主要目標 評估先前未曾接受晚期或轉移性疾病全身性治療的晚期或轉移性 HR+/HER2- 乳癌患者，接受 BGB-43395 加上 letrozole 治療 (A 組)，相較於 CDK4/6i 加上 letrozole 治療 (B 組) 的無惡化存活期 (PFS)。 重大次要目標 比較 A 組和 B 組的整體存活期 (OS)。 其他次要目標 進一步評估 A 組相較於 B 組的抗癌活性。 評估 A 組相較於 B 組的治療安全性。 評估 A 組相較於 B 組的患者自評疾病和治療相關症狀。

錠劑

BGB-43395

110

100mg/Tablet

PFS 由盲性獨立中央審查 (BICR) 依據 RECIST v1.1 判定，定義為自隨機分配日起至首次疾病惡化記錄或死亡的期間 (以先發生者為準)。

Patients are eligible to be included in the study only if they meet all the following criteria:
1. Patients must sign the ICF and be capable of giving written informed consent, which
includes compliance with the requirements and restrictions listed in the ICF and in this
protocol. Note for EU: Throughout this document a legally authorized representative is to
be interpreted as an impartial witness.
2. Patients must be at least 18 years of age or the legal age of consent in the jurisdiction in
which the study is taking place at the time of signing the informed consent.
3. Patients with histologically confirmed locally advanced or metastatic HR+ HER2- BC
(based on ASCO/CAP guidelines). ER positivity is defined as ≥ 1% ER-positive and/or
PR-positive stained cells, as assessed by an assay consistent with local standards. HER2
negativity should be documented through either immunohistochemistry (IHC) or in situ
hybridization per ASCO/CAP guidelines.
4. Female patients will be required (either continue ongoing or initiate as soon as feasible)
to have ovarian function suppression using LHRH/GnRH agonists (such as goserelin) or
be postmenopausal, defined as:
− Surgical bilateral oophorectomy OR
− Age ≥ 60 years OR
− Age < 60 years and absence of menses for ≥ 12 months with no prior
chemotherapy or ET with follicle-stimulating hormone and estradiol in the
postmenopausal range OR
− Age < 60 years with absence of menses for ≥ 12 months with history of
chemotherapy and serial follicle-stimulating hormone and estradiol in the
postmenopausal range
Note: Male patients are required to continue or initiate treatment with
LHRH/GnRH agonists such as goserelin and must continue LHRH/GnRH agonist
therapy while on study protocol.
5. Patients must be able to provide an archived FFPE tumor tissue sample (block or freshly
cut unstained FFPE slides. If no archival tissue is available, a fresh tumor biopsy is
required.
6. Patients must have measurable disease per RECIST v1.1. Patients with bone-only disease
are eligible provided they have BICR-confirmed evaluable bone-only disease with ≥ 1
lytic or mixed lytic-blastic bone lesion (patients with blastic-only metastases are not
eligible for enrollment).
7. Patients must have a stable ECOG Performance Status of ≤ 1.
8. Adequate organ function as indicated by the following laboratory values during
screening:
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days
before sample collection for the following:
− Absolute neutrophil count ≥ 1.5 × 109/L
− Platelet count ≥ 100 × 109/L
− Hemoglobin ≥ 90 g/L
b. eGFR ≥ 30 mL/min adjusted to actual BSA using the calculation for CKD-EPI
adjusted for BSA provided in Appendix 7.
c. Serum total bilirubin ≤ 1.5 × ULN (< 3 × ULN for patients with Gilbert’s syndrome).
d. AST and ALT ≤ 2.5 × ULN or < 5 × ULN if hepatic metastases are present.
Note: If laboratory tests at screening are not performed ≤ 7 days before study treatment(s)
administration on Day 1 of Cycle 1, these tests should be repeated, and the results should
be reviewed before study treatment administration.
9. Female patients of childbearing potential must be willing to use a highly effective method
of birth control and refrain from egg donation for the duration of the study, 6 months
after the last dose of BGB-43395, and 3 weeks after the last dose of letrozole,
abemaciclib, palbociclib, or ribociclib. They must also have a negative highly sensitive
urine or serum pregnancy test result ≤ 3 days before the first dose of study treatment(s).
See Appendix 1.
Note: A woman is considered to be of childbearing potential, ie, fertile, following
menarche and until becoming postmenopausal unless permanently sterile. Permanent
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy. See Appendix 1.
10. Nonsterile male patients with female partners of childbearing potential must be willing to
use a highly effective method of birth control and refrain from sperm donation for the
duration of the study and for 3 months after the last dose of BGB-43395, and 14 weeks
after the last dose of palbociclib (Appendix 1).
Note: A sterile male person is defined as having definitive evidence of infertility
previously demonstrated with azoospermia in a semen sample examination. A man is
considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

Patients are excluded from the study if they meet any of the following criteria:
1. Patients who have received prior systemic treatment in the advanced or metastatic setting.
Note: Patients who have received no more than two weeks of NSAI monotherapy (with
or without an LHRH/GnRH agonist, if pre-/peri-menopausal female or male) in this
disease setting immediately preceding screening and agree to discontinue NSAI until
study treatment initiation may participate.
2. Patients who have received prior treatment with endocrine-based therapy (with or without
a CDK4/6i) in the (neo)adjuvant setting and experienced disease recurrence during or
within 12 months after the last dose of endocrine-based therapy.
3. Patients who have received prior treatment with any selective CDK4 or CDK2 targeting
agent, or any other investigational anticancer drug in any disease setting, except for prior
investigational or approved SERDs in the adjuvant setting, provided that disease
recurrence occurred more than 12 months after the last dose of endocrine-based therapy.
4. Patients who are experiencing visceral crisis, defined as symptomatic visceral metastases
necessitating a cytotoxic treatment approach and/or rapid disease progression with
impending visceral compromise.
5. Patients who have a history of intolerance, severe allergic reactions, or hypersensitivity to
the active ingredient and excipients of the BGB-43395 tablet, letrozole, or abemaciclib,
palbociclib, ribociclib, as applicable.
6. Patients with active leptomeningeal disease (including carcinomatous meningitis) or
uncontrolled, untreated brain metastasis. Patients with a history of treated and, at the time
of screening, stable CNS metastases are eligible, provided they meet all the following
criteria:
a. Show no evidence of interim progression during brain imaging at screening, and
there is no evidence of new brain metastases.
b. Are clinically stable for ≥ 4 weeks before randomization and are asymptomatic.
c. Exclusion criterion 6c was removed.
d. Have no ongoing requirement for corticosteroids as therapy for CNS disease, off
corticosteroids for ≥ 4 weeks before randomization, and anticonvulsants at a
stable dose are allowed.
e. Have no stereotactic radiation or whole-brain radiation ≤ 14 days before
randomization.
7. Patients with any malignancy ≤ 3 years before randomization except for the specific
cancer under investigation in this study and any locally recurring cancer that has been
treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder
cancer, carcinoma in situ of the cervix or breast).
8. Patients with any active infection (including tuberculosis infection, other) requiring
systemic (oral or intravenous) antibacterial, antifungal, or antiviral therapy ≤ 28 days
before randomization, or symptomatic COVID-19 infection. Patients receiving
prophylactic antibiotics (eg, for prevention of urinary tract infection, chronic obstructive
pulmonary disease, or for dental extraction), and patients receiving antiviral treatment for hepatitis B, hepatitis C, and/or HIV per management guidelines are eligible. Patients who
have recovered from symptomatic COVID-19 infection can be rescreened for this study.
9. Patients who have a history of non-infectious ILD/pneumonitis that required
corticosteroids, who currently have ILD/pneumonitis, or for whom suspected
ILD/pneumonitis cannot be ruled out by imaging at screening.
10. Patients with oxygen saturation at rest < 92% on room air.
11. Patients with uncontrollable pleural effusion, pericardial effusion, or ascites requiring
frequent drainage (recurrence ≤ 14 days before randomization).
12. Patients with untreated chronic hepatitis B or chronic HBV carriers with HBV DNA
≥ 500 IU/mL (or ≥ 2500 copies/mL) at screening.
Note: Inactive hepatitis B surface antigen carriers, treated patients, and patients with
stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be
enrolled/randomized. Patients with detectable hepatitis B surface antigen or detectable
HBV DNA should be managed per treatment guidelines (see also Section 6.9).
13. Patients with active hepatitis C.
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody
test followed by a negative HCV RNA test at screening are eligible. For treatment
guidance, see Section 6.9.
14. Patients with medical history of untreated HIV infection. Patients with medical history of
HIV infection are eligible provided they meet all the following criteria:
a. Are stable on antiretroviral therapy for ≥ 4 weeks before randomization.
b. Agree to adhere to antiretroviral therapy per WHO guidelines.
c. Have no documented multidrug resistance that would prevent effective antiretroviral
therapy.
d. Have viral load of < 400 copies per mL at screening.
e. Have CD4+ T-cell count ≥ 350 cells/μL at screening.
f. Have no history of an AIDS-defining opportunistic infection ≤ 12 months before
randomization unless eligibility is agreed to by the medical monitor after
consultation.
g. Exclusion criterion 14g was removed.
15. Patients with any major surgical procedure ≤ 28 days before randomization. Patients
must have recovered adequately from the toxicity and/or complications from the
intervention before randomization.
16. Patients with any of the following cardiovascular risk factors:
a. Cardiac chest pain, defined as moderate pain that limits ADL, ≤ 28 days before
randomization.
b. Venous thromboembolism ≤ 3 months prior to randomization.
c. Any history of acute myocardial infarction ≤ 6 months before randomization.
d. Any history of heart failure meeting NYHA Classification III or IV (Appendix 8)
≤ 6 months before randomization.
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before
randomization.
f. Any history of cerebrovascular accident ≤ 6 months before randomization.
g. Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure
measurements showing systolic blood pressure > 170 mmHg and/or diastolic blood
pressure > 105 mm Hg at screening.
h. History of angina pectoris, symptomatic pericarditis, or coronary artery bypass graft
≤ 6 months before randomization.
i. Documented cardiomyopathy.
j. Left ventricular ejection fraction of < 50%.
k. At baseline, QTcF interval > 450 msec based on an average of triplicates
l. Significant risks of developing Torsades de Pointes, including congenital long QT
syndrome, unstable angina, bradyarrhythmias, severe aortic stenosis, uncontrolled
hypothyroidism, or electrolyte abnormalities.
17. Patients who have received palliative radiation treatment or other local regional therapies
≤ 14 days before the first dose of study treatment.
18. Patients with toxicities (because of prior anticancer therapy) that have not recovered to
baseline or stabilized to ≤ Grade 1 per NCI-CTCAE criteria, except for irreversible AEs
which the investigator believes are unlikely to worsen due to study treatment.
19. Patients who were administered a live vaccine ≤ 28 days before randomization.
Note: Vaccines for COVID-19 are allowed except for any live vaccine that may become
available. Seasonal vaccines for influenza are generally inactivated vaccines and are
allowed. Intranasal vaccines are live vaccines and are not allowed.
20. Any Chinese patent medicine with anticancer activity approved by the China NMPA
(regardless of the type of cancer) used ≤ 14 days before the first dose of study treatment.
21. Patients with underlying medical conditions (including laboratory abnormalities) or
alcohol or drug abuse or dependence that will be unfavorable for the administration of
study treatment, will affect the explanation of drug toxicity or AEs, or will result in
insufficient or impaired compliance with study conduct.
22. Female patients who are pregnant or are breastfeeding.
23. Patients with concurrent participation in another therapeutic (ie, interventional drug)
clinical study.
Note: Concurrent participation in observational or non-interventional studies is allowed.
24. Patients with any condition that requires treatment with prohibited or restricted
concomitant medications or therapy as described in Section 6.9 and Appendix 4.
25. Patients who are unable to swallow tablets or capsules (up to 20 mm in size).
26. Patients with active symptomatic inflammatory gastrointestinal disease; known
diverticular disease or previous stomach or small bowel resection or bariatric surgery
procedures, including lap ban surgery; any disease/procedure significantly affecting
gastrointestinal function, such as malabsorption syndrome, or partial or complete bowel
obstruction; gastrointestinal perforation or fistulae, or uncontrolled nausea, vomiting or
diarrhea.
Note: Gastroesophageal reflux disease under treatment with proton-pump inhibitors is
allowed. Refer to Appendix 4.
27. Patients who require ongoing treatment with a moderate or strong CYP3A inhibitors or
inducers, or P-gp inhibitors, or UGT2B7 inhibitors or inducers (see Appendix 4) ≤ 5
half-lives (if the half-life is known) or ≤ 14 days (if the half-life is unknown) before the
first dose of study treatment. For Arm A, the use of sensitive substrates of CYP3A and
P-gp is prohibited.
28. Within the EU, patients not affiliated to a social health system.
29. Within the EU, patients subject to a legal protection measure or unable to express their
consent.