Datopotamab Deruxtecan + Immunotherapy for Non-Small Cell Lung Cancer

(TROPION-Lung04 Trial)

Recruiting at 59 trial locations

Overseen By AstraZeneca Lung Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Disqualifiers: Autoimmune disorders, Cardiac disease, Hepatitis, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 cycles of carboplatin (approximately 12 weeks)

371 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will assess safety, tolerability, and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy with or without carboplatin in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

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

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

Is the combination of Datopotamab Deruxtecan and Durvalumab safe for humans?

Durvalumab, one of the drugs in the combination, has shown acceptable tolerability in patients with non-small cell lung cancer and other solid tumors, although treatment-related toxicity is an important consideration. Ongoing studies are expected to provide more detailed safety data. ^{1 2 3 4 5}

What makes the drug Datopotamab Deruxtecan + Durvalumab unique for non-small cell lung cancer?

This drug combination is unique because it combines Datopotamab Deruxtecan, a TROP2-directed antibody-drug conjugate, with Durvalumab, an immunotherapy that blocks PD-L1, potentially enhancing the immune system's ability to fight cancer cells in non-small cell lung cancer. ^{1 6 7 8 9}

Research Team

Global Clinical Leader

Principal Investigator

Daiichi Sankyo, Inc.

Eligibility Criteria

Adults with advanced or metastatic non-small cell lung cancer (NSCLC) who are either treatment-naïve or have had one prior chemotherapy without immune checkpoint inhibitors. Participants must have good organ function, measurable disease, no severe illnesses, and an ECOG performance status of 0 or 1. Those with certain genetic alterations in NSCLC or a history of other cancers are excluded.

Inclusion Criteria

You have a disease that can be measured according to specific guidelines within the 28 days before starting treatment.

I am 18 years or older and have signed the consent form.

My advanced lung cancer does not have EGFR or ALK mutations.

Exclusion Criteria

I have severe lung problems due to a recent illness.

I do not have active brain metastases or spinal cord compression.

I do not have an infection needing IV drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Dato-DXd in combination with immunotherapy with or without carboplatin. Part 1 involves dose escalation or confirmation, and Part 2 involves dose expansion.

4 cycles of carboplatin (approximately 12 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of disease control rate and pharmacokinetic parameters.

9 months

Long-term follow-up

Participants are monitored for overall survival and other secondary outcomes.

Approximately 60 months

Treatment Details

Interventions

• Carboplatin
• Datopotamab deruxtecan
• Durvalumab

Trial Overview The trial is testing the combination of Datopotamab deruxtecan (Dato-DXd), a new drug, with immunotherapy agents MEDI5752/AZD2936 and Durvalumab, plus Carboplatin for some groups. It aims to evaluate safety and how well these treatments work together in patients.

Participant Groups

Group I: Cohort 9 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC

Group II: Cohort 8 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC

Group III: Cohort 7 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC

Group IV: Cohort 6 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC

Group V: Cohort 5 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC

Group VI: Cohort 4A Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + carboplatin in participants with treatment-naïve NSCLC

Group VII: Cohort 4 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group VIII: Cohort 3 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group IX: Cohort 2 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Group X: Cohort 14 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with treatment-naïve NSCLC

Group XI: Cohort 13 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC

Group XII: Cohort 12 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC

Group XIII: Cohort 11 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 in participants with treatment-naïve NSCLC

Group XIV: Cohort 10 Experimental Treatment 3 Interventions

Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC

Group XV: Cohort 1 Experimental Treatment 2 Interventions

Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy

Datopotamab deruxtecan is already approved in Japan for the following indications:

Approved in Japan as Dato-DXd for:

• HER2-negative breast 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

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Daiichi Sankyo, Inc.

Industry Sponsor

Trials

390

Recruited

442,000+

Yuki Abe

Daiichi Sankyo, Inc.

Chief Medical Officer since 2022

MD

Hiroyuki Okuzawa

Daiichi Sankyo, Inc.

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Findings from Research

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

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]

The combination of MEDI0680 and durvalumab was found to be safe and tolerable in patients with advanced clear-cell renal cell carcinoma, but it did not show improved efficacy compared to nivolumab alone, with objective response rates of 16.7% for the combination and 23.8% for nivolumab.

Both treatment groups had a median progression-free survival of 3.6 months, and a notable percentage of patients (23.8% in the combination group) discontinued treatment due to adverse events, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. Voss, MH., Azad, AA., Hansen, AR., et al.[2023]

In a study involving 26 patients with various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, the PD-L1 inhibitor durvalumab demonstrated a clinical benefit in 50% of patients, with a 27% objective response rate, indicating its potential efficacy in this difficult-to-treat population.

Durvalumab was well-tolerated with no unexpected toxicities, and factors such as high structural variant burden and low IFN-γ expression were linked to a lack of clinical benefit, suggesting these could be important biomarkers for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours. Geurts, BS., Battaglia, TW., van Berge Henegouwen, JM., et al.[2023]

A meta-analysis of 21 studies involving 11,144 patients revealed that anti-CTLA4 therapy significantly increases the risk of various immune-related adverse events, such as diarrhea and colitis, with a relative risk of 2.43 to 11.39 for different conditions.

In contrast, while anti-PD1 therapy also raises the risk of pruritus (itching) with a relative risk of 4.01, it does not appear to increase the risk of other immune-related adverse events, highlighting the distinct safety profiles of these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies. Komaki, Y., Komaki, F., Yamada, A., et al.[2022]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

Daratumumab is a first-in-class monoclonal antibody that targets CD38 and is approved for treating relapsed or refractory multiple myeloma, highlighting its role as a new therapeutic option for this challenging disease.

Determining the right dosage regimen for daratumumab is complex due to its unique pharmacokinetics, which are influenced by the drug's target-mediated disposition, necessitating careful evaluation in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma. Xu, XS., Yan, X., Puchalski, T., et al.[2023]

In a study involving 97 chemotherapy-naïve patients with advanced non-small cell lung cancer, tigatuzumab combined with carboplatin/paclitaxel showed a median progression-free survival of 5.4 months, compared to 4.3 months for the placebo, indicating a slight improvement in disease control.

Despite being well tolerated, tigatuzumab did not significantly enhance overall survival compared to placebo, and there was a higher incidence of grade 3/4 neutropenia in the tigatuzumab group (20.4%) compared to the placebo group (8.3%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer. Reck, M., Krzakowski, M., Chmielowska, E., et al.[2022]

This phase I/II clinical trial is investigating the safety and efficacy of a combination treatment involving selumetinib, tremelimumab, and durvalumab in 40 patients with previously treated, unresectable non-small-cell lung cancer (NSCLC).

The study aims to determine the maximum tolerated dose and progression-free survival, while also exploring biomarkers of response and resistance, which could help tailor future treatments for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. Gaudreau, PO., Lee, JJ., Heymach, JV., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]

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

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

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

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours. [2023]

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

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies. [2022]

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

Daratumumab: First Global Approval. [2018]

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

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma. [2023]

8. Ireland pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer. [2022]

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

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. [2021]