Zongertinib + Trastuzumab Combinations for HER2+ Breast Cancer

Recruiting at 131 trial locations

Overseen By Boehringer Ingelheim

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Boehringer Ingelheim

Must be taking: Zongertinib

Must not be taking: QT prolonging drugs

Disqualifiers: Uncontrolled hypertension, Heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

582 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of a new drug, zongertinib (a HER-2 inhibitor), to shrink tumors when combined with other treatments for HER2+ cancers that have spread and cannot be surgically removed. The study will test different combinations with drugs like trastuzumab and capecitabine to identify the most effective regimen. It seeks participants whose cancer has HER2 changes, has metastasized, and has not responded well to other treatments. Participants will be randomly assigned to groups and receive various doses to find the most effective and tolerable combination. Regular check-ups will monitor tumor size and any side effects.

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 new drug.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on medications known to prolong the QT interval (a heart rhythm measure), you may need to stop them, as these are part of the exclusion criteria.

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

Research has shown that zongertinib is generally safe. In studies, it showed early signs of effectiveness against tumors in patients with HER2-altered tumors. While the treatment can cause side effects, they are usually not serious for most people. However, some participants did experience unwanted effects.

When combined with trastuzumab emtansine or trastuzumab deruxtecan, zongertinib remained generally safe. These drugs are often used for HER2-positive cancers. Previous studies showed that these combinations were usually well-tolerated.

Zongertinib alone or with trastuzumab also demonstrated a generally safe profile. Participants in studies handled these combinations without many serious side effects.

Overall, while researchers continue to study zongertinib and its combinations, current data suggests they are usually well-tolerated. Participants in ongoing trials may experience side effects, but these are typically not severe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving zongertinib because they introduce a novel approach to tackling HER2+ breast cancer. Unlike standard options like Trastuzumab alone or Trastuzumab in combination with chemotherapy, zongertinib is a new tyrosine kinase inhibitor that specifically targets cancer cell signaling pathways, potentially leading to more effective tumor suppression. Additionally, combining zongertinib with Trastuzumab deruxtecan or Trastuzumab emtansine offers a dual-action approach, leveraging both targeted therapy and antibody-drug conjugate technology, which could enhance treatment efficacy and reduce relapse rates. This innovative multi-faceted strategy may offer new hope for patients by potentially overcoming resistance to existing therapies.

What evidence suggests that this trial's treatments could be effective for HER2+ breast cancer?

This trial will explore various combinations of zongertinib with trastuzumab-based treatments for HER2-positive breast cancer. Studies have shown that zongertinib can shrink tumors by targeting HER2, a protein that promotes cancer cell growth. In breast cancer patients with HER2 alterations, zongertinib led to tumor shrinkage in about 27% of cases and disease control in 73%. In this trial, some participants will receive zongertinib combined with trastuzumab deruxtecan or trastuzumab emtansine, both of which have shown promise in treating HER2-positive cancers. Specifically, trastuzumab deruxtecan helps patients live longer without cancer progression. Other participants will receive zongertinib with trastuzumab and capecitabine, which may also inhibit tumor growth, as zongertinib blocks HER2. ^{2 3 4 5 6}

Are You a Good Fit for This Trial?

Adults aged 18+ with HER2+ metastatic breast or gastric cancer that's spread and can't be surgically removed. Participants must have tried other treatments without success, have at least one measurable tumor, and an ECOG score of 0 or 1 indicating they are fully active or restricted in physically strenuous activity but ambulatory.

Inclusion Criteria

I am fully active or have some restrictions but can still care for myself.

My cancer is HER2 positive and has spread to other parts of my body.

I have signed the consent form for this trial.

Exclusion Criteria

Women who are pregnant, nursing, or who plan to become pregnant or nurse during the trial or within 7 months after the last dose of trial treatment with T-DXd or T-DM1

Mean resting corrected QT interval (QT interval corrected for heart rate by Fridericia´s formula (QTcF)) >470 msec

I have no other cancers needing treatment now, except for certain treated skin, cervical, or ductal cancers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase Ib)

Participants receive increasing doses of zongertinib in combination with T-DXd or T-DM1 to determine the maximum tolerated dose

3 weeks

Regular visits for monitoring and dose adjustments

Dose Optimization (Phase II)

Participants are randomized to receive different doses of zongertinib in combination with T-DXd or T-DM1 to optimize dosing

up to 50 months

Regular visits for health checks and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab deruxtecan
• Trastuzumab emtansine
• Zongertinib

Trial Overview The trial is testing the drug Zongertinib combined with either Trastuzumab Deruxtecan (T-DXd) or Trastuzumab Emtansine (T-DM1) to find a tolerable dose and see if it shrinks tumors in HER2+ cancers. It has two parts: increasing doses of Zongertinib (Part 1), then random groups receiving different doses (Part 2).

How Is the Trial Designed?

Group I: Phase Ib - Cohort K: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group II: Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabine Experimental Treatment 3 Interventions

Dose escalation (Phase Ib)

Group III: Phase Ib - Cohort C: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group IV: Phase Ib - Cohort B: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group V: Phase Ib - Cohort A: zongertinib + Trastuzumab emtansine Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group VI: Phase II - Cohort J: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group VII: Phase II - Cohort J-ext: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Extension Phase II

Group VIII: Phase II - Cohort I: zongertinib Experimental Treatment 1 Intervention

Dose optimization (Phase II).

Group IX: Phase II - Cohort I-ext: zongertinib Experimental Treatment 1 Intervention

Extension Phase II

Group X: Phase II - Cohort H: zongertinib + trastuzumab + capecitabine Experimental Treatment 3 Interventions

Dose optimization (Phase II).

Group XI: Phase II - Cohort F: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group XII: Phase II - Cohort E: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group XIII: Phase II - Cohort D: zongertinib + Trastuzumab emtansine Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Trastuzumab deruxtecan is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
• Unresectable or metastatic HER2-low breast cancer
• Unresectable or metastatic HER2-positive solid tumors

Approved in European Union as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Approved in Japan as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Who Is Running the Clinical Trial?

Boehringer Ingelheim

Lead Sponsor

Trials

2,566

Recruited

16,150,000+

Published Research Related to This Trial

Trastuzumab deruxtecan (DS-8201a) is an innovative antibody-drug conjugate that combines a monoclonal anti-HER2 antibody with a cytotoxic agent, showing promising results in heavily pretreated HER2-positive breast cancer patients, with a 60% overall response rate and 97% disease control reported in a phase 2 trial.

The FDA has granted accelerated approval for DS-8201a for advanced or unresectable HER2-positive breast cancer after at least two prior HER2-targeting treatments, highlighting its potential as a new treatment option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer. Andrikopoulou, A., Zografos, E., Liontos, M., et al.[2021]

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]

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]

In a study involving 27 patients with HER2-positive metastatic breast cancer who had progressed on previous therapies, the combination of ado-trastuzumab emtansine (T-DM1) and neratinib showed promising efficacy, with 63% of evaluable patients achieving an objective response.

The recommended phase II dose for this combination was established as T-DM1 at 3.6 mg/kg and neratinib at 160 mg/d, with manageable safety profiles, although some patients experienced grade 3 toxicities like diarrhea and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. Abraham, J., Montero, AJ., Jankowitz, RC., et al.[2020]

In a study of 22 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan (T-DXd) showed a median progression-free survival of 9.7 months and an objective response rate of 61.9%, indicating its efficacy as a treatment option.

T-DXd was particularly effective in patients with heterogeneous or reduced HER2 expression, achieving partial responses in patients who did not respond to the previous treatment with ado-trastuzumab emtansine (T-DM1), highlighting its potential to overcome resistance in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Nakajima, H., Harano, K., Nakai, T., et al.[2022]

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]

In the phase 3 DESTINY-Breast02 trial involving 608 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 17.8 months compared to 6.9 months for treatment of physician's choice, demonstrating its efficacy in a population with limited treatment options.

While trastuzumab deruxtecan had a higher incidence of treatment-emergent adverse events, including nausea and interstitial lung disease, it still showed a favorable benefit-risk profile, indicating its potential as a viable treatment option for patients resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. André, F., Hee Park, Y., Kim, SB., et al.[2023]

In the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated superior progression-free survival and overall survival compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, while maintaining quality of life (QoL) throughout treatment.

Patients receiving T-DXd experienced a median time to first hospitalization that was three times longer than those on T-DM1, indicating better overall health management and fewer hospital visits during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Curigliano, G., Dunton, K., Rosenlund, M., et al.[2023]

In the DESTINY-Breast03 trial involving 524 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 28.8 months compared to 6.8 months for trastuzumab emtansine, indicating its superior efficacy.

Trastuzumab deruxtecan also demonstrated a favorable safety profile, with similar rates of severe adverse events compared to trastuzumab emtansine, although it was associated with a higher incidence of interstitial lung disease (15% vs. 3%), suggesting careful monitoring is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Hurvitz, SA., Hegg, R., Chung, WP., et al.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Citations

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Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares ... Zongertinib dose-dependently inhibited growth of tumors, delaying tumor growth at 2.5 mg/kg twice a day and 5 mg/kg every day and shrinking ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01727

HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI ... In patients with NSCLC receiving zongertinib once daily, median progression-free survival was 17.2 months (95% CI, 8.3 to NR). Conclusion.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.1023

Zongertinib in HER2-altered breast cancer In pts with BC, the confirmed OR rate was 26.7% (4 partial responses). The confirmed disease control rate was 73.3%. Regardless of confirmation, ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2503704

Zongertinib in Previously Treated HER2-Mutant Non–Small ... The median progression-free survival was 6.8 months (95% CI, 5.4 to not evaluable). In the exploratory cohort 3, a total of 6 patients with ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT449958

Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2- ... All responding pts remained on treatment at data cut-off. Conclusions: Zongertinib was well tolerated and demonstrated promising efficacy in pts with HER2 ...

6. esmo.org esmo.org/oncology-news/manageable-safety-profile-and-antitumour-activity-of-zongertinib-in-pretreated-patients-with-her2-altered-tumours-including-nsclc

Manageable Safety Profile and Antitumour Activity of ... Zongertinib had a manageable tolerability profile with preliminary signals of efficacy in pretreated patients with HER2-altered solid tumours, including HER2- ...