Dato-DXd + Pembrolizumab for Non-Small Cell Lung Cancer

Recruiting at 238 trial locations

Overseen By Daiichi Sankyo Contact for Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Daiichi Sankyo

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 57 months

1170 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with advanced non-small cell lung cancer (NSCLC) who have not received prior treatment. Researchers aim to determine if the drug datopotamab deruxtecan (a TROP2-directed antibody-drug conjugate) combined with pembrolizumab is more effective than the current standard treatment of pembrolizumab with chemotherapy. The trial includes different groups receiving various combinations of these drugs. Individuals with advanced non-squamous NSCLC who have not yet received treatment may be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

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

Research shows that the combination of datopotamab deruxtecan (Dato-DXd) and pembrolizumab is generally well-tolerated by patients with advanced non-small cell lung cancer (NSCLC). Most side effects are manageable, and while some patients experienced them, they were usually not severe.

When Dato-DXd is combined with pembrolizumab and platinum chemotherapy, safety remains similar. Studies indicate that this combination is generally well-tolerated, with no unexpected safety issues.

The trial is in an advanced stage, indicating that the treatment has already passed earlier safety tests. Although the FDA has not yet approved Dato-DXd for any condition, its combination with pembrolizumab has been tested in other situations with positive safety results. This supports confidence in its safety for participants in the current trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for non-small cell lung cancer because they introduce a novel approach with Datopotamab Deruxtecan (Dato-DXd). Unlike standard treatments that often rely solely on chemotherapy with drugs like cisplatin and carboplatin, Dato-DXd is an antibody-drug conjugate that specifically targets and delivers chemotherapy directly to cancer cells, potentially reducing side effects and enhancing effectiveness. The combination with pembrolizumab, an immune checkpoint inhibitor, may further boost the immune system's ability to fight cancer. This dual strategy of targeted delivery and immune activation represents a significant advancement in treating this type of lung cancer.

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

Research has shown that combining datopotamab deruxtecan (Dato-DXd) with pembrolizumab may offer promise for treating advanced non-small cell lung cancer (NSCLC). In this trial, participants may receive Dato-DXd with pembrolizumab, which has demonstrated positive results in shrinking or controlling the cancer. Another group will receive Dato-DXd with pembrolizumab and platinum chemotherapy, which has also yielded encouraging results, suggesting it could be an effective treatment option. These findings support the potential effectiveness of these treatment combinations for patients with this type of lung cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Are You a Good Fit for This Trial?

Adults over 18 with advanced non-squamous NSCLC who haven't had systemic cancer treatment, have specific levels of TROP2 and PD-L1 proteins, no major gene mutations treatable by approved therapies, good performance status, and no significant health issues like uncontrolled heart disease or active infections. Pregnant women and those with certain lung diseases or recent vaccinations are excluded.

Inclusion Criteria

My cancer can be measured by scans.

My tumor's PD-L1 level is below 50%.

Sign and date the Main Informed Consent Form (ICF), prior to the start of any study-specific qualification procedures.

Exclusion Criteria

I am not pregnant, breastfeeding, nor planning to become pregnant.

I do not have active or uncontrolled hepatitis B or C.

You have other health problems, heart disease, mental health issues, or use drugs or alcohol excessively.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive randomized treatment with Dato-DXd and pembrolizumab with or without platinum chemotherapy

Up to 57 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 57 months

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Datopotamab Deruxtecan
• Pembrolizumab
• Pemetrexed

Trial Overview The trial is testing the effectiveness of Dato-DXd combined with pembrolizumab versus pembrolizumab with pemetrexed and platinum chemo in first-line treatment for advanced NSCLC. It aims to see which combination works better for patients who meet specific biological criteria.

How Is the Trial Designed?

Group I: Dato-DXd + Pembrolizumab + Platinum Chemotherapy Experimental Treatment 4 Interventions

Participants will be randomized to receive 6.0mg/kg Dato-DXd plus 200 mg pembrolizumab plus platinum chemotherapy (cisplatin 75 mg/m\^2 or carboplatin area under the curve \[AUC) 5\]).

Group II: Dato-DXd + Pembrolizumab Experimental Treatment 2 Interventions

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

Group III: Pembrolizumab + Pemetrexed + Platinum Chemotherapy Active Control 4 Interventions

Participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m\^2 pemetrexed plus platinum chemotherapy (cisplatin 75 mg/m\^2 or carboplatin area under the curve \[AUC) 5\]).

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?

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

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

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

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

Published Research Related to This Trial

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a study of 109 patients with advanced non-squamous non-small cell lung cancer, the combination of pemetrexed and carboplatin followed by pemetrexed maintenance showed similar efficacy in elderly patients (≥70 years) compared to younger patients, with median progression-free survival of 5.2 months for the elderly versus 5.8 months for younger patients.

While elderly patients experienced more frequent grade 3/4 hematologic toxicities, these were manageable through dose adjustments, and non-hematologic toxicities were similar to those seen in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed and carboplatin combination therapy followed by pemetrexed maintenance in Japanese patients with non-squamous non-small cell lung cancer: A subgroup analysis of elderly patients. Nogami, N., Nishio, M., Okamoto, I., et al.[2022]

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 patients with metastatic non-small-cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells, pembrolizumab significantly improves progression-free and overall survival compared to traditional platinum-based chemotherapy.

Combining pembrolizumab with standard chemotherapy (pemetrexed and a platinum drug) enhances survival outcomes regardless of PD-L1 expression, indicating a broader efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. Wang, C., Kulkarni, P., Salgia, R.[2020]

Pemetrexed, an antifolate drug used for lung cancer treatment, can cause severe skin reactions like toxic epidermal necrolysis, as seen in a case involving a 58-year-old woman with a history of Sharp's syndrome.

While skin toxicity is a known side effect of pemetrexed, severe reactions are rare, highlighting the need for caution when administering this drug to patients with prior radiation therapy or existing skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome. Then, C., von Einem, JC., Müller, D., et al.[2015]

In a meta-analysis of 486 patients with advanced non-squamous non-small cell lung cancer, the pemetrexed plus carboplatin regimen at 5 mg/min•mL (PCb5) showed a significantly lower incidence of treatment-emergent adverse events (TEAEs) compared to the 6 mg/min•mL (PCb6) regimen, including less thrombocytopenia, anemia, and fatigue.

Despite the differences in safety profiles, both PCb5 and PCb6 regimens demonstrated similar efficacy outcomes in terms of overall survival and progression-free survival, indicating that PCb5 may be a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. Okamoto, I., Schuette, WH., Stinchcombe, TE., et al.[2018]

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]

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]

In a study involving 74 patients with advanced non-small-cell lung cancer, the combination of pembrolizumab with platinum-based chemotherapy showed promising antitumor activity, with objective response rates of 48% to 75% across different treatment cohorts.

The treatment was generally well-tolerated, with no dose-limiting toxicities reported, although 40% to 46% of patients experienced grade 3/4 adverse events, which aligns with the known side effects of platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Gadgeel, SM., Stevenson, JP., Langer, CJ., et al.[2019]

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]

Pemetrexed is an effective cytotoxic agent approved for first-line treatment of non-small cell lung cancer (NSCLC) in combination with cisplatin, showing promise in phase II and III trials.

The toxicity profile of pemetrexed is comparable to other NSCLC treatments, making it a safe option for patients, and its use in postinduction maintenance therapy is currently being evaluated in a phase III study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed as first-line therapy for non-squamous non-small cell lung cancer. Ricciardi, S., Tomao, S., de Marinis, F.[2021]

Pemetrexed (Alimta) shows a response rate of 16%-23% as a single agent for non-small-cell lung cancer (NSCLC) and a higher response rate of 38.9%-44.8% when combined with cisplatin, leading to a median survival of 8.9-10.9 months.

The main side effect of pemetrexed is neutropenia, but this can be mitigated with vitamin B12 and folate supplements, highlighting the importance of supportive care in enhancing treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer. Ettinger, DS.[2017]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01544

Datopotamab Deruxtecan Versus Docetaxel for Previously ... Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05555732

NCT05555732 | Datopotamab Deruxtecan (Dato-DXd) and ... This study is designed to assess the efficacy and safety of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab versus pembrolizumab in ...

3. onclive.com onclive.com/view/datopotamab-deruxtecan-plus-pembrolizumab-displays-efficacy-in-advanced-nsclc-with-or-without-chemotherapy

Datopotamab Deruxtecan Plus Pembrolizumab Displays ... Datopotamab deruxtecan has already shown efficacy NSCLC as a single agent and a phase 3 study [TROPION-Lung01] is ongoing in the second-line ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37249038/

TROPION-Lung08: phase III study of datopotamab ... Pembrolizumab monotherapy is a standard first-line treatment for PD-L1-high advanced non-small-cell lung cancer (NSCLC) without actionable ...

5. astrazeneca.com astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxtecan-combinations-showed-encouraging-tumour-responses-in-patients.html

Datopotamab deruxtecan combinations showed ... Datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01349

Results From the Phase II TROPION-Lung05 Study Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04526691

NCT04526691 | Datopotamab Deruxtecan (Dato-DXd) in ... This study will assess safety and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10564307/

First-in-Human, Phase I Dose-Escalation ... - PubMed Central This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd)