Alpelisib

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Dejan Juric - One of the best experts on this subject based on the ideXlab platform.

  • abstract pd2 07 Alpelisib letrozole in patients with pik3ca mutated hormone receptor positive hr human epidermal growth factor receptor 2 negative her2 advanced breast cancer abc previously treated with a cyclin dependent kinase 4 6 inhibitor cdk4 6i
    Cancer Research, 2021
    Co-Authors: Hope S Rugo, Dejan Juric, Aleix Prat, Pamela Drullinsky, Nicholas C Turner, Stephen Chia, Florence Lerebours, Rafael Villanueva Vazquez, Murat Akdere, Christina Arce
    Abstract:

    Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of Alpelisib, manageable toxicities were observed. These data suggest that Alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vazquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [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 PD2-07.

  • Alpelisib plus fulvestrant for pik3ca mutated hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer final overall survival results from solar 1
    Annals of Oncology, 2021
    Co-Authors: Fabrice Andre, G Rubovszky, Bella Kaufman, E. Ciruelos, Mario Campone, Sibylle Loibl, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, Kenichi Inoue
    Abstract:

    Background Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of Alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC. Patients and methods Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive Alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161. Results In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for Alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the Alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the Alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. Conclusions Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when Alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with Alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. ClinicalTrials.gov Id NCT02437318 .

  • time course and management of key adverse events during the randomized phase iii solar 1 study of pi3k inhibitor Alpelisib plus fulvestrant in patients with hr positive advanced breast cancer
    Annals of Oncology, 2020
    Co-Authors: Hope S Rugo, Fabrice Andre, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, H. Cerda, I. Toledano, Salomon M. Stemmer, J.c. Jurado, E. Ciruelos
    Abstract:

    Background Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of Alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. Patients and methods AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Results Patients were randomly assigned to receive fulvestrant plus Alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with Alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median Alpelisib dose intensity of 248 mg/day. Median progression-free survival with Alpelisib was 12.5 and 9.6 months for Alpelisib dose intensities of ≥248 mg/day and Conclusions Hyperglycemia and rash occurred early during Alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and Alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher Alpelisib dose intensities support the need for optimal AE management. ClinicalTrials.gov Id NCT02437318.

  • Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor Alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2020
    Co-Authors: Hope S Rugo, Fabrice Andre, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, H. Cerda, I. Toledano, Salomon M. Stemmer, J.c. Jurado, E. Ciruelos
    Abstract:

    Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of Alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Patients were randomly assigned to receive fulvestrant plus Alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with Alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median Alpelisib dose intensity of 248 mg/day. Median progression-free survival with Alpelisib was 12.5 and 9.6 months for Alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. Hyperglycemia and rash occurred early during Alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and Alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher Alpelisib dose intensities support the need for optimal AE management. CLINICALTRIALS. NCT02437318. Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

  • abstract ot1 03 01 phase 1 1b study of novel oral selective estrogen receptor degrader serd lsz102 in combination with Alpelisib byl719 in estrogen receptor positive er human epidermal growth factor receptor 2 negative her2 advanced breast cancer abc
    Cancer Research, 2019
    Co-Authors: Giuseppe Curigliano, Dejan Juric, Sara Cresta, Ys Yap, Francois Duhoux, C Terret, S Takahashi, Rachel M Layman, N Kundamal, D Baldoni
    Abstract:

    Background: Although ET remains the basis of therapy for ER+, HER2– ABC, treatment resistance frequently occurs. Novel strategies to target the receptor and/or alternative pathways to overcome therapeutic resistance are under investigation. LSZ102 is a novel, orally bioavailable, nonsteroidal SERD. Preclinically, LSZ102 inhibits ER gene transcription, induces receptor degradation, blocks ER-dependent cell growth, and has synergistic activity with the phosphoinositide 3-kinase (PI3K)-alpha inhibitor Alpelisib (BYL719). The present study is evaluating the safety and tolerability of LSZ102 plus Alpelisib in patients with ER+, HER2– ABC with progression on ET. Trial Design: This phase 1/1b, open-label study is enrolling ˜18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and Alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Enrollment in Arm C started after identification of a safe and tolerable single-agent dose for LSZ102. Alpelisib dosing began at 200 mg/day and will not be escalated beyond the maximum tolerated dose (MTD) determined in the Alpelisib single-agent arm of study CBYL719X2101 (400 mg/day). Dose escalation of Alpelisib in combination with LSZ102 is guided by BLRM and integrates Cycle 1 DLT rates, lower grade and later cycle AE, PK, PD and preliminary activity to identify a recommended dose for expansion (RDE). Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent. For inclusion in the study, patients must have histologically confirmed ER+, HER2– ABC and disease progression after ET for ABC or recurrence on/within 12 months of completion of adjuvant ET. In the escalation part of the study, patients are eligible regardless of PIK3CA status. Premenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligible patients must have adequate bone marrow and organ function, Eastern Cooperative Oncology Group performance status of 0 or 1, and have completed and recovered from acute toxicities of radiotherapy and/or prior anticancer therapy. Exclusion criteria include symptomatic central nervous system metastases, clinically significant cardiac disease or impaired cardiac function (including a QT interval corrected for heart rate using Fridericia9s formula [QTcF] >460 ms in women or >450 ms in men), uncontrolled diabetes mellitus type II (or type I), and prior treatment with a PI3K inhibitor. The primary objectives are characterization of safety and tolerability for the combination and identification of a recommended dose. Secondary objectives include characterization of pharmacokinetic properties and pharmacodynamic effects. Recruitment for Arm C is ongoing. NCT02734615 Citation Format: Curigliano G, Cresta S, Yap Y-S, Juric D, Duhoux FP, Terret C, Takahashi S, Layman RM, Kundamal N, Baldoni D, Liao S, Crystal A, Jhaveri K. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with Alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-03-01.

William J. Gradishar - One of the best experts on this subject based on the ideXlab platform.

  • phase i study of Alpelisib byl 719 and trastuzumab emtansine t dm1 in her2 positive metastatic breast cancer mbc after trastuzumab and taxane therapy
    Breast Cancer Research and Treatment, 2018
    Co-Authors: Sarika Jain, Alfred W. Rademaker, Massimo Cristofanilli, Cesar A Santamaria, Ami N Shah, Kalliopi P Siziopikou, Irene Helenowski, William J. Gradishar
    Abstract:

    Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of Alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC. Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with Alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan–Meier method. Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg Alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months. The combination of Alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.

  • phase i study of Alpelisib byl 719 and t dm1 in her2 positive metastatic breast cancer after trastuzumab and taxane therapy
    Journal of Clinical Oncology, 2017
    Co-Authors: Sarika Jain, Alfred W. Rademaker, Francis J. Giles, Massimo Cristofanilli, Cesar A Santamaria, William J. Gradishar
    Abstract:

    1026Background: 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...

  • Phase I study of Alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.
    Journal of Clinical Oncology, 2017
    Co-Authors: Sarika Jain, Cesar A. Santa-maria, Alfred W. Rademaker, Francis J. Giles, Massimo Cristofanilli, William J. Gradishar
    Abstract:

    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.

  • Phase I study of Alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer.
    Journal of Clinical Oncology, 2016
    Co-Authors: Sarika Jain, Cesar A. Santa-maria, Francis J. Giles, Lauren Nye, Hannah B Garrett, Ellen Dammrich, Amanda Williams, Lauren Bontemps, Lisa Flaum, William J. Gradishar
    Abstract:

    588Background: 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. Methods: This phase I study enrolled patients who received Alpelisib daily (cohort 1: 300 mg, (-)1: 250 mg) and T-DM1 3.6 mg/m2on 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. Blood was collected for pharmacokinetic (PK) and pharmacodynamic (PD) markers. Imaging and echocardiogram were obtained every 3 cycles. Data cut-off is Jan. 1, 2016. Results: Fifteen patients have been enrolled. Median age was 53 (40-66). Median prior lines of therap...

  • abstract p6 13 11 phase i study of Alpelisib and t dm1 in trastuzumab refractory her2 positive metastatic breast cancer
    Cancer Research, 2016
    Co-Authors: Sarika Jain, Francis J. Giles, Lauren Nye, Ellen Dammrich, Amanda Williams, Lauren Bontemps, Cesar A Santamaria, Hannah Garrett, William J. Gradishar
    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.

Ingrid A Mayer - One of the best experts on this subject based on the ideXlab platform.

  • Clinical and biomarker results from phase I/II study of PI3K inhibitor Alpelisib plus nab-paclitaxel in HER2-negative metastatic breast cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
    Co-Authors: Priyanka Sharma, Ingrid A Mayer, Vandana G. Abramson, Lauren Nye, Anne P O'dea, Harsh B Pathak, Marc Hoffmann, Shane R Stecklein, Manana Elia, Sharon Lewis
    Abstract:

    PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of Alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of Alpelisib (250mg-300mg-350mg) daily, plus nab-paclitaxel 100mg/m2 D1-8-15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating-tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, PFS, association of PIK3CA mutation with outcomes. 43 patients enrolled (phase I=13, phase II=30). 84% had visceral disease, 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was Alpelisib 350mg daily +nab-paclitaxel 100mg/m2 D1-8-15. Hyperglycemia (G3:26%,G4:0%), neutropenia (G3:23%,G4:7%), diarrhea (G3:5%,G4:0%), and rash (G3:7%,G4:0%) were most common adverse events. Among 42 evaluable patients, ORR was 59% (CR=7%, PR=52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. 40% demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared to those without mutation (11.9 vs 7.5 months, HR=0.44, p=0.027). Patients with normal metabolic status had longer PFS compared to prediabetic/diabetic patients (12.0 vs 7.5 months, p=0.014). No pharmacokinetic interactions were detected. Alpelisib plus nab-paclitaxel combination was well-tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. Impact of metabolic status on response to this combination merits further investigation. Copyright ©2021, American Association for Cancer Research.

  • clinical and biomarker results from phase i ii study of pi3k inhibitor Alpelisib plus nab paclitaxel in her2 negative metastatic breast cancer
    Clinical Cancer Research, 2021
    Co-Authors: Priyanka Sharma, Ingrid A Mayer, Vandana G. Abramson, Lauren Nye, Harsh B Pathak, Shane R Stecklein, Manana Elia, Anne Odea, Marc Steven Hoffmann, Sharon Lewis
    Abstract:

    Purpose: PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of Alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC). Experimental Design: Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of Alpelisib (250mg-300mg-350mg) daily, plus nab-paclitaxel 100mg/m2 D1-8-15 every 28 days. Phase II was according to Simon9s two-stage design. PIK3CA mutations in tumor/circulating-tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, PFS, association of PIK3CA mutation with outcomes. Results: 43 patients enrolled (phase I=13, phase II=30). 84% had visceral disease, 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was Alpelisib 350mg daily +nab-paclitaxel 100mg/m2 D1-8-15. Hyperglycemia (G3:26%,G4:0%), neutropenia (G3:23%,G4:7%), diarrhea (G3:5%,G4:0%), and rash (G3:7%,G4:0%) were most common adverse events. Among 42 evaluable patients, ORR was 59% (CR=7%, PR=52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. 40% demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared to those without mutation (11.9 vs 7.5 months, HR=0.44, p=0.027). Patients with normal metabolic status had longer PFS compared to prediabetic/diabetic patients (12.0 vs 7.5 months, p=0.014). No pharmacokinetic interactions were detected. Conclusions: Alpelisib plus nab-paclitaxel combination was well-tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. Impact of metabolic status on response to this combination merits further investigation.

  • Alpelisib plus fulvestrant for pik3ca mutated hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer final overall survival results from solar 1
    Annals of Oncology, 2021
    Co-Authors: Fabrice Andre, G Rubovszky, Bella Kaufman, E. Ciruelos, Mario Campone, Sibylle Loibl, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, Kenichi Inoue
    Abstract:

    Background Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of Alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC. Patients and methods Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive Alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161. Results In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for Alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the Alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the Alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. Conclusions Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when Alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with Alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. ClinicalTrials.gov Id NCT02437318 .

  • time course and management of key adverse events during the randomized phase iii solar 1 study of pi3k inhibitor Alpelisib plus fulvestrant in patients with hr positive advanced breast cancer
    Annals of Oncology, 2020
    Co-Authors: Hope S Rugo, Fabrice Andre, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, H. Cerda, I. Toledano, Salomon M. Stemmer, J.c. Jurado, E. Ciruelos
    Abstract:

    Background Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of Alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. Patients and methods AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Results Patients were randomly assigned to receive fulvestrant plus Alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with Alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median Alpelisib dose intensity of 248 mg/day. Median progression-free survival with Alpelisib was 12.5 and 9.6 months for Alpelisib dose intensities of ≥248 mg/day and Conclusions Hyperglycemia and rash occurred early during Alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and Alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher Alpelisib dose intensities support the need for optimal AE management. ClinicalTrials.gov Id NCT02437318.

  • Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor Alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2020
    Co-Authors: Hope S Rugo, Fabrice Andre, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, H. Cerda, I. Toledano, Salomon M. Stemmer, J.c. Jurado, E. Ciruelos
    Abstract:

    Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of Alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Patients were randomly assigned to receive fulvestrant plus Alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with Alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median Alpelisib dose intensity of 248 mg/day. Median progression-free survival with Alpelisib was 12.5 and 9.6 months for Alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. Hyperglycemia and rash occurred early during Alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and Alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher Alpelisib dose intensities support the need for optimal AE management. CLINICALTRIALS. NCT02437318. Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sarika Jain - One of the best experts on this subject based on the ideXlab platform.

  • phase i study of Alpelisib byl 719 and trastuzumab emtansine t dm1 in her2 positive metastatic breast cancer mbc after trastuzumab and taxane therapy
    Breast Cancer Research and Treatment, 2018
    Co-Authors: Sarika Jain, Alfred W. Rademaker, Massimo Cristofanilli, Cesar A Santamaria, Ami N Shah, Kalliopi P Siziopikou, Irene Helenowski, William J. Gradishar
    Abstract:

    Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of Alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC. Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with Alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan–Meier method. Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg Alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months. The combination of Alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.

  • phase i study of Alpelisib byl 719 and t dm1 in her2 positive metastatic breast cancer after trastuzumab and taxane therapy
    Journal of Clinical Oncology, 2017
    Co-Authors: Sarika Jain, Alfred W. Rademaker, Francis J. Giles, Massimo Cristofanilli, Cesar A Santamaria, William J. Gradishar
    Abstract:

    1026Background: 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...

  • Phase I study of Alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.
    Journal of Clinical Oncology, 2017
    Co-Authors: Sarika Jain, Cesar A. Santa-maria, Alfred W. Rademaker, Francis J. Giles, Massimo Cristofanilli, William J. Gradishar
    Abstract:

    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.

  • Phase I study of Alpelisib and T-DM1 in trastuzumab-refractory HER2-positive metastatic breast cancer.
    Journal of Clinical Oncology, 2016
    Co-Authors: Sarika Jain, Cesar A. Santa-maria, Francis J. Giles, Lauren Nye, Hannah B Garrett, Ellen Dammrich, Amanda Williams, Lauren Bontemps, Lisa Flaum, William J. Gradishar
    Abstract:

    588Background: 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. Methods: This phase I study enrolled patients who received Alpelisib daily (cohort 1: 300 mg, (-)1: 250 mg) and T-DM1 3.6 mg/m2on 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. Blood was collected for pharmacokinetic (PK) and pharmacodynamic (PD) markers. Imaging and echocardiogram were obtained every 3 cycles. Data cut-off is Jan. 1, 2016. Results: Fifteen patients have been enrolled. Median age was 53 (40-66). Median prior lines of therap...

  • abstract p6 13 11 phase i study of Alpelisib and t dm1 in trastuzumab refractory her2 positive metastatic breast cancer
    Cancer Research, 2016
    Co-Authors: Sarika Jain, Francis J. Giles, Lauren Nye, Ellen Dammrich, Amanda Williams, Lauren Bontemps, Cesar A Santamaria, Hannah Garrett, William J. Gradishar
    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.

Mario Campone - One of the best experts on this subject based on the ideXlab platform.

  • Alpelisib plus fulvestrant for pik3ca mutated hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer final overall survival results from solar 1
    Annals of Oncology, 2021
    Co-Authors: Fabrice Andre, G Rubovszky, Bella Kaufman, E. Ciruelos, Mario Campone, Sibylle Loibl, Dejan Juric, Ingrid A Mayer, Toshinari Yamashita, Kenichi Inoue
    Abstract:

    Background Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of Alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC. Patients and methods Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive Alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161. Results In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for Alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the Alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the Alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. Conclusions Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when Alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with Alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. ClinicalTrials.gov Id NCT02437318 .

  • A pharmacokinetic evaluation of Alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer.
    Expert opinion on drug metabolism & toxicology, 2020
    Co-Authors: Marion Bertho, Anne Patsouris, Paule Augereau, Marie Robert, Jean-sebastien Frenel, Cyriac Blonz, Mario Campone
    Abstract:

    Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of Alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, Alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of Alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests Alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.

  • Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer
    The New England journal of medicine, 2019
    Co-Authors: Fabrice Andre, G Rubovszky, Hiroji Iwata, Hope S Rugo, E. Ciruelos, Pierfranco Conte, Mario Campone, Sibylle Loibl, Ingrid A Mayer, Bella Kaufman
    Abstract:

    PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor Alpelisib has shown antitumor activity in early studies. In a randomized, phase 3 trial, we compared Alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the Alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with Alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the Alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the Alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued Alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Treatment with Alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.). Copyright © 2019 Massachusetts Medical Society.

  • abstract p5 21 06 Alpelisib plus letrozole in estrogen receptor positive er human epidermal growth factor receptor 2 negative her2 advanced breast cancer abc safety and preliminary efficacy analysis from a phase 1b trial
    Cancer Research, 2018
    Co-Authors: Dejan Juric, D. Sellami, Anthony Goncalves, Erika Hamilton, Valentina Boni, I A Mayer, S Turri, Y Wang, Florian D Vogl, Mario Campone
    Abstract:

    Background Endocrine therapy is the standard first-line treatment for postmenopausal patients (pts) with ER+, HER2– aBC. However, resistance eventually develops, often through dysregulation of PI3K/AKT/mTOR pathway, specifically mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The oral, selective PI3K inhibitor Alpelisib and letrozole synergistically inhibits tumor growth in preclinical models of ER+ breast cancer. Alpelisib plus letrozole in pts with ER+ aBC is being investigated in arm 2 of a multi-arm, phase 1b study (NCT01872260). Methods Postmenopausal women with ER+, HER2− aBC received Alpelisib (300 mg QD; continuous, 28 days cycle) plus letrozole (2.5 mg QD; continuous). Primary endpoints were to confirm MTD/RP2D of Alpelisib plus letrozole in the escalation phase and to further characterize safety and tolerability in the expansion phase. Secondary and exploratory endpoints included efficacy, pharmacokinetics, and biomarkers. Results As of August 19, 2016, 56 pts had received Alpelisib plus letrozole: 19 pts were enrolled in the escalation phase (designated here as previously treated group), of which, 95% of pts were previously treated for aBC and 37 pts were enrolled in the expansion phase (designated here as first-line group), of which, 81% of pts were treatment-naive for aBC. 16 previously treated pts and 11 first-line pts (48% of all pts) have discontinued treatment. Most common reasons for treatment discontinuation in the full population were disease progression (23.2%) and adverse events (AEs) (8.9%). Median duration of exposure of combination (Alpelisib plus letrozole) was 23 weeks and 12.7 weeks in previously treated and first-line groups, respectively. Most frequently reported any grade treatment-related AEs (≥20% incidence) in all pts were hyperglycemia (48.2%), diarrhea (48.2%), nausea (33.9%), and decreased appetite (28.6%). Most common, grade 3 or 4 AEs (≥3% incidence) suspected to be treatment-related in all pts included hyperglycemia (17.9%), rash (5.4%), and diarrhea (3.6%). Median progression-free survival was 5.7 months in the previously treated group and was not reached in the first-line group. A summary of best overall response, overall response rate and clinical benefit rate in evaluable pts is shown in the table. Conclusions Based on these preliminary data, the combination of Alpelisib plus letrozole had manageable safety profile in pts with ER+, HER2– aBC and demonstrated encouraging clinical activity, particularly in the first-line patient population. Citation Format: Juric D, Goncalves A, Hamilton E, Boni V, Mayer IA, Turri S, Wang Y, Vogl FD, Sellami D, Campone M. Alpelisib plus letrozole in estrogen receptor-Positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC): Safety and preliminary efficacy analysis from a phase 1b trial [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 P5-21-06.

  • 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
    Journal of Clinical Oncology, 2017
    Co-Authors: Hope S Rugo, G Rubovszky, Fabrice Andre, Kenichi Inoue, Bella Kaufman, E. Ciruelos, Mario Campone, Satoru Shimizu, Masato Takahashi, Pierfranco Conte
    Abstract:

    TPS1111Background: 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 targe...

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