Abstract
Abstract Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Data for camizestrant as monotherapy and in combination with palbociclib or abemaciclib have been presented previously.1–3 Here we present data from parts I and J (dose ranging and expansion, respectively), which examined camizestrant in combination with the pan-AKT inhibitor capivasertib. Methods: The primary objective was to determine the safety and tolerability of camizestrant 75 mg once daily (QD) in combination with capivasertib 400 mg twice daily (BID; intermittent: 4 days on, 3 days off). Secondary objectives included investigation of anti-tumor response and pharmacokinetics (PK). Participants were women of any menopausal status (pre-menopausal women received concomitant ovarian function suppression). Prior treatment with an endocrine therapy (ET) in the advanced setting was required with no limit on the number of lines of prior ET. Prior treatment with ≤2 lines of chemotherapy in the advanced setting was permitted. Prior treatment with CDK4/6 inhibitors (CDK4/6i) and/or fulvestrant was also permitted. Results: As of 21 March 2023, 29 patients had received camizestrant in combination with capivasertib. Patients were heavily pretreated in the advanced setting (48% prior chemotherapy, 90% prior CDK4/6i, 55% prior fulvestrant) and 72% had visceral metastases. The safety and tolerability profile of the combination of camizestrant and capivasertib was broadly consistent with that of each drug individually.4,5 In the 29 patients, adverse events considered related to camizestrant and/or capivasertib in >15% of patients (%; n grade 1/n Grade 2/n Grade >3) included diarrhea (66%; 14/2/3), visual effects (62%; all Grade 1), bradycardia (34%; all Grade 1), nausea (34%; 6/4/0), fatigue (21%; 4/2/0) maculopapular rash (17%; 0/3/2) and aspartate aminotransferase increased (17%; 3/0/2). The PK and safety data indicated no clinically relevant drug–drug interactions between camizestrant and capivasertib. The objective response rate was 29.6% (8/27), the clinical benefit rate at 24 weeks was 51.7% (15/29), and median progression–free survival was 8.3 months. Overall, 12 patients had a detectable ESR1 mutation (ESR1m) at baseline (Cycle 1, Day 1) and an evaluable Cycle 2, Day 1 (C2D1) result; of these, ESR1m was reduced by >50% at C2D1 in 91.7% of patients (11/12), including 66.7% (8/12) of patients where ESR1m was cleared. Conclusions: Camizestrant 75 mg QD in combination with capivasertib 400 mg BID was well tolerated and associated with encouraging clinical and pharmacodynamic activity. These data support further evaluation of this combination in women with ER+/HER2− advanced breast cancer.
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