DS-8201a + Pembrolizumab for Breast and Lung Cancer

Not currently recruiting at 42 trial locations

Overseen By AZ Breast Cancer Study Navigators

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Daiichi Sankyo

Must not be taking: Corticosteroids, Immunosuppressives, Anti-PD-1, others

Disqualifiers: Myocardial infarction, ILD, CNS metastases, others

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

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

Compensation: Varies

Number of Visits: 42

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the combination of two drugs, Trastuzumab deruxtecan (DS-8201a) and pembrolizumab, to treat certain types of breast and lung cancer. The trial aims to determine the right dose and assess the safety and effectiveness of these drugs when used together. Suitable participants have either HER2-positive breast cancer that has worsened after treatment or specific types of HER2-expressing lung cancer. Participants should have tried other treatments without success and must be willing to provide a tumor biopsy for the study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, there is a requirement for an adequate treatment washout period before enrollment, and certain medications like systemic corticosteroids and prior systemic anticancer therapies must be stopped within specific timeframes before starting the trial. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial requires an adequate treatment washout period before enrollment, which means you may need to stop taking certain medications for a period of time before joining the study. However, the specific medications you need to stop are not detailed in the protocol.

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

Research has shown that trastuzumab deruxtecan (also called DS-8201a) demonstrates promising safety results from earlier studies. In one study, over 92% of patients treated with this drug remained free of invasive disease after three years, indicating general safety. It has also proven effective for patients with metastatic breast cancer, whether their cancer is HER2-positive or HER2-low.

Pembrolizumab, another part of the trial treatment, has approval for several types of cancer, which generally supports its safety. However, researchers are still studying the combination of trastuzumab deruxtecan and pembrolizumab to understand their efficacy and safety together.

As this is an early phase study, the main focus is on determining the right dose and monitoring for side effects. While there is some safety evidence for each drug individually, the combination is still under exploration. Participants should consult their healthcare providers to understand the potential benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of DS-8201a (Trastuzumab deruxtecan) and Pembrolizumab because it offers a novel approach to treating certain types of breast and lung cancer. Unlike standard treatments that often target HER2-positive tumors alone, DS-8201a is an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, potentially enhancing effectiveness while minimizing side effects. Pembrolizumab, an immune checkpoint inhibitor, works by unleashing the body's immune system to attack cancer cells. Together, they offer a promising new strategy for patients whose cancers have progressed despite traditional therapies, targeting cancer in a more personalized and potentially more effective way.

What evidence suggests that this trial's treatments could be effective for breast and lung cancer?

Research has shown that trastuzumab deruxtecan (DS-8201a) effectively treats certain types of breast cancer. One study found it reduced the risk of recurrence or death by 53% in patients with high-risk HER2-positive breast cancer. The FDA has approved this treatment for advanced HER2-positive breast cancer, further supporting its effectiveness. In this trial, participants with various types of breast cancer and non-small cell lung cancer (NSCLC) will receive DS-8201a combined with pembrolizumab to potentially enhance the immune system's ability to fight cancer cells. Although researchers are still gathering early data on this combination for NSCLC and other breast cancer types, the promising results of trastuzumab deruxtecan offer hope for these conditions. ^{1 2 3 6 7}

Who Is on the Research Team?

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Are You a Good Fit for This Trial?

Adults (≥18 years) with advanced/metastatic breast cancer that is HER2-positive or HER2-low, and those with similar stages of NSCLC. Participants must have tried all other beneficial treatments or be unable to tolerate them. They should not have had prior treatment with pembrolizumab/DS-8201a, severe heart issues within the last 6 months, active hepatitis B/C, certain lung conditions, autoimmune diseases requiring steroids/immunosuppressants, or a history of severe allergic reactions to similar drugs.

Inclusion Criteria

You have at least one identifiable and measurable tumor according to a specific set of guidelines.

I am fully active or restricted in physically strenuous activity but can do light work.

My breast cancer is advanced or has spread, and tests show it's HER2 positive.

Exclusion Criteria

I still have side effects from past cancer treatments.

Your heart's electrical activity (QT interval) is longer than usual, which can be risky for your health.

I have been treated with drugs targeting PD-1 or PD-L1.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Escalating doses of DS-8201a in combination with pembrolizumab are assessed to determine the recommended dose for expansion

6 weeks

Every 21 days

Dose Expansion

Participants receive DS-8201a at the recommended dose in combination with pembrolizumab to evaluate efficacy, safety, and tolerability

Varies by cohort

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Trastuzumab deruxtecan (DS-8201a)

Trial Overview The trial tests DS8201a combined with Pembrolizumab in two parts: first to find the best dose and then to check how well it works and its safety. It's for people whose breast or lung cancer has spread and expresses a protein called HER2. The study aims to see if this drug combo can help when other treatments haven't worked.

How Is the Trial Designed?

Group I: Part 1 (Dose Escalation) Experimental Treatment 2 Interventions

HER2-positive breast cancer, HER2-low expressing breast cancer, HER2-expressing NSCLC, and HER2-mutant NSCLC participants who received escalating doses of DS8201a (initial dose 3.2 mg/kg Q3W) and pembrolizumab 200 mg.

Group II: HER2-positive breast cancer (Part 2 Dose Expansion) Experimental Treatment 2 Interventions

HER2-positive breast cancer participants with prior ado-trastuzumab emtansine (T-DM1) with disease progression and who received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group III: HER2-mutant NSCLC (Part 2 Dose Expansion) Experimental Treatment 2 Interventions

HER2-mutant NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group IV: HER2-low breast cancer (Part 2 Dose Expansion) Experimental Treatment 2 Interventions

HER2 low breast cancer participants with prior failed standard treatments who received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group V: HER2-expressing NSCLC (Part 2 Dose Expansion) Experimental Treatment 2 Interventions

HER2-expressing NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

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 UK Limited

Collaborator

Trials

1

Recruited

120+

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

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

Trastuzumab deruxtecan (DS-8201a) is effective in treating HER2-positive solid cancers, particularly breast and gastric cancers, with median progression-free survival (PFS) ranging from 9.0 to 22.1 months and objective response rates (ORR) between 37% and 79.9%.

The most common adverse events (AEs) associated with DS-8201a include nausea, decreased appetite, and fatigue, with significant grade 3 or higher AEs being decreased neutrophil count and anemia, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy profile of Trastuzumab deruxtecan in solid cancer: pooled reanalysis based on clinical trials. Xu, H., Zhang, H., Guo, W., et al.[2022]

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]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Trastuzumab deruxtecan (T-DXd) was evaluated for safety in 1457 patients across 8 clinical trials, revealing that gastrointestinal disorders and blood-related issues were the most common adverse events, with neutropenia being the most severe (21.4% incidence).

The study highlighted significant concerns regarding interstitial lung disease (10.9% incidence) and decreased left ventricular ejection fraction (1.2% incidence), suggesting that while T-DXd is generally well tolerated, these specific side effects require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of trastuzumab deruxtecan: A meta-analysis and pharmacovigilance study. Guo, Z., Ding, Y., Wang, M., et al.[2023]

Fam-trastuzumab deruxtecan-nxki (T-DXd) has been approved for treating HER2-low metastatic breast cancer, showing significant improvements in progression-free survival (PFS) and overall survival (OS) in a phase III trial with 557 patients.

The study demonstrated a 50% reduction in the risk of disease progression and a 36% reduction in the risk of death compared to standard chemotherapy, with a safety profile consistent with previous uses of T-DXd and no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer. Narayan, P., Dilawari, A., Osgood, C., et al.[2023]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04042701

DS8201a and Pembrolizumab in Participants With Locally ... HER2 low breast cancer participants with prior failed standard treatments who received DS8201a at the RDE in combination with pembrolizumab 200 mg. Intervention ...

2. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-reduced-the-risk-of-disease-recurrence-or-death-by-53-percent-vs-T-DM1-in-patients-with-high-risk-HER2-positive-early-breast-cancer-following-neoadjuvant-therapy-in-DESTINY-Breast05-Phase-III-trial.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) reduced ... More than 92% of patients treated with AstraZeneca and Daiichi Sankyo's ENHERTU were free of invasive disease at three years.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06250777

Efficacy and Safety of T-DXd in HER2-mutant Advanced ... HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd, DS-8201, Enhertu) is ...

4. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-followed-by-THP-before-surgery-resulted-in-a-pathologic-complete-response-in-67-percent-of-patients-with-high-risk-HER2-positive-early-stage-breast-cancer-in-DESTINY-Breast11-Phase-III-trial.html

ENHERTU® (fam-trastuzumab deruxtecan-nxki) followed ... Highest reported pathologic complete response rate seen in a Phase III registrational trial for HER2-positive early breast cancer with ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11299952/

FDA approval summary: fam-trastuzumab deruxtecan-nxki for ... FDA approval summary: Fam-Trastuzumab Deruxtecan-Nxki for the treatment of unresectable or metastatic HER2-positive breast cancer. Clin Cancer Res. 2021;27 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8570919/

FDA Approval Summary: Fam-trastuzumab deruxtecan-nxki ... T-DXd demonstrated adequate efficacy and safety in study DESTINY-Breast01 with supportive safety evidence from study DS8201-A-J101 to support an accelerated ...

7. datasourcebydaiichisankyo.com datasourcebydaiichisankyo.com/documents/20833/21672/SABCS%202024_T-DXd_Rugo_Poster_FINAL.pdf

Trastuzumab deruxtecan with pembrolizumab in previously ... 3 Given that T-DXd monotherapy has been shown to be effective in patients with metastatic breast cancer (mBC) with either positive (HER2-positive) or low (HER2- ...