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Figure 1.
Patient Enrollment and Disposition
Patient Enrollment and Disposition

Between October 10, 2010, and March 22, 2017, this open-label, phase 1b study screened 117 patients for eligibility, 87 of whom were enrolled and received treatment with alpelisib plus fulvestrant.

Figure 2.
Progression-Free Survival in Patients With PIK3CA-Altered and PIK3CA-Wild-Type Tumors
Progression-Free Survival in Patients With PIK3CA-Altered and PIK3CA-Wild-Type Tumors

Data cutoff date was March 22, 2017.

aPatients with PIK3CA-altered tumors received alpelisib, 300 to 400 mg, once daily plus fulvestrant.

bPatients with PIK3CA-wild-type tumors received alpelisib, 400 mg, once daily plus fulvestrant.

Figure 3.
Best Percentage Change From Baseline in Sum of Longest Diameters and Best Overall Response in Patients With Estrogen Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Best Percentage Change From Baseline in Sum of Longest Diameters and Best Overall Response in Patients With Estrogen Receptor–Positive Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

A, PIK3CA-altered tumors. Forty-three patients excluded from missing best percentage change from baseline because of no postbaseline assessment or nonmeasurable lesion at baseline. B, PIK3CA-wild-type tumor. Seventeen patients excluded from missing best percentage change from baseline because of no postbaseline assessment or nonmeasurable lesion at baseline. Data cutoff point was March 22, 2017. CR indicates complete response; mTOR, mammalian target of rapamycin; PD, progressive disease; PR, partial response; SD, stable disease; and UNK, unknown. The dotted lines correspond to a +20% and −30% change from baseline.

aIncludes 3 patients with human epidermal growth factor receptor 2–positive, estrogen receptor–positive, locally advanced or metastatic breast cancer.

Table 1.  
Patient Characteristics at Baseline
Patient Characteristics at Baseline
Table 2.  
Adverse Events Reported in ≥20% of Patients Regardless of Causalitya
Adverse Events Reported in ≥20% of Patients Regardless of Causalitya
Supplement 1.

eMethods. Further Methods

eFigure 1. Concentration–Time Profiles of Alpelisib 300–400 mg QD Plus Fulvestrant During Cycle 1

eFigure 2. Strip Plots of Alpelisib Exposure (300–400 mg QD) At Steady State (Cycle 1, Day 8) As Single Agent And In Combination With Fulvestrant

eFigure 3. Maximum Fold Change of (A) Maximum C-Peptide (nmol/L), (B) Maximum Insulin (pmol/L), and (C) Maximum Glucose (mmol/L) From Baseline During the First 28 Days by Treatment

eFigure 4. Swimmers Plots of Duration of Exposure and Overall Response (per RECIST v1.0) in Patients With (A) PIK3CA-Altered, (B) PIK3CA-UNK, or (C) PIK3CA-Wild-Type ER+ LA/MBC

eFigure 5. Most Frequent Somatic Genetic Alterations Observed in Tumor Samples With Known/Likely Functional Significance

eTable 1. Recruitment Sites

eTable 2. Summary of Pharmacokinetic Parameters for Alpelisib by Cohort (300–400-mg QD) as a Single Agent and in Combination With Fulvestrant

eTable 3. Summary of Best Overall Response to Alpelisib (300–400-mg QD) Plus Fulvestrant per RECIST v1.0 in Patients with ER+, HER2– Advanced Breast Cancer with PIK3CA-Altered or PIK3CA-Wild-Type Tumors

eTable 4. Duration of Exposure to Alpelisib 300–400 mg QD Plus Fulvestrant in Patients with ER+ ABC by PIK3CA Status and mTOR Pretreatment

eTable 5. NGS Data by Patients Who Received Alpelisib in Combination With Fulvestrant: PIK3CA Mutation

eTable 6. NGS Data Collected at Screening (by Patients who Received Alpelisib Plus Fulvestrant) – Mutations of Known Significance

eTable 7. NGS Data Collected at Screening (by Patients Who Received Alpelisib Plus Fulvestrant) – Mutations of Unknown Significance

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Original Investigation
December 13, 2018

Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor–Positive Advanced Breast Cancer: A Phase 1b Clinical Trial

Author Affiliations
  • 1Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston
  • 2Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston
  • 3at the time of the study, Vall d’Hebron Institute of Oncology, Barcelona, Spain
  • 4Department of Oncology, Sarah Cannon Research Institute, Tennessee Oncology Professional Limited Liability Corporation, Nashville
  • 5Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
  • 6Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, German Cancer Consortium, Germany
  • 7Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
  • 8Department of Hematology/Oncology, SozialStiftung Bamberg, Bamberg, Germany
  • 9Department of Medical Oncology, Catalan Institute of Oncology–Bellvitge Biomedical Research Institute, Barcelona, Spain
  • 10Department of Oncology, Churchill Hospital Cancer Centre, Oxford, United Kingdom
  • 11At the time of the study, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
  • 12Medical Oncology Department, Vall d’Hebron Institute of Oncology, Cellex Center, Barcelona, Spain
  • 13Translational Clinical Oncology, Novartis Pharma AG, Basel, Switzerland
  • 14At the time of the study, Novartis Oncology Translational Research, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
  • 15Tango Therapeutics, Cambridge, Massachusetts
  • 16Department of Medicine, University of California at San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco
JAMA Oncol. Published online December 13, 2018. doi:10.1001/jamaoncol.2018.4475
Key Points

Question  Is alpelisib, an oral α-specific phosphatidylinositol-3-kinase inhibitor, plus fulvestrant tolerable, and is there evidence of differential activity in patients with PIK3CA-altered vs PIK3CA-wild-type, estrogen receptor–positive advanced breast cancer that has progressed during or after antiestrogen therapies?

Findings  In this phase 1b clinical trial of 87 women, alpelisib plus fulvestrant had a manageable safety profile with the alpelisib maximum tolerated dose of 400 mg and a recommended phase 2 dose of 300 mg once daily. Median progression-free survival was longer (9.1 vs 4.7 months) and objective response rate was higher (29% vs 0%) in patients with PIK3CA-altered vs PIK3CA-wild-type tumors.

Meaning  Oral α-specific phosphatidylinositol-3-kinase inhibition is a promising treatment strategy in estrogen receptor–positive PIK3CA-altered advanced breast cancer.

Abstract

Importance  The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor–positive (ER+), endocrine therapy–resistant breast cancers.

Objective  To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC).

Design, Setting, and Participants  An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017.

Interventions  Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase.

Main Outcomes and Measures  The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity.

Results  From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group.

Conclusions and Relevance  Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors.

Trial Registration  ClinicalTrials.gov identifier: NCT01219699

Introduction

Breast cancer is the most frequently diagnosed cancer in women worldwide, with approximately 75% of metastatic breast cancers being estrogen receptor–positive (ER+).1,2 The recommended treatment for patients with ER+ advanced breast cancer (ABC) is endocrine therapy, alone or with mammalian target of rapamycin (mTOR) or cyclin-dependent kinase 4/6 inhibitors.3-5 However, resistance and disease progression eventually occur.6

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in ER+ breast cancer and has been implicated in resistance to endocrine therapies.7,8 Furthermore, PIK3CA, which encodes the PI3K p110α isoform, is altered in approximately 40% of ER+ breast cancers.9,10 Estrogen-independent breast cancer cell growth can be inhibited by adding PI3K inhibitors to antiestrogens, supporting the concept of using PI3K inhibitors with endocrine therapy.11 Targeting PIK3CA-mutated cancers with PI3K pathway inhibitors is a promising strategy,9,12-14 as demonstrated in 2 phase 3 trials of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) ABC whose cancer progressed during or after treatment with an aromatase inhibitor with13 or without prior mTOR inhibition.12 While treatment with buparlisib plus fulvestrant more than doubled median progression-free survival (mPFS) in patients with PIK3CA-mutant vs wild-type tumors, it was associated with a challenging off-target toxicity profile.12,13 Selective targeting of a single PI3K isoform may reduce adverse effects (AEs) associated with broader PI3K inhibition.

Alpelisib (BYL719) is an oral, α-specific PI3K inhibitor.9 In a phase 1a study of single-agent alpelisib in advanced solid tumors, the maximum tolerated dose (MTD) was 400 mg once daily.15 Clinical activity was observed at doses of 270 mg or higher once daily, especially in patients with ER+ breast cancer.15 The MTD of alpelisib was established as 300 mg once daily plus fixed-dose letrozole in patients with ER+, HER2– metastatic breast cancer refractory to endocrine therapy.9 This combination was generally well tolerated and clinical activity was observed.9

Herein, we report results from a phase 1b study that evaluated the MTD of alpelisib plus fulvestrant in postmenopausal women with PIK3CA-altered or wild-type, ER+ advanced breast cancer whose cancer progressed during or after antiestrogen therapy.

Methods
Study Design and Setting

This was a multicenter, open-label, phase 1b trial of alpelisib plus fulvestrant, which enrolled patients at 10 centers in 5 countries (eTable 1 in Supplement 1). The trial protocol is available in Supplement 2. The study was approved by the independent ethics committees or institutional review boards for each site and was conducted per the Declaration of Helsinki16 and Good Clinical Practice. All participants provided written informed consent and received financial compensation.

Participants

The dose-escalation phase enrolled patients with ER+ breast cancer with altered (mutated or amplified) PIK3CA status. The dose-expansion phase enrolled patients with ER+, HER2– breast cancer with any locally assessed PIK3CA status. Other enrollment criteria, including disease progression during or after antiestrogen therapy, or relapse after adjuvant antiestrogen therapy, are detailed in the eMethods in Supplement 1.

Procedures

The primary objective was to determine the MTD or recommended phase 2 dose of alpelisib, plus fulvestrant. Secondary objectives included safety, pharmacokinetics, and preliminary efficacy (overall response rate: complete response and partial response as best reported response per Response Evaluation Criteria in Solid Tumors, version 1.0, and PFS at MTD or recommended phase 2 dose) of alpelisib plus fulvestrant. For dose escalation, patients received increasing doses of oral alpelisib once daily, starting at 300 mg, continuously in 28-day cycles, with fixed-dose, intramuscular fulvestrant, 500 mg, administered on days 1 and 15 of cycle 1 and day 1 of each subsequent cycle. Alpelisib dose escalation was guided by a Bayesian logistic regression model with overdose control.17 For dose expansion, patients received alpelisib at the MTD plus fulvestrant. Alpelisib was administered after a light breakfast (eMethods in Supplement 1). Treatment continued until disease progression, unacceptable toxic effects, death, or discontinuation for any other reason. Dose adjustments (≤2 dose reductions up to the lowest alpelisib dose tested) and interruptions (≤21 days) were permitted to manage AEs. Routine laboratory assessments were conducted at baseline and at regular intervals (eMethods in Supplement 1). Pharmacokinetic and pharmacodynamic profiling are described in the eMethods in Supplement 1. PIK3CA alteration status was assessed locally at screening. Archival or fresh tumor biopsy samples were assessed independently using next-generation sequencing (eMethods in Supplement 1).

Statistical Analysis

The MTD was declared as the alpelisib dose with the highest probability of the dose-limiting toxic effect (DLT) rate in cycle 1 falling within the target toxicity range of 16% to 33%, without exceeding the overdose criterion (<25% probability of DLT rate ≥33%; evaluated in the dose-determining set, composed of all patients in the safety set who experienced a DLT in cycle 1 and those who received alpelisib for ≥21 days, were observed for ≥28 days, and underwent the required safety evaluations for cycle 1) (eMethods in Supplement 1). Dose-limiting toxic effects were defined as prespecified AEs or laboratory abnormalities that may have been associated with study treatment and occurred fewer than 28 days following the first alpelisib dose (cycle 1). Dose-limiting toxic effects were considered clinically relevant and unrelated to underlying disease, disease progression, intercurrent illness, or concomitant medications.

The safety set comprised all patients who received at least 1 dose of alpelisib or fulvestrant and had at least 1 postbaseline safety assessment. The full analysis set comprised all patients who received at least 1 dose of alpelisib or fulvestrant. The Kaplan-Meier method was used to estimate mPFS. SAS, version 9.4 (SAS Institute Inc) was used for data analysis.

Results
Baseline Characteristics

Between October 5, 2010, and March 22, 2017, 87 patients from 10 centers in 5 countries were allocated to receive study treatment (Table 1 and Figure 1). Patients received a median of 5 prior antineoplastic therapies, including everolimus in 21 patients (24%) and fulvestrant in 39 (45%). Fifty-two patients (60%) had PIK3CA-altered tumors, 33 (38%) had PIK3CA-wild-type tumors, and 2 (2%) had unknown PIK3CA status owing to technical issues.

Patient Disposition

At data cutoff (March 22, 2017), treatment was ongoing for 2 patients (2%) who received alpelisib plus fulvestrant from baseline. Treatment was also ongoing for 1 patient who received single-agent alpelisib, 400 mg, for 28 weeks before switching to receive alpelisib, 400 mg, plus fulvestrant; this case was not included in the main analysis. The primary reasons for discontinuation were disease progression (65 [75%]), AEs (9 [10%]), withdrawal of consent (6 [7%]), administrative problems (2 [2%]), abnormal test procedure results, investigator decision, and loss to follow-up (1 each [1%]).

Maximum Tolerated Dose

In the dose-escalation phase, 23 of 28 patients (82%) were evaluable for MTD determination (alpelisib, 300 mg [n = 4], 350 mg [n = 4], 400 mg [n = 10]). Alpelisib dose was escalated from 300 to 400 mg once daily. Additional patients were then enrolled at 300-mg (n = 5) and 350-mg (n = 4) dose levels to further investigate safety of the combination. No DLTs were reported with alpelisib, 300 or 350 mg, once daily in the dose-escalation phase. One of 10 patients who received alpelisib, 400 mg, once daily in the dose-determining set experienced multiple DLTs of diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). Alpelisib, 400 mg, plus fulvestrant fulfilled the dose escalation with overdose control criterion with a 28% probability of DLTs within the target toxicity range. Doses of alpelisib larger than 400 mg once daily plus fulvestrant were not investigated as they were above the single-agent MTD of alpelisib. In the dose-expansion phase, 45 of 59 patients (76%) who received alpelisib, 400 mg, once daily plus fulvestrant met the dose-determining set criteria. Dose-limiting toxic effects were reported in 5 (11%) of these 45 patients: grade 4 hyperglycemia in 1 (2%) and grade 3 rash in 4 (9%). The MTD of alpelisib plus fulvestrant was 400 mg once daily.

Safety and Tolerability

Eighty-seven patients received alpelisib once daily at 300 to 400 mg, plus fulvestrant 300 mg (n = 9), 350 mg (n = 8), or 400 mg (n = 70). Eighty-three patients had ER+, HER2– breast cancer, 3 had ER+, HER2+ breast cancer, and 1 had ER–, HER2– breast cancer. The median duration of exposure to alpelisib was 20 weeks (range, 4-208 weeks). The most frequent AEs (all grade, all causality) were diarrhea (52 [60%]), nausea (46 [53%]), and hyperglycemia (44 [51%]) (Table 2). In most patients, diarrhea was grade 1/2; only 4 patients (5%) experienced a grade 3 event. Skin and subcutaneous tissue disorders were reported in 56 patients (64%). The most frequent all-causality grade 3/4 AEs were hyperglycemia (19 [22%]), maculopapular rash (11 [13%]), and rash (7 [8%]), and were observed mainly in patients who received alpelisib, 350 or 400 mg, once daily plus fulvestrant (Table 2). Hyperglycemia and rash were managed with concomitant medications (eg, oral antidiabetic medications for hyperglycemia; antihistamines and/or corticosteroids for rash), dose adjustment, or temporary interruption.

Of the 87 patients in the full analysis set, 60 individuals (69%) experienced AEs requiring dose modifications (interruptions or reductions). For alpelisib, 300 vs 400 mg once daily (both plus fulvestrant), lower rates of dose modifications (33% vs 71%, respectively) and discontinuations (0% vs 13%, respectively) were observed. Twenty-two patients (25%) required dose modifications owing to hyperglycemia and 11 (13%) owing to rash. Nine of 87 patients (10%) permanently discontinued treatment owing to AEs (all received alpelisib 400 mg once daily). There were 5 deaths during treatment (4 from disease progression and 1 of unknown causes 9 days after a computed tomographic scan revealed progressive disease); all of the patients received alpelisib 400 mg once daily plus fulvestrant; none of the deaths were suspected to be study treatment related.

Pharmacokinetics

Exposure (24-hour area under the curve) to alpelisib, 300 and 350 mg, once daily plus fulvestrant was similar to single-agent alpelisib at the same doses in a fed state (eTable 2 in Supplement 1). Concentration–time profiles were similar across doses (eFigure 1 in Supplement 1). At steady state (cycle 1, day 8), median peak serum concentration and 24-hour area under the curve values were approximately 35% for alpelisib, 400 mg, once daily plus fulvestrant compared with 400-mg single-agent alpelisib; this association was not observed at lower doses (eFigure 2 in Supplement 1). There was greater variability in peak serum concentration and 24-hour area under the curve among patients receiving alpelisib, 400 mg once daily (with or without fulvestrant) than at lower doses (eTable 2 in Supplement 1). At steady state, pharmacokinetic parameters were largely consistent for alpelisib, 300 to 400 mg, once daily when administered with fulvestrant vs alpelisib alone at the same doses (eTable 2 in Supplement 1). No dose-dependent association was observed in maximum-fold change from baseline over cycle 1 for any pharmacodynamic parameter (C-peptide, insulin, or glucose levels) (eFigure 3 in Supplement 1).

Eighty-one patients with ER+, HER2– disease were evaluable for response. The overall response rate among the 49 patients (60%) with PIK3CA-altered tumors receiving alpelisib, 300 to 400 mg, once daily plus fulvestrant was 29% (95% CI, 17%-43%). No objective responses were observed in the 32 patients (40%) with PIK3CA-wild-type tumors (eTable 3 in Supplement 1).

Clinical Activity

The mPFS at the alpelisib MTD (400 mg once daily) plus fulvestrant was 5.4 months (95% CI, 4.6-9.0 months). mPFS of alpelisib 300 to 400 mg once daily plus fulvestrant was numerically longer in patients with PIK3CA-altered (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months) (Figure 2; eTable 3 in Supplement 1). The mPFS was numerically longer in patients with PIK3CA-altered tumors who were mTOR inhibitor-naive (6.7 months; range, 1.0-39.6 months) vs mTOR inhibitor-pretreated (6.5 months; range, 0.5-49.5 months), and in those with PIK3CA-wild-type tumors who were mTOR inhibitor-naive (2.4 months; range, 0.6-36.8 months) vs mTOR pretreated (3.0 months; range, 0.3-5.7 months).

Tumor Response

Eight patients continued treatment for more than 2 years (range, 123-208 weeks). Of these patients, 6 received alpelisib, 400 mg, once daily plus fulvestrant, 1 received alpelisib, 350 mg, once daily plus fulvestrant, and 1 received alpelisib, 400 mg, once daily alone for 28 weeks before switching to combination treatment (at the data cutoff point, this patient was still receiving treatment, with the most recent follow-up at 136 weeks) (eFigure 4 in Supplement 1). Six of these 8 patients had PIK3CA-altered tumors (exon 9 [n = 2], exon 20 [n = 3], and P366R mutation [n = 1]), 1 had a PIK3CA-wild-type tumor, and 1 had indeterminate PIK3CA status. Twenty-seven patients had centrally confirmed PIK3CA mutations of known functional significance in exons 7, 9, 10, and 20; 20 patients had single mutations and 7 had compound mutations. The most frequent PIK3CA mutations in exons 9 and 20 at baseline were Glu545Lys (n = 6) and His1047Arg (n = 7), respectively. Two of the 8 patients receiving treatment for more than 2 years had ER+, HER2+ cancers. All but 1 patient had received prior endocrine therapies in the metastatic setting, and 3 had also received prior treatment with an mTOR inhibitor with initial response (eTable 4 in Supplement 1). Two patients achieved partial responses after prior mTOR treatment and stayed in the study for 178 and 208 weeks; the latter patient had the longest duration of treatment with an objective response in the study. Overall, duration of exposure to study treatment ranged from 4 to 208 weeks (4 years); at the data cutoff point, 3 patients continued treatment between 31 and 48 months.

Of 40 patients with ER+, HER2– breast cancer and measurable target lesions per Response Evaluation Criteria in Solid Tumors, version 1.0, 33 (83%) achieved tumor shrinkage (Figure 3). Of 31 patients with measurable disease and samples containing somatic genetic alterations of known or likely significance on central assessment, 25 (81%) achieved some shrinkage (eFigure 5 in Supplement 1). Robust analysis of centrally, next-generation sequencing–assessed PIK3CA mutation status and tumor response was not feasible because of limited patient numbers (eTables 5-7 in Supplement 1).

Discussion

This study demonstrates that alpelisib plus fulvestrant has a manageable safety profile and encouraging clinical activity in patients with ER+ ABC. The MTD of alpelisib in this combination was 400 mg once daily, equivalent to that established for single-agent alpelisib in patients with advanced solid tumors.15 Alpelisib, 300 mg, once daily was chosen for subsequent studies based on similar clinical activity across dose levels and fewer dose modifications. This dose is the same as the MTD for alpelisib plus letrozole in patients with ER+, HER2– metastatic breast cancer.9

The most frequently observed AEs in patients receiving alpelisib plus fulvestrant included hyperglycemia, fatigue, and low-grade gastrointestinal tract toxic effects, consistent with AEs observed with single-agent alpelisib15 or alpelisib plus letrozole.9 Hyperglycemia is an on-target effect of PI3K inhibition linked to the role of PI3K/mTOR pathway signaling in glucose homeostasis.18 Hyperglycemia was successfully managed in this study with dose interruptions and antidiabetic medications. At 300 to 400 mg once daily, the frequency of treatment-related, all-grade hyperglycemia with alpelisib plus fulvestrant (49%) was similar to that with single-agent alpelisib (53%).15 The incidence of maculopapular rash with the alpelisib MTD (400 mg once daily) plus fulvestrant was 24%. The incidence of maculopapular rash with alpelisib, 300 mg, once daily plus letrozole was 45%,9 and with buparlisib plus fulvestrant, 32%.12 These data suggest that skin may be sensitive to combined PI3K inhibition with endocrine therapy, possibly due to trophic effects of both pathways on the skin.19 Rash was successfully managed with use of antihistamines or topical and/or systemic corticosteroids in most patients.

Part of the rationale to study the PI3Kα-specific inhibitor alpelisib was the hypothesis that targeting a single PI3K isoform may allow for higher doses with fewer AEs than pan-PI3K inhibitors. Alpelisib does not appear to be associated with certain AEs that are seen with buparlisib, such as anxiety and depression or increased aminotransferase levels.12,13 Although results of different trials cannot directly be compared, the rate of grade 3/4 AEs in the present study was similar to that reported with fulvestrant plus buparlisib or pictilisib.13,20 However, the AE-related discontinuation rate was lower with alpelisib plus fulvestrant (10%) than reported with buparlisib (21%), suggesting greater tolerability.13

Exposure to alpelisib once daily at 300 or 350 mg plus fulvestrant was largely unchanged vs alpelisib alone at the same doses. Exposure to alpelisib at 400 mg plus fulvestrant was lower than alpelisib alone, possibly owing to the increased variation in the range of pharmacokinetic parameters at this dose. Based on the available information on fulvestrant and our understanding of alpelisib clearance,21 we do not consider that a pharmacokinetic interaction between alpelisib and fulvestrant occurred.

The numerically higher clinical activity observed in patients with PIK3CA-altered tumors vs those with PIK3CA-wild-type tumors (mPFS, 9.1 vs 4.7 months) is consistent with a previous report22 and may represent a novel biomarker to predict response to alpelisib. It is also consistent with the higher preclinical activity of alpelisib in cell lines harboring PIK3CA alterations.22,23 Some patients in this study continued receiving treatment for more than 2 years, including mTOR inhibitor–pretreated patients and those with visceral metastases, and most of these patients had PIK3CA-altered tumors. One patient in this group had PIK3CA-wild-type cancer, and another had indeterminate PIK3CA status. The observed increased benefit with alpelisib in PIK3CA-altered vs wild-type tumors is consistent with the significant improvement in PFS observed in patients with PIK3CA-altered vs wild-type HR+, HER2– breast cancer treated with buparlisib, although none of these studies were designed to be biomarker driven and results must be interpreted with caution.12,13 Randomized studies are needed to conclusively evaluate the role of PIK3CA alterations in selecting patients for combined treatment with α-specific PI3K inhibitors and fulvestrant, with repeated testing owing to observed changes in PIK3CA mutation status over time.24 The ongoing phase 3 Clinical Studies of Alpelisib in Breast Cancer-1 (SOLAR-1) study of alpelisib with fulvestrant includes evaluation of PIK3CA status based on circulating tumor DNA and tumor tissue to identify patients with HR+, HER2– ABC who may derive the greatest benefit from alpelisib plus fulvestrant.25

Limitations

This study has limitations. This was a nonrandomized trial designed to assess the preliminary safety and efficacy of the combination of alpelisib and fulvestrant only. As such, this trial was not powered to detect statistically significant differences between patient groups and no standard-of-care comparator was used.

Conclusions

Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and encouraging clinical activity in patients with PIK3CA-altered vs wild-type tumors. In the era of precision medicine, α-specific PI3K inhibitors represent a potentially valuable addition to the ER+ ABC treatment landscape. Additional studies with alpelisib plus endocrine therapy, including the ongoing phase 3 SOLAR-1 study and the phase 2 study of alpelisib (BYL719) in patients with PIK3CA-mutant, HR+, HER2–advanced breast cancer progressing on or after cyclin-dependent kinase 4/6 inhibitor therapy (BYLieve), will define the role of alpelisib in ABC.

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Article Information

Accepted for Publication: July 20, 2018.

Published Online: December 13, 2018. doi:10.1001/jamaoncol.2018.4475

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Corresponding Author: Dejan Juric, MD, Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston, MA 02114 (juric.dejan@mgh.harvard.edu).

Author Contributions: Drs Juric and Quadt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Juric, Janku, Burris, Baselga, Demanse, Huang, Quadt, Rugo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Juric, Janku, Rodón, Burris, Baselga, Bootle, Quadt.

Critical revision of the manuscript for important intellectual content: Juric, Janku, Rodón, Burris, Mayer, Schuler, Seggewiss-Bernhardt, Gil-Martin, Middleton, Baselga, Demanse, Blumenstein, Schumacher, Huang, Rugo.

Statistical analysis: Demanse, Schumacher.

Administrative, technical, or material support: Juric, Schuler, Seggewiss-Bernhardt, Middleton, Bootle, Schumacher, Huang, Rugo.

Supervision: Juric, Janku, Rodón, Burris, Mayer, Gil-Martin, Baselga.

Conflict of Interest Disclosures: Dr Juric has reported a paid consultant role with Novartis, EMD Serono, Eisai, and Genentech. Dr Janku has reported grant funding from Novartis, Piqur, BioMed Valley Discoveries, Deciphera, FujiFilm, Astellas, Agios, Plexxikon, Symphogen, Trovagene, Biocartis, Guardant Health, Genentech, and Foundation Medicine; and personal fees for advisory board participation from Novartis, Deciphera, Trovagene, Guardant Health, Foundation Medicine, and Sequenom. Dr Rodón reported advisory board fees from Novartis during the course of the study. Dr Mayer reported serving in a consultant or advisory role with Novartis and Genentech and receiving research grants from Novartis and Pfizer. Dr Schuler reported receiving personal fees for consulting from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, and Roche; honoraria from Alexion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, MSD, and Novartis; and having patents with Universität Duisburg-Essen. Dr Seggewiss-Bernhardt has reported a consultant or advisory role with AstraZeneca, Roche, and Novartis; and has reported travel, accommodation, and/or expenses paid by Astellas, Bristol-Myers Squibb, Novartis, Roche, and Celgene. Dr Middleton reported grant funding from Roche, AstraZeneca (paid to his institution), and GSK; personal fees for serving on advisory boards and consulting from Amgen, Roche, GSK, Novartis, Bristol-Myers Squibb, Merck, Rigontec, and Eisai (member of independent data safety monitoring committee); travel fees from Immunocore; and study fees (paid to his institution) from Novartis, Astellas, Millennium, Immunocore, Bristol-Myers Squibb, Vertex, Eisai, AbbVie, Clovis, Pfizer, and Merck; and is supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr Baselga reports nonfinancial support and reasonable reimbursement for travel from Roche/Genentech; receiving fees from and stock ownership in the following companies: Aura Biosciences (including serving on the board of directors from 2013-2017), Infinity Pharmaceuticals (including serving on the board of directors from 2013-2017), PMV Pharma Biotechnologies (including serving on the scientific advisory board from 2014-present), Juno Therapeutics (acquired by Celgene) (including serving on the scientific advisory board from 2014-2017), Grail (including serving as member or chair of the scientific advisory board from 2016-2018), Varian Medical Systems (including serving on the board of directors from 2017-2018), Bristol-Myers Squibb (including serving on the board of directors from March to September 2018), Seragon (acquired by Roche) (including serving on the scientific advisory board from 2013-2014); stock ownership in ApoGen Biotechnologies (including serving on the scientific advisory board from 2014-present), and Foghorn Therapeutics (including serving on the board from 2017-present); serving as cofounder, receiving fees from, and stock ownership in Tango (formerly Synthetic Lethal) from 2016-present and Northern Biologics (formerly Mosaic Biomedicals) (including serving on the scientific advisory board from 2013-present); receiving consulting and travel fees from Novartis and Eli Lilly; serving as cofounder of Venthera; and serving as investigator on a patent licensed to Memorial Sloan Kettering for use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations and serving as investigator for patents pending assignment to Memorial Sloan Kettering for combination therapy using PDK1 and PI3K inhibitors and inhibition of KMT2D for the treatment of breast cancer. Mr Bootle is an employee of Novartis Pharmaceuticals Corporation. Dr Demanse is an employee of Novartis Pharmaceuticals Corporation. Dr Blumenstein is an employee of and reports stock ownership in Novartis. Dr Schumacher is an employee of and reports stock ownership in Novartis. Dr Huang was a Novartis employee at the time of the study. Ms Quadt is an employee of and reports stock ownership in Novartis. Dr Rugo has reported research support (paid to institution) from Novartis, Genentech, Eli Lilly, Pfizer, Macrogenics, and Merck. No other conflicts were reported.

Funding/Support: This study was supported by Novartis Pharmaceuticals Corporation.

Role of the Funder/Sponsor: The study was designed, conducted, and analyzed by the funder in conjunction with the investigators and study steering committee. The funder provided the study treatments.

Additional Contributions: We thank the patients who participated in the trial, their families, and the site staff involved. Rajkumar Radhakrishnan, MS (Novartis; Hyderabad, India) provided support with statistics, and Lellean JeBailey, PhD (Novartis Institute for BioMedical Research, Cambridge, Massachusetts) and Rose Brannon, PhD (at the time of the study, Novartis Institute for BioMedical Research, Cambridge, Massachusetts), provided support with the next-generation sequencing–related outputs. They received no financial compensation outside of salary. Medical editorial assistance was provided by Alison Lovibond, PhD, Sara Shaw, PhD, and John Munro, BSc, and was funded by Novartis Pharmaceuticals Corporation.

Additional Information: The authors confirm adherence to the study protocol and vouch for the accuracy and completeness of the data. The corresponding author also had access to the study data, was involved in their interpretation and analysis, and had final responsibility for the decision to submit for publication.

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