic acid, vitamin B12, and corticosteroids during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summaries: pemetrexed (Alimta). Hazarika, M., White, RM., Johnson, JR., et al.[2022]

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

In the phase III CASPIAN study, durvalumab combined with etoposide and either cisplatin or carboplatin significantly improved overall survival in patients with extensive-stage small-cell lung cancer, with a median overall survival of 12.9 months compared to 10.5 months for the control group.

After more than 3 years of follow-up, durvalumab plus etoposide showed a 36-month overall survival rate of 17.6%, indicating that this combination is a promising first-line treatment option for extensive-stage small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. Paz-Ares, L., Chen, Y., Reinmuth, N., et al.[2022]

In a phase 2 trial involving 40 patients with malignant mesothelioma, the combination of tremelimumab and durvalumab resulted in an immune-related objective response in 28% of patients, with a median response duration of 16.1 months, indicating promising efficacy for this treatment approach.

The treatment was generally well-tolerated, with 75% of patients experiencing treatment-related adverse events, mostly manageable and reversible, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Calabrò, L., Morra, A., Giannarelli, D., et al.[2019]

Citations

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3. sciencedirect.com sciencedirect.com/science/article/pii/S0169500223009601

Patient-reported outcomes with durvalumab, with or without ... In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival ...

4. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2023/761270Orig1s000MultidisciplineR.pdf

761270Orig1s000 - accessdata.fda.gov population of adult patients with metastatic non-small cell lung cancer (NSCLC), with results that were statistically significant and ...

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8. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal ...