Inclusion Criteria:
1. Female patients with histologically or cytologically confirmed premenopausal or postmenopausal, hormone receptor-positive, stage IV breast cancer.
\*Definition of hormone receptor positivity: nuclear staining of tumor cells for ER or PR between 1% and 100% on immunochemical staining using a tumor sample (ASCO/CAP guideline 2020).
2. Patients who have given written informed consent for this clinical study.
3. Patients who have not received systemic cytotoxic chemotherapy in the metastatic setting. Hormone therapy and anti-HER2 targeted therapy are not limited; however, patients are excluded if an anti-HER2 agent and a cytotoxic chemotherapeutic agent were used together as first-line therapy. (Patients who have received a PARP inhibitor are eligible for enrollment.)
4. Patients over 19 years of age as of the date of written informed consent.
5. Patients who meet the criteria for hypermutation based on whole-exome sequencing.
\*Criteria for hypermutation: the number of nonsynonymous mutations is initially set at 70 or more, and is adjusted to the value corresponding to the top 20% or higher through interim analysis performed for every 30 cases. That is, the standard may change approximately every 30 cases.
6. Patients with a metastatic tumor that can be biopsied for whole-exome sequencing. Biopsy of a breast or axillary lymph node tumor is also allowed for patients with local recurrence after surgery or with stage IV disease from diagnosis.
7. Patients with one or more measurable lesions based on RECIST v1.1. Biopsied tissue is considered a measurable lesion if not resected.
8. Patients whose disease progression has been confirmed since the most recent treatment (not applicable at the prescreening stage; i.e., tissue biopsy is possible while maintaining the existing treatment).
9. Patients with an expected life span of 12 weeks or more.
10. ECOG performance status of 0 to 1.
11. Patients whose organ function eligibility test, conducted within 14 days prior to the start of treatment, meets the criteria summarized in Table 2 below.
Table 2. Adequate Organ Function Laboratory Values
12. In the case of women of childbearing potential, a negative pregnancy reaction confirmed by a urine or serum pregnancy test within 72 hours prior to the first administration of the study drug. If the urine test is positive or negative but difficult to confirm, a serum pregnancy test is required.
13. For women of childbearing potential, willingness to use an appropriate method of contraception as described in Appendix 3 by day 180 after the last dose of the investigational drug.
Note: If abstinence is the subject's routine lifestyle and preferred method of contraception, that method is also permitted.
Exclusion Criteria:
1. Women of childbearing potential who have a positive urine pregnancy test within 72 hours prior to the first administration of the study drug (see criterion 7). If the urine test cannot be confirmed as negative, a serum pregnancy test must be performed. In this case, if the serum pregnancy test is positive, the subject must be excluded from the study.
2. Has a history of prior treatment with agents targeting anti-PD-1, anti-PD-L1, or anti-PD-L2, or other stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX40, CD137).
3. Has received prior systemic therapy, including the study drug, within 4 weeks before the first dose \[for kinase inhibitors or other short half-life drugs, if a period of at least 5 half-lives has not elapsed before randomization\]. However, enrollment is permitted even within 4 weeks if 5 half-lives have elapsed and the adverse effects of the prior systemic therapy have completely resolved.
4. Has received prior radiation therapy within 2 weeks before the start of treatment. Subjects must have recovered from all radiation-related toxicity, must not require corticosteroids, and must not have developed radiation pneumonitis. A 1-week washout period is permitted for palliative radiation (≤2 weeks of radiation therapy) for non-CNS disease.
5. Has received a live vaccine within 30 days before the first dose of the investigational drug.
-Note: Seasonal influenza vaccines are generally inactivated influenza virus vaccines and are therefore permitted for study participation. However, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not permitted for study participation.
6. Is currently participating in a clinical trial, or has participated in a clinical trial of an investigational drug and received investigational treatment or used an investigational medical device within 4 weeks before the first dose of the investigational drug.
-Note: Subjects currently participating in an observational study may be enrolled in this trial if 4 weeks have elapsed since the last study drug administration.
7. Has been diagnosed with immunodeficiency, or is chronically receiving systemic steroid therapy (at a dose exceeding the equivalent of 10 mg prednisone daily) or any other form of immunosuppressive therapy within 7 days before the first dose of the study drug.
8. Has a known additional invasive malignancy that is progressing or has required active treatment within the past 2 years.
\- Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the cervix who have been treated with curative intent are not subject to this exclusion.
9. Has active central nervous system (CNS) metastases and/or carcinomatous meningitis; such subjects are excluded from the trial. Subjects previously treated for brain metastases may participate if they are stable (no evidence of disease progression on imaging for at least 4 weeks before the first dose of the study drug and neurological symptoms have returned to baseline), have no new or enlarging brain metastases, and will not require steroids for at least 7 days before study treatment. Carcinomatous meningitis is excluded regardless of clinical stability.
10. Has a history of hypersensitivity to pembrolizumab or its excipients.
11. Has hypersensitivity (grade 2 or higher peripheral neuropathy) or a contraindication to paclitaxel or its excipients.
12. Has an active autoimmune disease that has required systemic treatment within the past 2 years (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs); such subjects are excluded. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
13. Has clinically significant cardiovascular disease (including unstable angina, myocardial infarction, stroke, and transient ischemic attack) or uncontrolled hypertension (SBP \> 140 mmHg or DBP \> 90 mmHg despite medication), as judged by the investigator, that occurred within 24 weeks before study participation.
14. Has active non-infectious pneumonitis or a history of non-infectious pneumonitis; such subjects are excluded.
15. Has an active infection requiring systemic treatment; such subjects are excluded.
16. Has a history of immunodeficiency virus (HIV 1/2 or HTLV-1 antibody).
17. Has active hepatitis B (HBs antigen +) or hepatitis C (anti-HCV antibody +) on laboratory testing within 180 days before the first dose of the study drug.
However, enrollment is permitted if the following are demonstrated within 60 days before the first dose of the study drug:
* For HBs antigen +: enrollment is permitted if the subject is inactive without treatment (HBV DNA \< 20 IU/mL), or if the viral load is undetectable while on antiviral therapy (HBV DNA \< 20 IU/mL).
* For anti-HCV antibody +: enrollment is permitted if an HCV RNA PCR test is performed and is negative. However, subjects who are anti-HCV antibody + and have not undergone HCV RNA PCR testing are not eligible for enrollment.
18. Has current active tuberculosis.
19. Has any condition, treatment, or laboratory abnormality that could confound the study results or interfere with the subject's participation for the entire duration of the study, or is, in the investigator's opinion, otherwise unsuitable for participation in the study.
20. Has a psychiatric disorder or substance abuse disorder that would interfere with the requirements of the clinical study.
21. Is a woman who is currently pregnant or breastfeeding, or a woman of childbearing potential who is unwilling to continuously use an effective method of contraception from the time of the prescreening or screening visit through 180 days after the last dose of the study drug.
22. Has received an allogeneic tissue/solid organ transplant.
