Durvalumab + Tremelimumab for Non-Small Cell Lung Cancer

(NEPTUNE Trial)

Recruiting at 204 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Steroids

Disqualifiers: Brain metastases, Autoimmune disorders, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 14

Duration: 48 weeks

953 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for advanced non-small cell lung cancer (NSCLC) that has not been treated before. It evaluates whether using two antibodies, durvalumab and tremelimumab, is more effective than standard chemotherapy. Suitable participants have Stage IV NSCLC without specific gene changes (EGFR or ALK) and have not received prior treatments for this cancer. The trial aims to determine which approach is safer and more effective for these patients. As a Phase 3 trial, it represents the final step before FDA approval, offering patients access to potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on steroids for brain metastases, you must be off them for at least 14 days before starting the study treatment.

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

Research has shown that the combination of durvalumab and tremelimumab has a manageable safety profile, meaning the side effects reported so far can be treated. In studies, most patients tolerated the treatment well. Common side effects included tiredness and skin reactions, similar to those seen with other cancer treatments.

This combination has been tested in other studies for non-small cell lung cancer (NSCLC) and has been found safe for patients. Information from patients in earlier trials helps confirm its safety.

Overall, while side effects can occur, the treatment is considered safe enough for further testing in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Durvalumab and Tremelimumab are unique because they are monoclonal antibodies targeting specific proteins involved in immune system regulation, which is different from traditional chemotherapy. Durvalumab targets PD-L1, a protein that helps cancer cells evade immune detection, while Tremelimumab targets CTLA-4, a checkpoint that keeps the immune system in check. By blocking these proteins, the treatment aims to unleash the body's immune response against cancer cells. Researchers are excited about these treatments because they offer a new mechanism of action that could enhance the effectiveness of the immune system in fighting non-small cell lung cancer.

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

Research shows that using Durvalumab and Tremelimumab together may help treat non-small cell lung cancer (NSCLC). In this trial, some participants will receive this combination therapy. Studies have found that this combination can lead to longer survival compared to chemotherapy alone. Other participants in this trial will receive standard chemotherapy treatments. Patients with a higher number of mutations in their cancer cells seem to benefit more from the Durvalumab and Tremelimumab treatment. A review of multiple studies also supports the effectiveness and safety of this treatment for advanced NSCLC. Overall, these findings suggest that Durvalumab and Tremelimumab could be a strong first-choice treatment for certain patients. ^{2 4 6 7 8}

Who Is on the Research Team?

Gilberto de Castro

Principal Investigator

Faculdade de Medicina da Universidade de São Paulo

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced NSCLC who haven't had chemotherapy or immune therapy before. They should be in good physical condition and not have certain gene mutations (EGFR, ALK). People with mixed small cell lung cancer, autoimmune diseases like Crohn's, or unstable brain metastases can't join.

Inclusion Criteria

I haven't received any treatment for my recurrent or metastatic NSCLC.

I have never received immune therapy for cancer, except for cancer vaccines.

I am fully active or able to carry out light work.

Exclusion Criteria

My lung cancer is a mix of small cell and non-small cell types.

I have stable brain metastases and haven't taken steroids for 14 days.

I have or had an autoimmune or inflammatory disorder like Crohn's disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab + tremelimumab combination therapy or standard of care chemotherapy

48 weeks

Tumour scans every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 44 months

Tumour scans every 8 weeks after 48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab + Tremelimumab
• Gemcitabine + Carboplatin
• Gemcitabine + Cisplatin
• Paclitaxel + Carboplatin
• Pemetrexed + Carboplatin
• Pemetrexed + Cisplatin

Trial Overview The study compares a combination of two immunotherapy drugs (Durvalumab + Tremelimumab) against standard platinum-based chemotherapy as the first treatment for patients with NSCLC. It's randomized and open-label, meaning neither the researchers nor participants are blinded to which group they're in.

How Is the Trial Designed?

Group I: Combination Therapy Experimental Treatment 1 Intervention

Durvalumab (PD-L1 monoclonal antibody) + Tremelimumab (monoclonal antibody directed against CTLA-4)

Group II: Standard of Care Active Control 5 Interventions

Standard of Care chemotherapy treatment

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 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]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In the phase III POSEIDON study involving 1,013 patients with metastatic non-small-cell lung cancer (mNSCLC), the combination of durvalumab plus chemotherapy significantly improved progression-free survival (PFS) compared to chemotherapy alone, with a median PFS of 5.5 months versus 4.8 months.

The addition of tremelimumab to durvalumab and chemotherapy further enhanced both PFS and overall survival (OS) compared to chemotherapy alone, with a median OS of 14.0 months versus 11.7 months, while maintaining a similar safety profile to chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson, ML., Cho, BC., Luft, A., 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 NEPTUNE phase 3 study involving 823 patients with metastatic non-small cell lung cancer (mNSCLC), the combination of durvalumab and tremelimumab did not significantly improve overall survival compared to standard chemotherapy in patients with a blood tumor mutational burden (bTMB) of 20 mutations per megabase or more.

However, the combination therapy showed a lower incidence of severe treatment-related adverse events (20.7%) compared to chemotherapy (33.6%), suggesting a potentially better safety profile for durvalumab plus tremelimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC. de Castro, G., Rizvi, NA., Schmid, P., et al.[2023]

In a phase 1b study involving 102 patients with advanced non-small cell lung cancer, the combination of durvalumab and tremelimumab demonstrated manageable safety, although 36% of patients experienced serious treatment-related adverse events, including three treatment-related deaths.

The treatment showed evidence of antitumor activity in both PD-L1-positive and PD-L1-negative tumors, with a confirmed objective response rate of 23% in the cohort receiving tremelimumab 1 mg/kg, indicating potential effectiveness regardless of PD-L1 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Antonia, S., Goldberg, SB., Balmanoukian, A., et al.[2022]

In a phase Ib study involving 136 patients, durvalumab (Du) combined with tremelimumab (Tr) and standard platinum-doublet chemotherapy was found to be safe, with most drug-related adverse events being mild (≤ grade 2) and primarily due to chemotherapy.

Among 73 patients with non-small cell lung cancer (NSCLC), the treatment achieved a 51% objective response rate, with a median progression-free survival of 6.5 months and overall survival of 19.8 months, indicating promising efficacy comparable to other immunotherapy and chemotherapy combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226. Juergens, RA., Hao, D., Ellis, PM., et al.[2021]

The phase III POSEIDON trial demonstrated that a three-drug regimen combining the CTLA4 inhibitor tremelimumab, the PD-L1 inhibitor durvalumab, and chemotherapy significantly improves progression-free survival and overall survival in patients with metastatic non-small cell lung cancer compared to chemotherapy alone.

This study suggests that targeting multiple immune pathways with this combination therapy may enhance treatment effectiveness for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [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]

Citations

1. esmoopen.com esmoopen.com/article/S2059-7029(25)00927-5/fulltext

outcomes by tumor mutational burden in POSEIDON Tremelimumab plus durvalumab and chemotherapy (T + D + CT) showed durable long-term overall survival (OS) benefit versus CT alone in first-line metastatic non- ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12238800/

Evaluation of the efficacy and safety of durvalumab ... Conclusions: Our meta-analysis demonstrated that Durvalumab combination treatment is both effective and safe for advanced NSCLC, particularly in patients ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02542293

NCT02542293 | Study of Durvalumab With Tremelimumab ... This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of durvalumab + tremelimumab combination therapy ...

4. jto.org jto.org/article/S1556-0864(24)02264-0/fulltext

Durvalumab With or Without Tremelimumab in ... After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e20551

Efficacy and safety of durvalumab plus tremelimumab ... This study aims to assess the therapeutic efficacy of Durvalumab combined with Tremelimumab in NSCLC focusing on key end points including progression-free ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37146752/

Brief Report: Safety and Antitumor Activity of Durvalumab ... Conclusions: Durvalumab plus tremelimumab had a manageable safety profile, but the combination did not have efficacy after PD-(L)1 treatment failure. Keywords: ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2059702924014157

Safety and clinical activity of durvalumab combined with ... In this phase I study, durvalumab, a PD-L1 inhibitor, plus tremelimumab, a CTLA-4 inhibitor, was well tolerated and safe. •. This combination did not improve ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12128435/

Differential safety profiles of durvalumab monotherapy and ... A retrospective analysis was conducted using safety data pooled from phase I to III clinical trials in patients with advanced non-small cell ...