Pembrolizumab + Paclitaxel in Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2-negative (HER2-) Non-luminal (by PAM50) Advanced Breast Cancer After Cyclin-dependent Kinase 4/6 (CDK4/6) Inhibitors Progression

This is an open-label, single arm, multicenter phase II study evaluating treatment with pembrolizumab in combination with paclitaxel in patients with locally advanced or metastatic non-luminal Hormone receptor-positive, HER2-negative (hereafter referred to as HR+/HER2-) breast cancer who had recurrence or progression while receiving previous therapy with a CDK inhibitor in the adjuvant setting or to treat advanced disease (or both).

The study will utilize a 2-stage, single arm, Simon's 2-stage design1 with one (efficacy) interim and a final analysis. The interim analysis will be conducted when 15 patients are evaluable for Overall Response Rate (ORR) as determined locally by the investigator through the use of RECIST v.1.1. If 5 or fewer responses are observed in up to 15 patients of evaluable population (EP), the trial will be terminated in favor of the null for futility. Otherwise, up to a further 31 patients may be evaluated,for a maximum total of 46 evaluable patients. If a total of 19 or more responses are seen at the end of the second stage, then the null will have been rejected in favor of the alternative; and further investigation of the combination is warranted.

Recruitment will not be halted during the interim analysis period. Therefore, no interruption in the accrual will be done during the interim analysis in order to maintain the dynamic of accrual in the trial.

After confirmation of all eligibility criteria, eligible patients will receive pembrolizumab 200 mg every 3 weeks (on D1 of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m2 administered at days 1, 8, 15 of each 21-day cycle beginning at cycle 2. Treatment will continue until disease progression, the development of unacceptable toxicity, withdrawal of consent, 24 months from the date of the first dose of pembrolizumab or end of study, whichever occurs first.

All patients will be followed for survival from screening until the last patient recruited has been followed for 12 months, has progressed or has died, whichever occurs first. The patient will be followed for survival approximately every 3 months (± 21 days) until death, withdrawal of consent, loss to follow-up, or study termination by the sponsor. In addition, information regarding use of subsequent anti-cancer agents for metastatic HR+/HER2- during the survival follow-up period will be collected.

Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 and Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST) will be performed every 9 weeks (63 days ± 5 days) until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. Tumor assessments will be performed on the specified schedule regardless of treatment delays.

Safety assessments will include the incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities graded per the NCI CTCAE v.5.

Laboratory safety assessments will include the regular monitoring of hematology, blood chemistry and pregnancy test

Eligibility Criteria:
Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of locally advanced or metastatic, histologically documented hormone receptor positive (ER and/or PR expression \>1%) and HER2- breast cancer by local testing, not amenable to surgical therapy will be enrolled in this study.

   1. HER2 negativity is defined as either of the following by local laboratory assessment: Immunohistochemistry (IHC) 0, IHC 1+ or IHC 2+/in situ hybridisation (ISH) negative as per American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline (ISH negative is defined as a ratio of HER2 to chromosome 17 centromere (CEP17) \<2.0)117.
   2. ER and/or PR positivity are defined as \>1% of cells expressing HR via IHC analysis as per ASCO-CAP guideline118
2. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
3. Eligible for taxane therapy.
4. No prior chemotherapy for inoperable locally advanced or metastatic breast cancer.
5. Prior radiation therapy for metastatic disease is permitted. Subjects who were treated with radiation therapy may participate as long as at least 2 weeks have elapsed since the last dose of radiation therapy or have recovered from the effects of radiation before allocation whichever is the latest.
6. Disease refractory to CDK4/6 inhibitors, defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 6 months after the end of treatment for advanced/metastatic disease.

   Notes: CDK4/6 inhibitors do not have to be the last treatment prior to randomization. Other prior anticancer endocrine therapy, e.g. aromatase inhibitors, fulvestrant or tamoxifen, are also allowed.
7. Previous chemotherapy with a taxane for early breast cancer (neoadjuvant or adjuvant setting) is permitted.
8. Availability of formalin-fixed paraffin-embedded (FFPE) tumor block, collected during advanced/metastatic disease, with an associated pathology report. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for PAM50 analysis prior to enrollment. Patients whose tumor tissue is not evaluable for central testing are not eligible. If PAM50 analysis of tumor sample has alredy been performed at central lab (i.e analysis from other SOLTI clinical trial) PAM50 result can be valid for this study.

   1. Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases.
   2. Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable.
9. Non-Luminal subtype as per PAM50 analysis (i.e. HER2-enriched or Basal-like).
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 10 days prior to the date of allocation/randomization.
11. Life expectancy ≥ 12 weeks
12. Measurable disease, as defined by RECIST v1.1. (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.)
13. Adequate hematologic and end-organ function, defined by the study protocol with results obtained within 10 days prior to the first study treatment at Cycle 1, Day 1 (C1D1):

    Male participants:
14. A male participant must agree to use contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 180 days after the last dose of paclitaxel and 120 days form the last doses of pembrolizumab and refrain from donating sperm during this period.

    Female participants:
15. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 180 days after the last dose of paclitaxel and 120 days from the last dose of pembrolizumab.

Exclusion Criteria:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1 (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior therapy with an anti-PD1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.
3. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil).
4. Resolution of all acute toxic effects of prior anti-cancer therapy or major surgical procedures to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).

   Note: Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.
5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Note: It is not recommended the use of live or attenuated COVID-19 vaccines within 30 days of initiation or during study treatment. However, if vaccination with these vaccines is required, please ask for advice on how to proceed the Medical Monitor.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling catheters, such as PleurX® are allowed).
7. Uncontrolled hypercalcemia (\>1.5 mmol/L \[\>6 mg/dL\] ionized calcium or serum calcium \[uncorrected for albumin\] \>3 mmol/L \[\>12 mg/dL\] or corrected serum calcium \>ULN) or clinically significant (symptomatic) hypercalcemia
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
10. Has known active Central Nervous System metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
14. Prior allogeneic stem cell or solid organ transplantation
15. Has an active infection requiring systemic therapy.
16. Has a known history of Human Immunodeficiency Virus (HIV).
17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (HCV) (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
18. Has a known history of active Tuberculosis Bacillus.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel.