Dato-DXd + Pembrolizumab for Advanced Lung Cancer

(TROPION-Lung08 Trial)

Recruiting at 239 trial locations

Overseen By (US Sites) Daiichi Sankyo Contact for Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Daiichi Sankyo, Inc.

Must not be taking: Topoisomerase inhibitors, TROP2 therapies

Disqualifiers: Prior NSCLC treatment, CNS metastases, 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: Up to 44 months

740 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is designed to assess the efficacy and safety of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab versus pembrolizumab alone in participants with advanced or metastatic non-small cell lung cancer (NSCLC) of non-squamous histology.

Will I have to stop taking my current medications?

The trial requires an adequate treatment washout period (time without taking certain medications) before starting the study. However, the specific medications you need to stop are not detailed in the provided information.

What data supports the effectiveness of the drug combination Dato-DXd and Pembrolizumab for advanced lung cancer?

Research shows that pembrolizumab alone is a standard treatment for certain types of advanced lung cancer, but many patients do not experience long-term control. The combination of Dato-DXd and pembrolizumab has shown promising safety and antitumor activity in advanced lung cancer, suggesting it may be more effective than pembrolizumab alone. ^{1 2 3 4 5}

Is the combination of Dato-DXd and Pembrolizumab safe for humans?

Pembrolizumab, one of the drugs in the combination, has been used in various cancer treatments and is generally safe, but it can cause side effects like type 1 diabetes in rare cases (0.2% of patients). Adverse events have been reported in up to 60% of patients, with serious side effects in some cases. ^{2 6 7 8 9}

How is the drug Dato-DXd + Pembrolizumab unique for advanced lung cancer?

This drug combination is unique because it combines pembrolizumab, a standard treatment for certain lung cancers, with datopotamab deruxtecan, a novel antibody-drug conjugate targeting a specific protein on cancer cells, potentially offering more effective treatment for patients who do not respond well to existing therapies. ^{1 2 3 10 11}

Research Team

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Eligibility Criteria

This trial is for adults with advanced or metastatic non-small cell lung cancer (NSCLC) who haven't had previous systemic treatments. Participants must have high PD-L1 expression, good physical condition, adequate bone marrow function, and no significant heart issues. They should not have certain infections like hepatitis B/C or HIV, severe eye diseases, recent vaccines, autoimmune diseases, other cancers within a set time frame, or untreated brain metastases.

Inclusion Criteria

Sign and date the Tissue Screening and Main Informed Consent Forms, prior to the start of any study-specific qualification procedures.

I have given a tissue sample for TROP2 protein testing.

Participants eligible for inclusion in the study must meet all inclusion criteria within 28 days of randomization into the study.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

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

I had radiotherapy less than 4 weeks ago or received high-dose lung radiation in the last 6 months.

Timeline

Tissue Screening

Participants undergo tissue screening to confirm eligibility based on PD-L1 expression and histology

2-4 weeks

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either pembrolizumab alone or in combination with Dato-DXd

Up to 44 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 71 months

Treatment Details

Interventions

• Datopotamab Deruxtecan
• Pembrolizumab

Trial Overview The study compares the effectiveness of Dato-DXd combined with pembrolizumab versus pembrolizumab alone in treating NSCLC without specific genetic changes. It aims to determine which treatment works better for this type of lung cancer by randomly assigning participants to one of the two groups.

Participant Groups

Group I: Pembrolizumab + Datopotamab Deruxtecan (Dato-DXd) Experimental Treatment 2 Interventions

Participants will be randomized to receive 200 mg pembrolizumab followed by 6.0mg/kg Dato-DXd.

Group II: Pembrolizumb Active Control 1 Intervention

Participants will be randomized to receive 200 mg pembrolizumab.

Who Is Running the Clinical Trial?

Daiichi Sankyo, Inc.

Lead 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

Daiichi Sankyo

Lead 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

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

AstraZeneca

Industry 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

The TROPION-Lung08 phase III study is investigating the combination of datopotamab deruxtecan (Dato-DXd) and pembrolizumab as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) who have high PD-L1 expression and no actionable genomic alterations, aiming to improve long-term disease control compared to pembrolizumab alone.

Primary endpoints of the study include progression-free survival and overall survival, with secondary endpoints assessing response rates and safety, indicating a comprehensive evaluation of the new treatment's efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. Levy, BP., Felip, E., Reck, M., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

In a phase 1a/b trial involving 26 patients with PD-L1-positive non-small cell lung cancer (NSCLC), the combination of ramucirumab and pembrolizumab showed a manageable safety profile, with 84.6% experiencing treatment-related adverse events, primarily hypertension.

The treatment demonstrated promising efficacy, with an objective response rate of 42.3%, and particularly strong results in patients with high PD-L1 expression (TPS ≥ 50%), who had a median progression-free survival that was not reached.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC. Herbst, RS., Arkenau, HT., Bendell, J., et al.[2023]

Pembrolizumab, a monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

Pembrolizumab (Keytruda) is an effective anti-PD1 therapy that has shown overall response rates (ORRs) of 21-34% in melanoma and 19-25% in non-small cell lung cancer (NSCLC), leading to its FDA approval for these cancers.

While pembrolizumab can cause adverse events in up to 60% of patients, serious grade 3/4 toxicities are rare (<10%), although immune-related side effects like thyroid dysfunction and pneumonitis can be severe and may require stopping treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab (Keytruda). Kwok, G., Yau, TC., Chiu, JW., et al.[2023]

In the KEYNOTE-189 study, patients with non-squamous non-small cell lung cancer who received the combination of pembrolizumab, pemetrexed, and platinum had a median progression-free survival (PFS) of 9.3 months, significantly longer than the 6.6 months observed in the placebo group, indicating enhanced efficacy of the treatment.

The objective response rate was also higher in the pembrolizumab group (58.7%) compared to the placebo group (28.9%), while the incidence of severe treatment-emergent adverse events (grade ≥3) was similar across both treatment arms, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed maintenance with or without pembrolizumab in non-squamous non-small cell lung cancer: A cross-trial comparison of KEYNOTE-189 versus PARAMOUNT, PRONOUNCE, and JVBL. Garon, EB., Kim, JS., Govindan, R.[2021]

Pembrolizumab is an effective treatment for advanced gastric cancer (AGC) in patients who have already undergone two courses of chemotherapy, showing durable responses and an acceptable safety profile.

Approved by the FDA in 2017 for patients with PD-L1 positive AGC, pembrolizumab is now being studied in combination with other treatments, indicating its potential for broader applications in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pembrolizumab in recurrent or advanced gastric cancer expressing PD-L1 refractory to platinum and fluoropyrimidine. Mishima, S., Kawazoe, A., Shitara, K.[2022]

In a study of 226 gastric adenocarcinoma patients, the 22C3 and 28-8 pharmDx assays showed strong concordance in measuring programmed death ligand-1 (PD-L1) expression, indicating they may be interchangeable for assessing PD-L1 levels.

The 22C3 assay identified a higher rate of PD-L1 positivity (28%) compared to the 28-8 assay (20%), but both assays correlated with tumor characteristics such as mismatch repair proteins and Epstein-Barr virus status, suggesting their relevance in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 immunohistochemistry comparison of 22C3 and 28-8 assays for gastric cancer. Narita, Y., Sasaki, E., Masuishi, T., et al.[2022]

References

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

TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

3. France pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. [2017]

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

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC. [2023]

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

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. [2020]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

7. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. [2022]

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

Pembrolizumab (Keytruda). [2023]

9. Ireland pubmed.ncbi.nlm.nih.gov

Pemetrexed maintenance with or without pembrolizumab in non-squamous non-small cell lung cancer: A cross-trial comparison of KEYNOTE-189 versus PARAMOUNT, PRONOUNCE, and JVBL. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Safety of pembrolizumab in recurrent or advanced gastric cancer expressing PD-L1 refractory to platinum and fluoropyrimidine. [2022]

11. China pubmed.ncbi.nlm.nih.gov

PD-L1 immunohistochemistry comparison of 22C3 and 28-8 assays for gastric cancer. [2022]