KEYNOTE-B49 

1. Has locally recurrent inoperable or metastatic HR+/HER2- breast cancer, which has not been previously treated with cytotoxic chemotherapy in the noncurative setting. Prior treatments with the combination of hormonal and non-hormonal targeted agents or PARP inhibitors are permitted.

2. Has progressed on two or more lines of endocrine therapy for metastatic HR+/HER2- disease, with at least one given in combination with a CDK4/6 inhibitor.

OR

Has progressed on one line of endocrine therapy for metastatic HR+/HER2- disease, if had a relapse within 24 months of definitive surgery for primary tumor and while on adjuvant endocrine therapy. Treatment with CDK4/6 inhibitors should have been given for metastatic or adjuvant therapy.

OR

If no prior CDK 4/6 inhibitors, participant must have progressed within 6 months of starting 1 line of endocrine therapy for metastatic disease and have presented a relapse within 24 months of definitive surgery for primary tumor and while on

adjuvant therapy.

3. Has presented a documented progression [confirmed by imaging and/or histology (biopsy or cytology)] during the last administered endocrine therapy prior to entering the study. A laboratory report indicating tumor marker elevation cannot be used as documentation of local or distant disease recurrence, unless accompanied by a dated biopsy, pathology, or imaging study report.

4. Is a chemotherapy candidate that meets the following criteria:

o Participants who received taxane and/or anthracyclines in the (neo)adjuvant setting can be treated with same class of chemotherapy (taxane or anthracycline), if ≥ 12 months, they have elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence.

o Participants who will be selected to receive liposomal doxorubicin should have a LVEF of at least 50% or above the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed prior to the first dose administration.

o Participants presenting with de novo metastatic disease at diagnosis, are eligible for the study, if they have progressed on two or more lines of endocrine therapy for metastatic HR+/HER2- disease, with at least one given in combination with a CDK4/6 inhibitor and they present a documented progression [confirmed by imaging and/ or histology (biopsy or cytology)] during the last administered endocrine therapy prior to entering the study. A laboratory report indicating tumor marker elevation cannot be used as documentation of local or distant disease recurrence, unless accompanied by a dated biopsy, pathology, or imaging study report.

5. Provides a new or the last obtained core needle biopsy, preferably consisting of multiple cores, taken from the locally recurrent or a distant metastatic lesion for central determination of hormone receptor status (ER and PgR), HER2, and PD-L1 status. Archival tumor tissue of the primary tumor is also acceptable; however, tissue of a metastatic lesion is preferred. Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory. Submission of another tumor specimen may be required, if adequate tumor tissue is not provided the first time. If new biopsy needs to be performed, it should be done before baseline tumor imaging assessment.

6. Has centrally-confirmed PD-L1 positive (CPS ≥1) and HR+ (ER and/ or PR) /HER2– breast cancer as defined by the most recent ASCO/CAP guidelines.

7. Has an ECOG performance status of 0 or 1, as assessed within 7 days prior to the start of study treatment.

8. Has a life expectancy ≥ 12 weeks from randomization.

9. Demonstrates adequate organ function, within 10 days prior to the start of study treatment, as defined in the table at the bottom of this document. (Table ).

Demographics

10. Is male or female at least 18 years of age at the time of signing the informed consent.

Male Participants

11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of chemotherapy:

• Refrain from donating sperm PLUS either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent

OR

• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.

• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.

Female Participants

12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

• Is not a WOCBP

OR

• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 during the intervention period and for at least 180 days after the last dose of chemotherapy or 120 days 6 months after the last dose of pembrolizumab, whichever occurs last, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.

• A WOCBP must have a negative highly sensitive pregnancy test [urine or serum] as required by local regulations within 24 hours for urine or within 72 hours for serum before the first dose of study intervention.

• [If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.]

• Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.4.

• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.

Informed Consent

13. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.

Additional Categories

14. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Participants with bone-only disease must have bone lesions with an accompanying measurable soft tissue component.

o Submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. If new biopsy needs to be performed, it should be done before baseline tumor imaging assessment.

o Note: Chest wall recurrence can be used as a target lesion, only if measurable by diagnostic quality imaging modality (digital photography alone is not adequate).

15. If receiving bone resorptive therapy, including but not limited to bisphosphonates or denosumab, have been receiving stable doses for ≥ 4 weeks prior to the date of randomization. 

1. Has breast cancer amenable to treatment with curative intent.

2. Has a history or current evidence of any condition (e.g., transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant’s involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.

3. Has significant cardiac disease, such as:

• History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months;

• Congestive heart failure (CHF) New York Heart Association

(NYHA) Class II-IV or history of CHF NYHA Class III or IV.

4. Has visceral crisis defined as presence of lymphangitic lung metastases, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, shortness of breath requiring supplemental oxygen, symptomatic pleural effusion requiring supplemental oxygen, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control.

5. Has skin only disease. Participants who have also measurable disease per RECIST 1.1 (inclusion #14) besides skin lesions are eligible.

6. Has a known germline BRCA mutation (deleterious or suspected deleterious) and has not received previous treatment with PARP inhibition.

Prior/Concomitant Therapy

7. Has received prior chemotherapy for locally recurrent inoperable or metastatic breast cancer.

8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).

9. Has received prior systemic anti-cancer therapy with other investigational agents within 4 weeks prior to randomization. Participants previously treated with endocrine therapy plus CDK4/6 inhibitors should participate as long as at least 3 weeks have elapsed since the last dose of therapy was administered.

10. Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline with the exception of the baseline values per Table . Note: Alopecia of any grade is an exception to this criterion. Participants with ≤ Grade 2 neuropathy may be eligible.

11. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to randomization.

12. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation- related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

13. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines are allowed.

Prior/Concurrent Clinical Study Experience

14. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Note: Participants who were treated with radiation therapy may participate as long as at least 2 weeks have elapsed since the last dose of radiation therapy was administered.

Diagnostic Assessments

15. 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 the first dose of study drug.

16. 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 (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

17. Has known active CNS metastases and/or carcinomatous meningitis. Participants with known brain metastases may participate provided that the brain metastases have been previously treated (except with chemotherapy) and are radiographically stable per local radiology/investigator review. To demonstrate radiographic stability of previously treated brain metastases, a minimum of 2 post-treatment brain imaging assessments are required:

1) The first brain imaging must be acquired after treatment of brain metastases has been completed;

2) The second brain imaging must be obtained during screening (i.e. within 28 days of randomization) and 4 weeks after the previous post-treatment brain imaging.

Note: Known brain metastases are considered active, if any of the following criteria are applicable:

a. Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least 4 weeks earlier. Radiographic stability of previously treated brain metastases is based on local radiology/investigator review but dated reports of 2 imaging studies (the most recent performed during screening) documenting stability of brain metastasis(es) over ≥ 4 weeks must be submitted to the Sponsor. Such brain imaging studies should be available at the site for submission to CIV, if later needed.

b. Neurological symptoms attributed to brain metastases have not returned to baseline

c. Steroids were used for management of symptoms related to brain metastases within 28 days of randomization.

18. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients. Or has severe hypersensitivity (≥ Grade 3) to the planned chemotherapy agent (paclitaxel, nab-paclitaxel, liposomal doxorubicin, or capecitabine) and/or any of their excipients.

19. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

20. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

21. Has an active infection requiring systemic therapy.

22. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority. Refer to Appendix 7 for country-specific requirements.

23. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (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. Refer to Appendix 7 for country-specific requirements.

24. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).

25. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

26. Has a known psychiatric or substance abuse disorder including alcohol or drug dependency that would interfere with the participant’s ability to cooperate with the requirements of the study.

Other Exclusions

27. Is breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days (or longer as specified by local institutional guidelines) after the last dose of study treatment.

28. Has had an allogenic tissue/solid organ transplant.

Table 7 - Adequate Organ Function Laboratory Values

System Laboratory Value

Hematological

Absolute neutrophil count (ANC) ≥ 1500/µL

Platelets ≥ 100 000/µL

Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La

Renal

Creatinine OR

Measured or calculatedb creatinine clearance

(GFR can also be used in place of creatinine or CrCl) ≤ 1.5 × ULN OR ≥ 50 mL/min for participant with creatinine levels > 1.5 × institutional ULN

Hepatic

Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN

AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver metastases)

ALP ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver metastases)

Albumin ≥ 3.0 g/dL

Coagulation

International normalized ratio (INR) OR prothrombin time (PT)

Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ALP=alkaline phosphatase; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

aCriteria must be met without erythropoietin dependency without packed red blood cell or platelets transfusion within last 2 weeks.

bCreatinine clearance (CrCl) should be calculated per institutional standard.

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. 

Research Nurse: Emma Davies (Ext No. 55649) Emma.Davies16@nhs.net

Administrator: Arun Prakash