Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer

Abstract

Purpose: The activating mutation AKT1 ^E17K occurs in approximately 7% of estrogen receptor-positive (ER⁺) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1 ^E17K-mutant ER⁺ MBC.

Patients and methods: Patients with an AKT1 ^E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR₂₄). Biomarker analyses were conducted in the combination cohort.

Results: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1 ^E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1 ^E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].

Conclusions: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1 ^E17K-mutant ER⁺ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

Figure 1.. Study Design of the ER+ AKT1-Mutant Breast Cancer Patient Cohorts

The breast cancer cohorts were part of a larger open-label, multipart, Phase I study of the first-in-human evaluation of oral capivasertib in patients with advanced solid malignancies. These Phase I expansion cohorts were non-randomized; the monotherapy cohort enrolled first, followed by the combination therapy cohort. Protocol-specified analyses planned for each study part: For monotherapy, analyses were planned after 20 patients were followed up for 12 weeks/withdrawn from the study. For combination therapy, interim analysis was planned after 12 patients in each cohort were followed up for 24 weeks/withdrawn from the study, and final analysis was planned after up to 24 patients in total in each cohort were followed up for 24 weeks/withdrawn from the study. ^aUp to 120. CBR₂₄, clinical benefit rate at 24 weeks; ER, estrogen receptor; ORR, objective response rate; PFS, progression-free survival.

Figure 2.. Efficacy of Capivasertib Monotherapy in ER+ AKT1^E17K-Mutant MBC (n=20)

Plot based on patients with available RECIST data at baseline and at least one follow-up assessment. Investigator-assessed best percentage change from baseline was the change in the sum of longest diameters of target lesions. BoR, best objective response; ER, estrogen receptor; MBC, metastatic breast cancer; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 3.. Combined Efficacy and Biomarker Data From the Combination Therapy (Capivasertib + Fulvestrant) Cohort in ER+ AKT1^E17K-Mutant MBC (n=43)

Best RECIST response and associated PFS integrated with genomic analyses for all 43 patients enrolled in the combination cohorts. Top to bottom: prior exposure to a CDK4/6 inhibitor; best objective response; best change from baseline in target lesion diameter according to RECIST v1.1; PFS in months; AKT1^E17K mutation detection at baseline by various testing platforms (BEAMing, ddPCR, NGS) in tissue and/or ctDNA, and at C2D1 by ddPCR in ctDNA; and percentage change (≥50% decrease) in AKT1^E17K-mutant copies in ctDNA by ddPCR measured on C2D1 of study treatment compared with baseline (C1D1). For 33 patients with somatic mutations detected in ctDNA by NGS, the AKT1^E17K MAF, as well as the MAF from other key alterations, is presented together with the median MAF of all somatic mutations detected in each sample. Two patients lacked genomic data (not tested), and eight patients had no somatic mutations detected in their ctDNA samples by NGS, although they did by the more sensitive OncoBEAM™ and/or ddPCR assays and were deemed low shedders. Key co-occurring gene mutations detected by NGS analysis in ctDNA samples are indicated in the genomic heat map at the bottom of the figure. AF, allele frequency; C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; ER, estrogen receptor; FMI, Foundation Medicine, Inc; MAF, mutant allele fraction; MBC, metastatic breast cancer; NGS, next-generation sequencing; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.