Study Of Alpelisib Research Articles

GOG3069: Phase 2 study of alpelisib and fulvestrant for PIK3CA-mutated estrogen receptor (ER)-positive endometrioid endometrial cancers.

TPS5639 Background: Treatment options for persistent, metastatic, or recurrent endometrial cancer continues to evolve as we learn more about the molecular landscape of this disease. Recent studies have shown a benefit to endocrine-based combinations such as aromatase inhibitors with mTOR or CDK4/6 inhibitors especially in patients who had not received prior chemotherapy ( 1– 3). The presence of oncogenic PIK3CA mutations have been shown to impact response to aromatase inhibitors in breast cancer. The combination of alpelisib and fulvestrant was approved for the treatment of metastatic hormone receptor-positive, HER2-negative breast cancer harboring oncogenic mutations in the PIK3CA gene that progressed on prior endocrine therapy( 4). PIK3CA mutations are commonly identified in endometrial cancers and may similarly confer endocrine resistance. GOG3069 is a phase II trial designed to evaluate the efficacy and safety of alpelisib and fulvestrant in a biomarker-selected endometrial cancer patient population. Methods: This is a phase II non-randomized, open label, multicenter, two-stage study. Eligible patients must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma with measurable disease by RECISTv1.1 criteria. Patients cannot be curable by surgery or radiotherapy. Disease must be of endometrioid histology with positive expression of estrogen receptor (defined as ≥1% of tumor cells demonstrating positive nuclear staining by immunohistochemistry) and oncogenic PIK3CA mutation. Patients may have received no more than 3 prior lines of therapy including 1 prior line of systemic chemotherapy. Enrolled patients will receive treatment with alpelisib 300mg orally daily and fulvestrant 500mg IM on Day 1 and Day 15 of Cycle 1, then 500mg IM on Day 1 of each 28-day cycle. The primary endpoint is overall response rate as measured by RECISTv1.1-defined tumor response. Secondary endpoints include safety, tolerability, progression-free survival, duration of response, and 24-month overall survival rate. GOG3069 activated in November 2023 and expects to enroll across 15 US sites. The statistical plan uses a conditional stratified design factoring differing probabilities of response based on whether the patient had prior chemotherapy exposure. ClinicalTrials.gov Identifier: NCT05154487

EPIK-B5: A phase III, randomized study of alpelisib (ALP) plus fulvestrant (FUL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) progressing on/after an aromatase inhibitor (AI) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i).

TPS1109 Background: Endocrine therapy (ET) + CDK4/6i is standard of care for HR+, HER2− ABC; however, CDK4/6i resistance, in which the phosphatidylinositol-3-kinase (PI3K) pathway has a key role, remains challenging. Progression-free survival (PFS) for ≥ 2nd-line ET monotherapy post CDK4/6i is poor; prognosis may be worse in patients with a PI3KCA mutation. ALP (PI3K-α selective inhibitor and degrader) + FUL is approved by the European Medicines Agency (EMA) for HR+, HER2–, PIK3CA-mutated ABC after ET monotherapy. Outside the EMA, ALP + FUL approval includes post-CDK4/6i use. ALP + FUL has shown clinical activity and consistent safety in a small subpopulation in SOLAR-1 with prior CDK4/6i treatment (n = 9) and in BYLieve Cohort A (CDK4/6i + AI as immediate prior treatment; n = 121). The EPIK-B5 study aims to confirm the efficacy and safety of ALP + FUL in a larger population with HR+, HER2–, PIK3CA-mutated ABC with prior CDK4/6i + AI treatment. Methods: EPIK-B5 is a Phase III, randomized (1:1), double-blind, placebo-controlled study assessing the efficacy and safety of ALP (300 mg/d orally starting Cycle 1 Day 1 [C1D1]) + FUL (500 mg intramuscularly on C1D1 and C1D15, and D1 of subsequent cycles) in patients (N ≈ 234) with HR+, HER2–, PIK3CA-mutated ABC progressing on/after CDK4/6i + AI. Patients randomized to placebo + FUL can cross over to ALP + FUL after progression. Randomization is stratified by presence of lung and/or liver metastasis and prior CDK4/6i setting. Adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mutated ABC and ≥ 1 measurable lesion are eligible. The primary endpoint is PFS per blinded independent review committee assessment. Secondary endpoints include overall survival, overall response and clinical benefit rates, duration of and time to response, PFS by PIK3CA-mutation status in circulating tumor DNA, PFS on next-line treatment, time to definitive deterioration of ECOG status, quality of life (QoL), and safety and tolerability. Exploratory endpoints include biomarker analyses, additional QoL endpoints, and time to subsequent chemotherapy. Recruitment is ongoing, with enrollment planned over 2 years in 18 countries; completion of primary data collection is anticipated in 2026. Clinical trial information: NCT05038735; EUDRACT2021-001966-39.

A phase II, single-arm, non-randomized study of alpelisib (BYL719) in combination with continued endocrine therapy following progression on endocrine therapy in hormone receptor–positive, HER2-negative, PIK3CA-mutant metastatic breast cancer: A Big Ten Cancer Research Consortium Study (btcrc-BRE19-409).

TPS1114 Background: The PI3K pathway is frequently altered in hormone receptor positive (HR+) breast cancer (BC) and 40% of patients have PIK3CA mutations. The PI3Kα-specific inihibitor, Alpelisib, is FDA-approved in combination with fulvestrant for treatment of patients with HR+ HER2 negative (HER2-) PIK3CA mutated, advanced BC following progression on or after a non-fulvestrant endocrine therapy (ET) based regimen. We hypothesized that the benefit seen in the seminal SOLAR-1 study that compared alpelisib plus fulvestrant to placebo with fulvestrant, was due to the addition of alpelisib, rather than the change to fulvestrant, such that addition of alpelisib to ongoing ET at time of progression could lead to similar outcomes. Unlike SOLAR-1, our study continues prior ET at time of progression and requires prior CDK4/6 inhibitor therapy. Methods: We designed a phase II single arm study that tests the efficacy of adding alpelisib to ongoing ET at time of progression on ET. The primary objective is to estimate the progression–free survival (PFS) of alpelisib with continued ET (aromatase inhibitor or fulvestrant) following progression in patients with HR+ HER2-, PIK3CA mutant advanced BC. Secondary objectives are to estimate overall response rate, clinical benefit rate, duration of response, overall survival and safety/tolerability. Correlative studies include evaluation of PIK3CA activity in circulating tumor cell liquid biopsy at baseline, C1D15, C2D1, C4D1 and at progression and correlation with primary and secondary objectives. Eligibility: Men and postmenopausal female patients with histologically confirmed ER and/or PR ≥1%, HER2- metastatic or unresectable BC with PIK3CA mutation and either measurable disease or at least one predominantly lytic bone lesion. No more than two lines of ET and no chemotherapy in the metastatic setting is allowed and patients must have received treatment with a CDK4/6 inhibitor and have progressed on ET as last line of therapy. Exclusions include prior PIK3CA, mTOR or AKT inhibitors in the metastatic setting, symptomatic active CNS metastases or CNS metastases that require therapeutic interventions. Statistical Analysis. The sample size calculation is based on testing the null hypothesis that the median PFS is at most 5 months against the alternative that the PFS is greater than 5 months (based on data from SOLAR-1). An increase of at least 3 months in the median PFS will be considered a sufficient efficacy signal. A sample size of 44 subjects is required to detect an anticipated increase in the median PFS from 5 to 8 months at the one-sided 0.10 significance level with 90% power, assuming a uniform accrual period of 24 months. Clinical trial information: NCT04762979.

Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation

Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation

Abstract OT3-05-02: BYLieve: A phase 2 study of alpelisib with fulvestrant or letrozole for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/after cyclin-dependent kinase (CDK)4/6 inhibitor therapy

Abstract Background: Endocrine therapy (ET) is the standard of care for treatment of HR+, HER2– aBC. However, ET resistance occurs frequently leading to disease progression. Dysregulation of the PI3K/AKT/mTOR pathway, specifically mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K, has been implicated in ET resistance. In a phase 1 study, alpelisib, a PI3Kα-specific inhibitor, in combination with fulvestrant has shown antitumor activity in patients with PIK3CA mutant, HR+, HER2– aBC. The present BYLieve (NCT03056755) study aims to assess the efficacy and safety of alpelisib + fulvestrant/letrozole in PIK3CA-mutant, HR+, HER2– aBC progressing on/after prior CDK4/6 inhibitor (CDK4/6i) therapy. Methods: BYLieve is a phase 2, multicenter, open-label, 2-cohort, non-comparative study. Men and postmenopausal women (≥ 18 years) with PIK3CA-mutant, HR+, HER2− locally advanced or metastatic breast cancer that has progressed on/after prior CDK4/6i therapy are eligible. Other eligibility criteria include ≥ 1 measurable lesion (RECIST v1.1) or predominantly lytic bone lesion; ECOG PS ≤ 2; and no prior PI3K inhibitor therapy. Patients are allocated to 2 cohorts based on the prior ET partner (aromatase inhibitor (AI) or fulvestrant) used in combination with CDK4/6i. Cohort A (patients who had received CDK4/6i + AI): oral alpelisib (300 mg once daily) + intramuscular fulvestrant (500 mg on days 1 and 15 of cycle 1, and day 1 of cycles ≥ 2 [28-day cycles]) and cohort B (patients who had received CDK4/6i + fulvestrant): oral alpelisib (300 mg once daily) + oral letrozole (2.5 mg once daily). Study treatment will continue until disease progression or intolerable toxicity. The primary end point is the proportion of patients who are alive without disease progression at 6 months (RECIST v1.1; local assessment), which will be evaluated separately in each cohort and presented together with 2-sided 90% confidence intervals using Clopper and Pearson (1934) exact method. Evidence of treatment effect will be demonstrated if the lower bound of the 90% CI is greater than 30%. A total sample size of 80 patients in each cohort is planned. Secondary end points include progression-free survival (PFS), PFS on next-line treatment (PFS2), overall response rate, clinical benefit rate, duration of response, safety, and tolerability. Detection of frequency of PIK3CA mutations in ctDNA and its correlation with response is an exploratory end point. Citation Format: Rugo HS, Turner N, Chia S, Ciruelos E, Nienstedt C, Ridolfi A, Kong O, Sankaran B, Juric D. BYLieve: A phase 2 study of alpelisib with fulvestrant or letrozole for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/after cyclin-dependent kinase (CDK)4/6 inhibitor therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-02.

A phase 3 study of alpelisib (ALP) plus fulvestrant (FUL) in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) ABC progressing on or after aromatase inhibitor (AI) therapy: SOLAR-1.

TPS1111 Background: Patients (pts) with HR+ breast cancer (BC) often havedysregulatedphosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, which further leads to resistance to endocrine therapy (ET). In a phase 1 study, alpelisib (BYL719), a PI3Kα-specific inhibitor in combination with fulvestrant (FUL) has demonstrated antitumor activity in pts with estrogen receptor-positive, HER2– advanced BC (ABC) with PIK3CA-altered tumors. SOLAR-1 (NCT02437318) aims to assess the efficacy of ALP + FUL in PIK3CA-mutant and non-mutant tumors in HR+, HER2– ABC setting. Methods: SOLAR-1 is a phase 3, randomized, double-blind study conducted in men and postmenopausal women with HR+, HER2– ABC. Pts are randomly (1:1) allocated to oral alpelisib/placebo (300 mg qd) and intramuscular FUL (500 mg) until disease progression or treatment (tx) discontinuation. Stratification factors are presence of liver and/or lung metastases and prior use of CDK4/6 inhibitors. The eligibility criteria for the targeted BC patient population are shown in the Table. The primary endpoint is progression-free survival (PFS; RECIST v1.1; local assessment), while overall survival (OS) is a key secondary endpoint in the PIK3CA-mutant cohort. Other secondary endpoints are PFS and OS in the PIK3CA non-mutant cohort, the association between PFS and baseline PIK3CAstatus in ctDNA, overall response rate, clinical benefit rate, and safety. Recruitment of the planned 560 pts is currently ongoing. Clinical trial information: NCT02437318. [Table: see text]

Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.

1026 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3Kα isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that failed standard therapy. Methods: In this phase I study, pts received alpelisib daily (cohort 1: 300 mg, (-1): 250 mg) and T-DM1 3.6 mg/m2 on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Data cut-off is Jan. 1, 2017. Results: 17 pts were enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (0-13) including 9 pts who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 2 (1-5). Median number of cycles per pt who completed at least 1 cycle was 8 (1-19). Five pts were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 53%), fatigue (n = 9, 53%), nausea (n = 7, 35%), and rash (n = 8, 47%). Grade 3 alpelisib-related AEs included rash (n = 7), hyperglycemia (n = 3), weight loss (n = 1), hypertension (n = 2), and pancreatitis (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Median follow-up was 11.6 months (0.3-19.5). Median PFS was 6 months (95% CI 2.9-10.6). In 11 pts without prior T-DM1 mPFS was 4.3 months (95% CI 2.0-8.8) and in 6 pts with prior T-DM1 it was 10.6 months (95% CI 1.6-12.6), p = 0.18. Conclusions: The combination of alpelisib 250 mg daily and T-DM1 appears to be safe in HER2-positive MBC pts with significant anti-tumor activity, even in pts previously treated with T-DM1. A phase II study is planned. Clinical trial information: NCT02038010.

Abstract OT2-01-04: SOLAR-1: A phase III study of alpelisib and fulvestrant in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (BC) progressing on or after aromatase inhibitor (AI) therapy

Abstract Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is often dysregulated in HR+ BC and is associated with resistance to endocrine therapy (ET). Alpelisib (BYL719; PI3Kα-specific inhibitor) and fulvestrant showed signs of antitumor activity in patients (pts) with estrogen receptor-positive (ER+), HER2– advanced BC (phase I), especially in PIK3CA-altered tumors (Janku et al. SABCS 2014, PD5-5). Methods: SOLAR-1 (NCT02437318) is a phase III, randomized, double-blind study in men and postmenopausal women with HR+, HER2– advanced BC. Pts are assigned to 1 of 2 cohorts based on PIK3CA tumor status (mutant vs non-mutant), and randomized 1:1 to oral alpelisib/placebo (300 mg once daily) and intramuscular fulvestrant (500 mg on Day 1 and 15 of Cycle 1; Day 1 of Cycles ≥2 [28-day cycles]) until disease progression or discontinuation. Randomization is stratified by presence of liver and/or lung metastases and prior CDK4/6 inhibitor therapy. Key inclusion criteria: recurrence or progression on or after AI therapy, ≥1 measurable lesion (RECIST v1.1) or predominantly lytic bone lesion, and ECOG performance status ≤1. Key exclusion criteria: symptomatic visceral disease or disease burden precluding ET, acute pancreatitis ≤1 year prior to screening or history of chronic pancreatitis, and prior therapy with fulvestrant, chemotherapy (except [neo]adjuvant), or PI3K/AKT/mTOR inhibitors. The primary and key secondary endpoints are progression-free survival (PFS; RECIST v1.1; local assessment) and overall survival (OS), respectively, in the PIK3CA-mutant cohort. Other secondary endpoints include PFS and OS in the PIK3CA non-mutant cohort, PFS (Blinded Independent Central Review; RECIST v1.1), the association between PFS and baseline PIK3CA status in circulating tumor DNA, overall response rate, clinical benefit rate, safety, and pharmacokinetics. The primary endpoint will be analyzed by a stratified log-rank test at one-sided 2% level of significance. Recruitment of the planned 560 pts is ongoing. Citation Format: Andre F, Kaufman B, Juric D, Ciruelos EM, Iwata H, Mayer IA, Rugo HS, Conte P, Liobl S, Rubovszky G, Inoue K, Tesch H, Lu Y-S, Ryvo L, Longin A-S, Mills D, Wilke C, Germa C, Campone M. SOLAR-1: A phase III study of alpelisib and fulvestrant in men and postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (BC) progressing on or after aromatase inhibitor (AI) therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-04.

137TiP A phase III study of alpelisib and fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) progressing on or after aromatase inhibitor (AI) therapy (SOLAR-1)

137TiP A phase III study of alpelisib and fulvestrant for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) progressing on or after aromatase inhibitor (AI) therapy (SOLAR-1)

Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer.

588Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpeli...

Abstract P6-13-11: Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer

Abstract BACKGROUND: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3K alpha isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib in combination with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that has progressed on or after trastuzumab and/or taxane-based regimens. METHODS: This phase I study enrolled patients with HER2-positive MBC who received alpelisib daily (cohort 1: 300 mg, cohort (-)1: 250 mg) and T-DM1 3.6 mg/m2 on Day 1 of a 3 week cycle using a 3+3 design with dose expansion at the MTD. Treatment was continued until progression, unacceptable toxicity, or patient preference. Blood was collected for pharmacokinetic (PK) and pharmacodynamic (PD) markers. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3 or 4 adverse events (AE) during the first cycle. Imaging and echocardiogram were obtained every 3 cycles. RESULTS: Dose escalation is completed and included in this analysis (N=8). Median age was 53 (range 46-79) with median ECOG Performance Status of 1. Median prior lines of therapy in the metastatic setting was 6 (range 0-12) including 5 patients who progressed on prior T-DM1 (after median 6 cycles). Two patients had de novo MBC and 3 with ER and/or PR positive disease. Median number of metastatic sites was 2 (range 1-5) including brain (inactive), liver, and lung. Median number of cycles of alpelisib and T-DM1 per patient was 5.5 (range 1-12). Five patients were enrolled in cohort 1 with 2 DLTs (both grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common treatment-related AEs were fatigue (n=7, 86%), nausea (n=6, 75%), aspartate aminotransferase increase (n=4, 50%), and thrombocytopenia (n=4, 50%). Grade 3 AEs were rash (n = 3), hyperglycemia (n=1), hypertension (n=1) and thrombocytopenia (n=1), which occurred in only cohort 1. Grade 3 rash typically occurred during cycle 1, which resolved with temporary interruption and subsequent dose reduction of alpelisib and the use of topical steroids for median 9.3 days (range 6-12). Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. A total of 4 dose reductions occurred in cohort 1. No Grade 3/4 AEs or dose reductions occurred in cohort -1. In total, only 0.07% of all AEs were Grade 3 and none Grade 4. The MTD for alpelisib was established as 250 mg daily. In 7 evaluable patients, there were 6 objective responses after 3 cycles, a response rate of 86% (1 confirmed complete response, 2 confirmed partial response [PR], and 3 unconfirmed PR). Five (67%) of these patients continue to have durable responses (median 6.5 cycles) at doses 200-250 mg daily. One patient had progression of disease. PK/PD results and PIK3CA mutation testing are pending. CONCLUSION: The combination of alpelisib and T-DM1 appears to be safe, well tolerated, with clinical activity in HER2-positive MBC patients including those who progressed on prior T-DM1 therapy. The study is currently in dose expansion with goal of enrolling 10 additional patients with T-DM1 and alpelisib 250 mg daily. Citation Format: Jain S, Nye L, Santa-Maria C, Bontemps L, Williams A, Garrett H, Dammrich E, Giles F, Gradishar W. Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-11.

342 A Phase Ib/II study of alpelisib (BYL719) and ganitumab (AMG 479) in adult patients with selected advanced solid tumors

342 A Phase Ib/II study of alpelisib (BYL719) and ganitumab (AMG 479) in adult patients with selected advanced solid tumors