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
This phase 1b clinical trial evaluates the dose response and safety of alpelisib plus fulvestrant treatment in women with advanced breast cancer.
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.3,4,5 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,9,12,13,14 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.
Table 1. Patient Characteristics at Baseline.
| Characteristic | Alpelisib Dose Level Plus Fulvestrant, 500 mg | |||
|---|---|---|---|---|
| 300 mg Once Daily (n = 9) | 350 mg Once Daily (n = 8) | 400 mg Once Daily (n = 70) | All Patients (N = 87) | |
| Age, median (range), y | 56 (39-73) | 55 (43-65) | 59 (37-79) | 58 (37-79) |
| ECOG performance status, No. (%) | ||||
| 0 | 4 (44) | 3 (38) | 32 (46) | 39 (45) |
| 1 | 5 (56) | 5 (63) | 36 (51) | 46 (53) |
| 2 | 0 | 0 | 1 (1) | 1 (1) |
| Missing | 0 | 0 | 1 (1) | 1 (1) |
| Breast cancer stage at initial diagnosis, No. (%) | ||||
| 0 | 0 | 0 | 1 (1) | 1 (1) |
| I/Ia | 2 (22) | 2 (25) | 7 (10) | 11 (13) |
| II/IIa/IIb/IIc | 2 (22) | 1 (13) | 29 (41) | 32 (37) |
| III/IIIa/IIIb/IIIc | 0 | 1 (13) | 11 (16) | 12 (14) |
| IV | 4 (44) | 1 (13) | 18 (26) | 23 (26) |
| Missing | 1 (11) | 3 (38) | 4 (6) | 8 (9) |
| No. of metastatic sites, median (range) | 3 (1-5) | 3 (1-5) | 3 (1-8) | 3 (1-8) |
| Time between initial diagnosis and study treatment initiation, median (range), mo | 62 (9-176) | 106 (20-292) | 94 (12-349) | 93 (9-349) |
| No. of prior antineoplastic therapies, median (range) | 6 (1-11) | 5 (2-7) | 5 (1-16) | 5 (1-16) |
| Prior mTOR inhibitor, No. (%) | 1 (11) | 2 (25) | 18 (26) | 21 (24) |
| Prior fulvestrant, No. (%) | 5 (56) | 6 (75) | 28 (40) | 39 (45) |
| Prior chemotherapy, No. (%) | 7 (78) | 6 (75) | 66 (94) | 79 (91) |
| Locally assessed PIK3CA status, No. (%) | ||||
| Altered (mutation/amplification) | 9 (100) | 8 (100) | 35 (50) | 52 (60) |
| Wild type | 0 | 0 | 33 (47) | 33 (38) |
| Unknown | 0 | 0 | 2 (3) | 2 (2) |
Abbreviations: ECOG, Eastern Cooperative Oncology Group; mTOR, mammalian target of rapamycin.
Figure 1. 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.
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.
Table 2. Adverse Events Reported in ≥20% of Patients Regardless of Causalitya.
| Adverse Event | No. (%) | |||||
|---|---|---|---|---|---|---|
| 300 mg Once Daily (n = 9) | 350 mg Once Daily (n = 8) | 400 mg Once Daily (n = 70) | ||||
| All-Grade | Grade 3/4 | All-Grade | Grade 3/4 | All-Grade | Grade 3/4 | |
| Nausea | 5 (56) | 0 | 6 (75) | 0 | 35 (50) | 0 |
| Diarrhea | 5 (56) | 0 | 6 (75) | 1 (13) | 41 (59) | 3 (4) |
| Hyperglycemia | 4 (44) | 1 (11) | 5 (63) | 2 (25) | 34 (49) | 16 (23) |
| Fatigue | 4 (44) | 0 | 7 (88) | 0 | 25 (36) | 3 (4) |
| Dysgeusia | 4 (44) | 0 | 1 (13) | 0 | 14 (20) | 0 |
| Vomiting | 3 (33) | 0 | 4 (50) | 0 | 23 (33) | 2 (3) |
| Stomatitis | 3 (33) | 0 | 3 (38) | 0 | 19 (27) | 1 (1) |
| Headache | 3 (33) | 0 | 3 (38) | 0 | 11 (16) | 0 |
| Rash | 3 (33) | 0 | 4 (50) | 1 (13) | 10 (14) | 6 (9) |
| Dizziness | 3 (33) | 0 | 2 (25) | 0 | 6 (9) | 0 |
| Decreased appetite | 2 (22) | 0 | 4 (50) | 0 | 33 (47) | 1 (1) |
| Arthralgia | 2 (22) | 0 | 2 (25) | 0 | 13 (19) | 0 |
| Increased AST | 2 (22) | 0 | 2 (25) | 0 | 11 (16) | 5 (7) |
| Anemia | 2 (22) | 0 | 1 (13) | 0 | 13 (19) | 2 (3) |
| Constipation | 2 (22) | 0 | 1 (13) | 0 | 10 (14) | 0 |
| Amylase level increased | 2 (22) | 0 | 0 | 0 | 1 (1) | 0 |
| Rhinorrhea | 2 (22) | 0 | 0 | 0 | 1 (1) | 0 |
| Muscle spasms | 1 (11) | 0 | 5 (63) | 0 | 7 (10) | 0 |
| Upper respiratory tract infection | 1 (11) | 0 | 3 (38) | 0 | 10 (14) | 0 |
| Pruritus | 1 (11) | 0 | 3 (38) | 0 | 10 (14) | 2 (3) |
| Asthenia | 1 (11) | 0 | 3 (38) | 0 | 7 (10) | 0 |
| Dry skin | 1 (11) | 0 | 2 (25) | 0 | 13 (19) | 0 |
| Alopecia | 1 (11) | 0 | 2 (25) | 0 | 11 (16) | 0 |
| Dry mouth | 1 (11) | 0 | 2 (25) | 0 | 6 (9) | 0 |
| Hypomagnesemia | 1 (11) | 0 | 2 (25) | 0 | 3 (4) | 0 |
| Abdominal pain | 0 | 0 | 4 (50) | 0 | 9 (13) | 1 (1) |
| Weight decreased | 0 | 0 | 3 (38) | 0 | 11 (16) | 0 |
| Pyrexia | 0 | 0 | 3 (38) | 0 | 9 (13) | 0 |
| Thirst | 0 | 0 | 3 (38) | 0 | 0 | 0 |
| Musculoskeletal pain | 0 | 0 | 2 (25) | 0 | 8 (11) | 0 |
| Dehydration | 0 | 0 | 2 (25) | 0 | 5 (7) | 1 (1) |
| Dyspepsia | 0 | 0 | 2 (25) | 0 | 2 (3) | 0 |
| Erythema | 0 | 0 | 2 (25) | 0 | 3 (4) | 0 |
| Flushing | 0 | 0 | 2 (25) | 0 | 1 (1) | 0 |
| Cough | 0 | 0 | 1 (13) | 0 | 17 (24) | 0 |
| Rash (maculopapular) | 0 | 0 | 2 (25) | 2 (25) | 17 (24) | 9 (13) |
Abbreviation: AST, aspartate aminotransferase.
There were 5 deaths during treatment, all in patients receiving alpelisib, 400 mg, once daily plus fulvestrant. None of the during-treatment deaths were suspected as study treatment related.
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).
Figure 2. 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.
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).
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.
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.
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.
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
Trial Protocol
References
- 1.Fitzmaurice C, Allen C, Barber RM, et al. ; Global Burden of Disease Cancer Collaboration . Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):-. doi: 10.1001/jamaoncol.2016.5688 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Shah PD, Dickler MN. Endocrine therapy for advanced breast cancer. Clin Adv Hematol Oncol. 2014;12(4):214-223. [PubMed] [Google Scholar]
- 3.Cardoso F, Costa A, Senkus E, et al. . 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Breast. 2017;31:244-259. doi: 10.1016/j.breast.2016.10.001 [DOI] [PubMed] [Google Scholar]
- 4.Rugo HS, Rumble RB, Macrae E, et al. . Endocrine therapy for hormone receptor–positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34(25):3069-3103. doi: 10.1200/JCO.2016.67.1487 [DOI] [PubMed] [Google Scholar]
- 5.NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Breast Cancer. Version 2.2017. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 12, 2017.
- 6.García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci. 2012;14(1):108-145. doi: 10.3390/ijms14010108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452-4461. doi: 10.1200/JCO.2010.34.4879 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Bosch A, Li Z, Bergamaschi A, et al. . PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer. Sci Transl Med. 2015;7(283):283ra51. doi: 10.1126/scitranslmed.aaa4442 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mayer IA, Abramson VG, Formisano L, et al. . A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23(1):26-34. doi: 10.1158/1078-0432.CCR-16-0134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sabine VS, Crozier C, Brookes CL, et al. . Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J Clin Oncol. 2014;32(27):2951-2958. doi: 10.1200/JCO.2013.53.8272 [DOI] [PubMed] [Google Scholar]
- 11.Martinello R, Genta S, Galizia D, et al. . New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer. Expert Opin Pharmacother. 2016;17(16):2179-2189. doi: 10.1080/14656566.2016.1236914 [DOI] [PubMed] [Google Scholar]
- 12.Baselga J, Im SA, Iwata H, et al. . Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904-916. doi: 10.1016/S1470-2045(17)30376-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Di Leo A, Johnston S, Lee KS, et al. . Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87-100. doi: 10.1016/S1470-2045(17)30688-5 [DOI] [PubMed] [Google Scholar]
- 14.Juric D, Krop I, Ramanathan RK, et al. . Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov. 2017;7(7):704-715. doi: 10.1158/2159-8290.CD-16-1080 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Juric D, Rodon J, Tabernero J, et al. . Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol. 2018;36(13):1291-1299. doi: 10.1200/JCO.2017.72.7107 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
- 17.Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008;27(13):2420-2439. doi: 10.1002/sim.3230 [DOI] [PubMed] [Google Scholar]
- 18.Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606-619. doi: 10.1038/nrg1879 [DOI] [PubMed] [Google Scholar]
- 19.Calautti E, Li J, Saoncella S, Brissette JL, Goetinck PF. Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem. 2005;280(38):32856-32865. doi: 10.1074/jbc.M506119200 [DOI] [PubMed] [Google Scholar]
- 20.Krop IE, Mayer IA, Ganju V, et al. . Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(6):811-821. doi: 10.1016/S1470-2045(16)00106-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.James A, Blumenstein L, Glaenzel U, et al. . Absorption, distribution, metabolism, and excretion of [(14)C]BYL719 (alpelisib) in healthy male volunteers. Cancer Chemother Pharmacol. 2015;76(4):751-760. doi: 10.1007/s00280-015-2842-4 [DOI] [PubMed] [Google Scholar]
- 22.Janku F, Wheler JJ, Westin SN, et al. . PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30(8):777-782. doi: 10.1200/JCO.2011.36.1196 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Fritsch C, Huang A, Chatenay-Rivauday C, et al. . Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13(5):1117-1129. doi: 10.1158/1535-7163.MCT-13-0865 [DOI] [PubMed] [Google Scholar]
- 24.Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 2014;16(1):201. doi: 10.1186/bcr3605 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.ClinicalTrials.gov Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. NCT02437318. https://clinicaltrials.gov/ct2/show/NCT02437318. Accessed November 1, 2018.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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
Trial Protocol