Dato-DXd + Durvalumab + Carboplatin for Advanced Non-Small Cell Lung Cancer

(AVANZAR Trial)

Recruiting at 245 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Disqualifiers: Small-cell lung cancer, Brain metastases, Hepatitis B/C, 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: Unknown

Duration: Approximately 3 years

1350 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug combination for adults with advanced NSCLC without specific genetic mutations. The treatment includes Dato-DXd, durvalumab, and carboplatin, which work together to kill cancer cells, boost the immune system, and stop cancer cell growth.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination Dato-DXd, Durvalumab, and Carboplatin for advanced non-small cell lung cancer?

Durvalumab, one of the drugs in the combination, has shown effectiveness in improving survival rates when used with chemotherapy in patients with extensive-stage small cell lung cancer, as seen in the CASPIAN trial. Additionally, Durvalumab has demonstrated durable responses in non-small cell lung cancer patients in earlier phase studies. ^{1 2 3 4 5}

Is the combination of Dato-DXd, Durvalumab, and Carboplatin safe for humans?

Durvalumab, when combined with chemotherapy agents like carboplatin, has shown a manageable safety profile in various studies, with most side effects being mild to moderate. However, some serious side effects have been reported, including pneumonitis (lung inflammation), myocarditis (heart inflammation), and enterocolitis (intestinal inflammation), and there have been treatment-related deaths. Overall, the combination of durvalumab with chemotherapy has been used safely in clinical settings, but close monitoring for adverse effects is necessary. ^{4 6 7 8 9}

What makes the drug combination of Dato-DXd, Durvalumab, and Carboplatin unique for treating advanced non-small cell lung cancer?

This drug combination is unique because it includes Dato-DXd, a targeted therapy that delivers chemotherapy directly to cancer cells, combined with Durvalumab, an immunotherapy that helps the immune system attack cancer, and Carboplatin, a chemotherapy drug, offering a multi-faceted approach to treating advanced non-small cell lung cancer. ^{10 11 12 13 14}

Research Team

Charu Aggarwal

Principal Investigator

Perelman Center for Advanced Medicine

Eligibility Criteria

Adults over 18 with advanced non-small cell lung cancer (NSCLC) stages IIIB, IIIC, or IV without certain genetic changes can join. They should be in good physical condition (ECOG PS of 0 or 1), have not had previous systemic therapy for their cancer stage, and must have proper organ function and bone marrow reserve.

Inclusion Criteria

My lung cancer is at an advanced stage and cannot be removed by surgery.

My cancer does not have certain genetic changes that can be treated with specific drugs.

I am fully active or can carry out light work.

Exclusion Criteria

My lung cancer is a mix of small-cell and non-small cell or is a sarcomatoid variant.

I have a serious eye condition affecting my cornea.

I still have side effects from cancer treatment that haven't improved.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Dato-DXd in combination with durvalumab and carboplatin or pembrolizumab in combination with histology-specific platinum-based chemotherapy

Approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Carboplatin
• Datopotamab deruxtecan
• Durvalumab

Trial Overview The trial is testing a new combination of drugs: Datopotamab Deruxtecan (Dato-DXd) with Durvalumab and Carboplatin against the standard treatment Pembrolizumab with platinum-based chemotherapy. It's to see which is better as a first-line treatment for NSCLC.

Participant Groups

Group I: Dato-DXd + Durvalumab + Carboplatin Experimental Treatment 3 Interventions

Participants will be randomized to receive 6.0mg/kg Dato-DXd plus 1120 mg durvalumab plus carboplatin area under the curve \[AUC\] 5 mg/mL/minute.

Group II: Histologic-specific therapy Active Control 5 Interventions

Non-squamous NSCLC participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m2 pemetrexed plus either AUC 5 mg/mL/minute carboplatin or 75 mg/m2 cisplatin. Squamous NSCLC participants will be randomized to receive 200 mg of pembrolizumab plus 200 mg/m2 paclitaxel plus AUC 5 or 6 mg/mL/minute carboplatin.

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

Findings from Research

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

Durvalumab, an anti-PD-L1 monoclonal antibody, is being tested in a Phase II study for its feasibility and effectiveness in patients with early-stage non-small cell lung cancer (NSCLC) by administering three infusions before surgery.

The study aims to achieve a complete surgical resection rate of at least 85% and assess major pathological response, with a total of 81 patients required to determine if neoadjuvant immunotherapy can improve survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. Mignard, X., Antoine, M., Moro-Sibilot, D., et al.[2019]

In the phase III CASPIAN trial involving previously untreated adults with extensive-stage small cell lung cancer (ES-SCLC), the addition of durvalumab to chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Durvalumab combined with etoposide and either carboplatin or cisplatin demonstrated a manageable safety profile, making it a valuable first-line treatment option and an accepted standard of care for patients with ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Extensive-Stage SCLC. Al-Salama, ZT.[2022]

The AEGEAN trial is a phase III study involving approximately 800 patients with resectable, early-stage non-small-cell lung cancer (NSCLC) that aims to evaluate the effectiveness of durvalumab combined with chemotherapy before surgery and as a monotherapy after surgery.

This study will assess key outcomes such as pathological complete response and event-free survival, potentially improving treatment strategies for patients with Stage II-III NSCLC, where current survival rates remain low despite standard postoperative chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Heymach, JV., Mitsudomi, T., Harpole, D., 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]

Durvalumab has been approved for use in patients with locally advanced PD-L1-positive non-small cell lung cancer (NSCLC) after chemoradiotherapy, based on its efficacy demonstrated in the PACIFIC trial and subsequent analysis of 211 patients in the Expanded Access Program (EAP).

In the EAP, 126 patients who received durvalumab were included, some of whom had oligometastatic disease and a history of autoimmune conditions, indicating that durvalumab may be effective and safe for a broader patient population than previously studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. Faehling, M., Schumann, C., Christopoulos, P., et al.[2020]

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]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Methotrexate (MTX) is the most commonly used drug in combination therapies for rheumatoid arthritis, showing the best results when paired with leflunomide, cyclosporine, or in a triple combination with sulphasalazine and hydroxychloroquine.

Combining MTX with biologics, especially TNF inhibitors, abatacept, rituximab, or tocilizumab, enhances treatment efficacy and helps prevent disease progression, with safety profiles similar to individual medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination therapy using methotrexate with DMARDs or biologics--current status]. Krüger, K.[2021]

In a study of 314 patients with early rheumatoid arthritis, achieving an optimal methotrexate (MTX) dose (≥10 mg/week initially, escalating to ≥20 mg/week) significantly improved the chances of reaching remission and normal functioning after one year, with odds ratios of 4.28 and 4.36, respectively.

Despite the benefits in symptoms and function, the optimal MTX dose did not affect radiological progression of the disease over the two-year study period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort. Gaujoux-Viala, C., Rincheval, N., Dougados, M., et al.[2022]

Methotrexate (MTX) shows a delayed therapeutic response in rheumatoid arthritis (RA), with maximum improvement in disability scores occurring around 30 months after starting treatment, indicating that patients may need to be on MTX for a longer period to see full benefits.

Despite initial improvements, disability scores began to re-progress after 42 months, suggesting that treatment strategies should be adjusted sooner to prevent return to baseline disability, highlighting the need for more proactive management of RA with potential dosage adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The methotrexate therapeutic response in rheumatoid arthritis. Ortendahl, M., Holmes, T., Schettler, JD., et al.[2013]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

2. France pubmed.ncbi.nlm.nih.gov

[IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Clinical Activity, Tolerability, and Long-Term Follow-Up of Durvalumab in Patients With Advanced NSCLC. [2020]

4. France pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Extensive-Stage SCLC. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. [2022]

6. Ireland 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. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP. [2020]

8. England 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. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

[Combination therapy using methotrexate with DMARDs or biologics--current status]. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Infliximab and methotrexate in the treatment of rheumatoid arthritis: a systematic review and meta-analysis of dosage regimens. [2022]

13. Canada pubmed.ncbi.nlm.nih.gov

The methotrexate therapeutic response in rheumatoid arthritis. [2013]

14. Japan pubmed.ncbi.nlm.nih.gov

A study on the selection of DMARDs for the combination therapy with adalimumab. [2015]