Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had >3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations.

Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-14.