Abstract PD2-06: Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 study
Authors: Ciruelos Eva M. , Loibl Sibylle , Mayer Ingrid A. , Campone Mario , Rugo Hope S. , Arnedos Monica , Iwata Hiroji , Conte Pier Franco , André Fabrice , Reising Albert , Ma Chong , Miller Michelle , Babbar Naveen , Juric Dejan 
Published: February 2021

Abstract
Introduction: The PI3K pathway is often hyperactivated in cancer as a result of an altered PI3K isoform and/or loss of phosphatase and tensin homolog function. Approximately 40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) have tumors with mutations in PIK3CA, which encodes the α-isoform of PI3K, p110α. These mutations are known to cause hyperactivation of the PI3K pathway, which contributes to cell proliferation, drug resistance, and poor prognoses. Alpelisib (ALP) is an α-selective PI3K inhibitor that, in combination with fulvestrant (FUL), prolonged median progression-free survival (mPFS) in pts with HR+, HER2−, PIK3CA-mutant ABC following progression on/after prior aromatase inhibitor in the phase 3 SOLAR-1 trial. In SOLAR-1, prospective PIK3CA mutation testing was performed on tumor tissue using PCR-based assays. Through retrospective analysis, efficacy of ALP was demonstrated in subgroups of pts with PIK3CA alteration(s) in tumor tissue and mutation(s) in ctDNA, detected by next-generation sequencing (NGS) and PCR, respectively. In this exploratory biomarker analysis, we assessed clinical outcomes of pts with PIK3CA alteration(s), detected in ctDNA by NGS.Methods: SOLAR-1 is a phase 3, randomized, double-blind, placebo-controlled study of ALP 300 mg vs placebo taken daily with FUL 500 mg every 28 days + Cycle 1 Day 15 in men and postmenopausal women with HR+, HER2- ABC. Retrospectively, the full exonic region of the PIK3CA gene was sequenced using the Foundation Medicine 324-gene ctDNA panel in plasma ctDNA collected at baseline. mPFS was assessed using Kaplan-Meier methodology per investigator assessment.Results: Of 572 pts in SOLAR-1, 381 pts (66.6%) across both PIK3CA-mutant and nonmutant cohorts had valid plasma ctDNA data. Of these pts, 193 (50.7%) had a PIK3CA alteration; 168 (87%) had PCR-detectable mutations and 147 (76%) had a single alteration. A total of 70 (36%) and 102 (53%) pts had alterations in exons 9 and 20, respectively. ALP plus FUL prolonged mPFS in pts with PIK3CA alterations detected in plasma ctDNA by NGS (n=101; Table). Clinical benefit was also observed in pts with PCR-detectable mutations (n=88), single mutations (n=83), and pts with mutations in exon 9 (n=34) and exon 20 (n=54). Pt numbers were low, and wide 95% CIs were observed in groups with alterations not detectable by PCR (n=13) and in pts with multiple alterations. Some limitations of this retrospective plasma analysis include that this is a subgroup (66.6%) of the SOLAR-1 pt population and that the subgroup of pts with non-altered PIK3CA included pts with a PIK3CA mutation in their tumor tissue. Conclusions: ALP plus FUL demonstrated clinical benefit in pts with PIK3CA mutations detected in plasma ctDNA by NGS, in pts with single alterations, and in pts with alterations in exons 9 and 20. Results were consistent across pt groups, except in those with alterations not detectable by PCR. In conclusion, these data demonstrate a consistent clinical benefit of ALP plus FUL in various groups of pts with PIK3CA alterations detected in ctDNA by NGS.
Clinical Outcomes of Patients With PIK3CA Alterations Detected in Plasma ctDNA by NGS in SOLAR-1Alpelisib + fulvestrantPlacebo + fulvestrantHR (95% CI)Events/N (%)mPFS, mo (95% CI)Events/N(%)mPFS, mo (95% CI)PIK3CA altered vs non-alteredAltered58/101(57.4)11.04(7.72-16.16)73/92(79.3)3.65(2.86-6.80)0.47(0.33-0.67)Non-altered40/87(46.0)10.87(5.59-16.76)60/101(59.4)5.45(3.75-9.00)0.60(0.40-0.91)PIK3CA: alteration detectable by PCR vs alteration not detectable by PCRDetectable52/88(59.1)12.48(7.36-18.37)66/80(82.5)3.58(2.37-5.65)0.44(0.30-0.64)Not detectable6/13(46.2)8.48(2.69-NA)7/12(58.3)7.39(1.87-12.98)1.12(0.35-3.56)PIK3CA: number of alterationsSingle45/83(54.2)12.88(7.36-18.50)50/64(78.1)3.58(1.87-6.11)0.43(0.28-0.65)Multiple13/18(72.2)9.00(3.68-18.37)23/28(82.1)4.63(3.48-9.63)0.55(0.25-1.20)PIK3CA alterations in exon 9 or exon 20Exon 918/34(52.9)15.21(7.03-NA)29/36(80.6)3.66(2.86-7.36)0.31(0.16-0.61)Exon 2034/54(63.0)10.91(5.72-18.37)40/48(83.3)3.52(1.87-6.11)0.51(0.31-0.82)CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; mPFS, median progression-free survival; mo, months; NA, not available; NGS, next-generation sequencing.
Citation Format: Eva M. Ciruelos, Sibylle Loibl, Ingrid A. Mayer, Mario Campone, Hope S. Rugo, Monica Arnedos, Hiroji Iwata, Pier Franco Conte, Fabrice André, Albert Reising, Chong Ma, Michelle Miller, Naveen Babbar, Dejan Juric. Clinical outcomes of alpelisib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer with PIK3CA alterations detected in plasma ctDNA by next-generation sequencing: Biomarker analysis from the SOLAR-1 study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-06.