An international, multicenter, two-stage optimal Simon's design, single-arm phase II clinical trial to evaluate zongertinib plus fulvestrant combination therapy in participants with hormone receptor-positive/HER2-negative advanced breast cancer harboring HER2 mutations.

This trial will study a type of HR-positive/HER2-negative advanced breast cancer (ABC) harboring HER2 mutations. Participants will be treated with zongertinib, a targeted treatment that inhibits HER2, and fulvestrant, an endocrine therapy. The main purpose of the Study is to analyze the efficacy of zongertinib plus fulvestrant in participants who have HR-positive/HER2-negative ABC harboring HER2 mutation. Participants will receive zongertinib 120 mg orally once daily plus fulvestrant 500 mg administered intramuscularly on days 1 and 15 of cycle 1, and every 28 days thereafter. Pre- and perimenopausal women and men will receive concomitant luteinizing hormone-releasing hormone analogues. Treatment will continue until disease progression, unacceptable toxicity, death, or treatment discontinuation for any reason. Zongertinib plus fulvestrant efficacy will be determined by assessing the objective response rate, defined as the rate of participants with complete response (CR) or partial response (PR).

Inclusion Criteria:

1. Participant, or legal representative (if applicable), must be capable to understand the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male participants ≥ 18 years of age at the time of signing ICF.
3. Pre- or perimenopausal women and men provided they are being treated with a LHRH analogue for at least 28 days (if shorter, post-menopausal levels of serum estradiol/follicle-stimulating hormone [FSH] must be confirmed analytically) prior to initiation of the Study treatment, or post-menopausal women.
4. Histologically- or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either unresectable locally advanced or metastatic disease confirmed by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
5. Documentation of HR-positive (estrogen receptor [ER] and/or progesterone receptor [PgR] expression in ≥1% of tumor cells) and HER2-negative (0-1+ by immunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test) tumor according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as per local assessment on the most recent analyzed biopsy.
6. Known activating HER2 mutation.
7. Measurable disease according to RECIST v.1.1.
8. ECOG performance status of 0-1.
9. Participants must have experienced disease progression after at least one line of endocrine therapy (including CDK4/6 inhibitor). Participants who received CDK4/6 inhibitor-based therapy in the adjuvant setting are also eligible provided that disease progression occurred after at least 12 months of treatment but within 12 months following completion of the CDK4/6 inhibitor.
10. Participants must not have received more than two prior chemotherapy regimens for advanced disease (an ADC is counted as one line of chemotherapy).
11. No prior treatment with a HER2-directed tyrosine kinase inhibitor is permitted, but other HER2-targeted agents (such as T-DXd) and fulvestrant are allowed in any setting.
12. Participants must have adequate bone marrow, liver, and renal function.
13. Resolution of all acute toxic effects of prior anticancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 (v.6.0) (except for alopecia or other toxicities not considered a safety risk for the participant at investigator's discretion).
14. Willing to provide biological samples.
15. Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 7 days before Study treatment dose. In addition, they must agree to use one highly effective method of birth control from the time of screening until 2 years after the last dose of Study treatments. Female participants must refrain from egg cell donation and breastfeeding during this same period. Women who are nursing can be enrolled if they stop nursing. In this case, the patient cannot resume nursing until 30 days after the last dose of Study treatment.
16. Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 2 years after the last dose of Study treatment. Male participants must not donate or bank sperm during this same period.
17. Minimum life expectancy of ≥ 12 weeks at screening.

Exclusion Criteria:

1. Participation in another clinical trial, interventional or observational, until the Study's safety visit. Note: Participation in retrospective studies or data analysis is allowed.

2. Treatment with any approved or investigational cancer therapy within 21 days or 5 half-lives (whichever is shorter) prior to initiation of Study treatments, except for fulvestrant, which may be administered within a shorter interval.

3. Participants who must or wish to continue the intake of restricted medication or any drug considered likely to interfere with the safe conduct of the trial.

4. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

   Note: Participants with a history of CNS metastases are eligible if they have been previously treated with local therapy, are clinically stable, and off anticonvulsants and steroids for at least 14 days before the first dose of Study treatment.

5. Have a concurrent malignancy or malignancy within 5 years of Study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I endometrioid uterine cancer that have been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor's Medical Monitor is required.

6. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) (zongertinib and fulvestrant) or their incorporated substances.

7. History of malabsorption syndrome or any other condition that would interfere with enteral absorption in the opinion of the investigator (e.g., ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, nausea, vomiting, Crohn's disease, ulcerative colitis, chronic diarrhea, prior gastric bypass) or results in the inability or unwillingness to swallow pills.

8. Radiotherapy within 2 weeks prior to the first dose of Study treatments, except palliative radiotherapy to regions other than the chest, which is allowed up to 1 week before the first dose of Study treatments.

9. Major surgical procedure or significant traumatic injury within 14 days before the first dose of Study treatments or anticipation of need for major surgery within the course of the Study treatment.

10. Clinically relevant cardiovascular/cerebrovascular disease and/or cardiac dysfunction or conduction abnormalities.

11. Active or known pre-existing history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

12. Coagulopathy or any history of coagulopathy within 6 months before Study enrollment, including history of deep vein thrombosis or pulmonary embolism. However, participants with the following conditions will be allowed to participate:

    • Adequately treated catheter-related venous thrombosis occurring more than 28 days prior to Study entry.
    • Treatment with an anticoagulant (e.g., warfarin or heparin) for a thrombotic event occurring more than 6 months before randomization, or for an otherwise stable and allowed medical condition (e.g., well controlled atrial fibrillation), provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to Study entry. Due to the intramuscular route of administration, fulvestrant should be used with caution in patients with anticoagulant treatment.

13. Participants with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti HBV therapy (according to local/institutional standard) and who have not been treated with suppressive antiviral therapy prior to initiation of Study treatments or patients with a history of hepatitis C virus (HCV) infection who meet one or both of the following criteria:

    • Currently receiving curative antiviral treatment.
    • HCV viral load is above the limit of quantification (HCV RNA positive).

14. Participants with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria:

    • CD4+ count < 350 cells/μL.
    • Viral load > 400 copies/μL (local lab assessment).
    • Participants not receiving antiretroviral therapy, or who have received established antiretroviral therapy for less than 4 weeks prior to initiation of Study treatment.
    • History of AIDS-defining opportunistic infections within 12 months prior to start of Study treatment.

    Note: Participants with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of a HIV/Infectious Diseases specialist, or an HIV/Infectious Diseases specialist must be consulted prior to inclusion.

15. Other active uncontrolled infection at the time of enrollment.

16. Participants with severe hepatic impairment (classified as Child-Pugh C or score 10-15).

17. A history of uncontrolled seizures, CNS disorders, or serious and/or unstable pre-existing psychiatric disability judged by the Investigator to be clinically significant and adversely affecting compliance to Study treatment or interfering with participant's safety.

18. Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate participant participation.

19. Pregnant or lactating women or participants not willing to apply highly effective contraception as defined in the protocol.

20. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the Study

21. Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator.