Evaluation of the potential incremental efficacy and safety of inavolisib in the neoadjuvant endocrine treatment of early-stage HER2-positive, HR-positive, PIK3CA mutant breast cancer.

This is a multicenter, prospective, randomized, open-label, parallel-group, phase II study to evaluate the potential incremental efficacy and safety of inavolisib in the neoadjuvant treatment of early-stage HER2-positive, HR-positive, PIK3CA mutant breast cancer.

170 patients with confirmed eligibility criteria and PIK3CA mutant breast cancer will be randomized in a 1:1 ratio to receive: Neoadjuvant endocrine therapy in combination with dual anti-HER2 blockade consisting of ready-to-use fixed-dose combination of pertuzumab and trastuzumab as subcutaneous (PH-FDC SC) formulation q3w for 6 cycles (18 weeks) with (6cycles) or without inavolisib. Endocrine therapy consists of either tamoxifen 20mg or an aromatase inhibitor +/- GnRH analogue for premenopausal women and men.

In both study arms, treatment will be given until surgery/core-biopsy, disease progression, unacceptable toxicity, or withdrawal of consent of the patient.

All patients will undergo surgery or biopsy after completing study therapy to assess pCR rate.

Inclusion Criteria

1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.

2. Untreated, unilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed.

3. Tumor lesion in the breast must be measurable in two dimensions, preferably by sonography.

4. Patients must be in the following stages of disease:

   • cT1b - cT3 regardless of nodal status In patients with multifocal or multicentric breast cancer the largest lesion (target lesion) should be measured.

5. HR+/HER2+ disease with centrally confirmed ER-status, PR-status, HER2-status, PIK3CA mutation (tumor), Ki-67 value and TILs on core biopsy (target lesion). ER/PgR positive and HER2-positive is defined according to current ASCO/CAP guidelines. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy of target lesion has therefore to be sent to the GBG central pathology laboratory prior to randomization. In patients with multifocal or multicentric breast cancer, all non-target lesions must also be HR+/HER2+, as confirmed by local testing.

6. Age ≥ 18 years, female and male.

7. ECOG Performance status 0-1.

8. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results for LVEF must be above 55%.

9. Laboratory requirements:

   Hematology

   • Absolute neutrophil count (ANC) ≥ 1.5/ nL
   • Platelets ≥ 100/ nL and
   • Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function
   • Total bilirubin < ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
   • AST and ALT ≤ 1.5x ULN and
   • Alkaline phosphatase ≤ 2.5x ULN

   Glucose Metabolism:

   • Glycosylated hemoglobin (HbA1c) < 6.5%

10. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. A woman is considered to be of childbearing potential if she is not hysterectomized or not postmenopausal.

    Postmenopausal is defined as:

    • ≥12 continuous months of amenorrhea with no identified cause other than menopause.
    • Having undergone bilateral oophorectomy.

11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for least 7 months after the last dose of PH-FDC SC. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include: bilateral tubal ligation; male partner sterilization; intrauterine devices. For men: men must remain abstinent or use a condom with a spermicidal product during the treatment period and for 7 months after the last dose of PH-FDC therapy to avoid exposing the embryo. Men and women must refrain from donating sperm/eggs during this same period.

12. Staging work-up according to country guidelines prior to randomization including:

    • Bilateral mammography and/or breast MRI in combination with a breast ultrasound. Exception: In men where MRI is medically not indicated breast ultrasound is sufficient.

13. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria

1. Patients with HER2-negative breast cancer and/or HER2-positive, HR-negative breast cancer.

2. Need of immediate neoadjuvant chemotherapy, e.g. inflammatory breast cancer.

3. Patients with definitive clinical or radiologic evidence of Stage IV cancer.

4. Excisional biopsy or lumpectomy and /or axillary lymph node dissection and/or sentinel lymph node biopsy performed prior to study entry (biopsy of clinical involved LN is warranted).

5. Prior chemotherapy or endocrine therapy or radiation therapy prior to study entry with the following exceptions:

   • If medically indicated, initiation of endocrine therapy up to 28 days prior to randomization and use of established fertility preservation methods in young patients interested in subsequent pregnancies is allowed.

6. Patients with a history of breast cancer are ineligible with the following exceptions:

   • Patient has been disease-free for more than 5 years and is at low risk for recurrence (at the investigator's discretion).

7. Patients with a history of any treated malignancy are ineligible in case of high risk of recurrence (at the investigator's discretion) and/or ongoing oncological treatment. This also applies to patients who are at high risk that oncological treatment is indicated during study therapy.

8. Patients with BMI>30 can be included at the investigator's discretion.

9. Known hypersensitivity reaction to one of the compounds or substances, and/or murine proteins, and/or recombinant human hyaluronidase used in this protocol.

10. Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on FPG and HbA1c.

11. Patients who are immunocompromised as the result of HIV or receiving immunosuppressive therapies.

12. Clinically significant and active liver disease, for example, sclerosing cholangitis, active viral hepatitis B or C infection, or autoimmune hepatic disorders.

13. Patients with inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, and active bowel inflammation (e.g., diverticulitis).

14. Patients with any concurrent ocular or intraocular condition, excluding baseline cataracts, that would require medical or surgical intervention during the study period to prevent or treat vision loss. In addition, patients with active uveitis or vitritis, history of uveitis, or active infectious process in the eye.

15. Patients with currently documented pneumonitis/interstitial lung disease.

16. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >160 / 90 mm Hg under treatment with three antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.

17. Damaged skin at planned site of subcutaneous (SC) injections (thigh).

18. Patients who may have had a recent episode of thromboembolism and are still trying to optimize the anticoagulation dose and/or have not normalized their INR.

19. Concurrent treatment with: • Chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).

    • Sex hormones. Prior treatment must be stopped before randomization (GnRH a is allowed).
    • Other experimental drugs or any other anti-cancer therapy.

20. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.

21. Female patients: pregnancy or lactation at the time of randomization.

22. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.

23. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.