Abstract P4-10-04: Clinical outcomes of alpelisib in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer by next-generation sequencing-detected PIK3CA alteration status and phosphatase and tensin homolog loss: Biomarker analysis from the SOLAR-1 study
Authors: Juric Dejan , Andre Fabrice , Singer Christian F. , Sohn Joohyuk , Campone Mario , Loibl Sibylle , Conte Pierfranco , Iwata Hiroji , Ciruelos Eva , Mayer Ingrid A. , Reising Albert , Ma Chong , Miller Michelle , Babbar Naveen , Rugo Hope S. 
Published: March 2020

Abstract
Introduction: Hyperactivation of the phosphoinositide-3-kinase (PI3K) pathway is a frequent event in human cancers and can be a result of phosphatase and tensin homolog (PTEN) loss, activation of receptor tyrosine kinases, or alterations in PI3K isoforms. About 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) breast cancers harbor alterations in the PIK3CA gene, which encodes the alpha subunit of PI3K (p110α). Mutations in PIK3CA can cause PI3K pathway hyperactivation, which may contribute to endocrine resistance. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), demonstrated improved median progression-free survival (PFS) vs placebo (PBO) + FUL (11.0 vs 5.7 mo, respectively; hazard ratio [HR] 0.65; 95% confidence interval [CI], 0.50-0.85; P&lt;0.001) in patients (pts) with PIK3CA-mutated, HR+, HER2- advanced breast cancer (ABC) in the ongoing phase 3 SOLAR-1 study. Prospective PIK3CA mutation testing was performed on tumor tissue in a central laboratory using polymerase chain reaction (PCR)-based assays designed to specifically detect 12 mutations in exons 7, 9, and 20, and was used to determine PIK3CA mutation status in SOLAR-1. Retrospective next-generation sequencing (NGS) analysis of samples identified additional alterations that were not detectable by the PCR-based assays used at screening. In this exploratory biomarker analysis, we analyzed clinical outcomes of pts with PIK3CA alteration(s) as detected by NGS, with or without PTEN loss.
Methods: SOLAR-1 is a phase 3, randomized, double-blind study of ALP 300 mg (or PBO) once daily + FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, PIK3CA alterations (mutations and amplifications) were assessed by NGS and PTEN levels were assessed by immunohistochemistry. PTEN loss was defined based on an H-score &lt;10. Median PFS (mPFS) was assessed using Kaplan-Meier methodology.
Results: Of 572 pts in SOLAR-1, 341 (60%) had a PIK3CA mutation in tumor tissue by PCR, valid NGS results were available for 404 (71%), and PTEN levels were available for 401 (70%). Of the pts with available PTEN results, 34 (8%) had PTEN loss. PFS results and HRs, by PIK3CA alteration status as detected by NGS and PTEN status, are shown in the Table. In pts whose tumors had any PIK3CA alteration (n=239), which included a small group of pts with alterations not detectable by the PCR-based test used for screening in SOLAR-1 (n=31), mPFS was improved in the ALP + FUL vs PBO + FUL arms. In the small group of pts (n=19) whose tumors had PTEN loss but no PIK3CA alteration, ALP showed an improved mPFS and favorable HR vs the placebo arm. In pts whose tumors had multiple alterations (n=44), HR and mPFS benefits of ALP were observed, albeit with wide 95% CIs.
Conclusions: These data demonstrate the efficacy of ALP in pts whose tumors harbor PIK3CA alterations as detected by NGS, including alterations that were not detectable by the PCR-based test used in SOLAR-1. Additional analyses suggest that ALP is also effective in pts with single and multiple PIK3CA mutations and in those whose tumors do not harbor a PIK3CA alteration but do have PTEN loss; however, low patient numbers in the PTEN loss subgroups may limit conclusions.
Alpelisib + FulvestrantPlacebo + FulvestrantHR (95% CI)Events/N (%)mPFS, mo (95% CI)Events/N(%)mPFS, mo (95% CI)PIK3CA:altered vs non-altered (by NGS)Altered68/121 (56.2)11.01 (8.05 - 15.21)85/118 (72.0)5.52 (3.55 - 7.36)0.59 (0.43 - 0.82)Non-altered36/82 (43.9)7.29 (5.22 - 9.17)39/83 (47.0)7.16 (5.03 - 11.01)0.99 (0.62 - 1.57)PIK3CA:single vs multiple alterations (by NGS)Single60/100 (60.0)11.01 (7.49 - 14.55)66/94 (70.2)4.63 (3.38 - 7.39)0.59 (0.41 - 0.84)Multiple8/20 (40.0)9.36 (6.31 - NA)19/24 (79.2)7.29 (2.07 - 12.85)0.56 (0.23 - 1.33)PIK3CA: alteration detectable by PCR vs alteration not detectable in SOLAR-1 (by NGS)Detectable64/105 (61.0)11.01 (7.49 - 15.21)79/103 (76.7)3.81 (3.52 - 7.29)0.56 (0.40 - 0.79)Not detectable4/16* (25.0)8.48 (5.55 - NA)6/15 (40.0)12.98 (3.38 - NA)0.75(0.21 - 2.73)PIK3CA alterations (by NGS) and/or PTEN loss (by IHC)PIK3CA non-altered, PTEN non-loss31/72 (43.1)7.39 (5.16 - 9.26)32/71 (45.1)7.16 (5.06 - 11.01)1.03 (0.62 - 1.70)PIK3CA altered, PTEN non-loss63/113 (55.8)11.01 (8.31 - 15.21)78/111 (70.3)5.52 (3.61 - 7.39)0.63 (0.45 - 0.88)PIK3CA non-altered, PTEN loss5/9 (55.6)6.23 (2.79 - NA)7/10 (70.0)1.86 (1.64 - NA)0.50 (0.13 - 1.89)PIK3CA altered, PTEN loss5/8 (62.5)7.72 (2.69 - NA)7/7 (100.0)3.55 (1.05 - 7.23)0.24 (0.06 - 0.97)CI, confidence interval; HR, hazard ratio; IHC, immunohistochemistry; mPFS, median progression-free survival; NA, not available; NGS, next-generation sequencing; PTEN, phosphatase and tensin homolog.*These 16 alterations not detectable by PCR include 15 mutations and 1 PIK3CA amplification.
Citation Format: Dejan Juric, Fabrice Andre, Christian F. Singer, Joohyuk Sohn, Mario Campone, Sibylle Loibl, Pierfranco Conte, Hiroji Iwata, Eva Ciruelos, Ingrid A. Mayer, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Hope S. Rugo. Clinical outcomes of alpelisib in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer by next-generation sequencing-detected PIK3CA alteration status and phosphatase and tensin homolog loss: Biomarker analysis from the SOLAR-1 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-04.