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).

Patients and Methods:

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 (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 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 II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.

Results:

A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.

Conclusions:

The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

Translational Relevance

PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. This phase I/II trial evaluated the α-specific PI3K inhibitor alpelisib in combination with nab-paclitaxel in patients with HER2-negative metastatic breast cancer. The alpelisib plus nab-paclitaxel combination demonstrated a manageable safety profile with encouraging efficacy in both hormone receptor–positive and triple-negative breast cancer. A total of 21% of patients had response lasting >12 months, suggesting durability of response. Efficacy of the combination was higher in patients with PIK3CA mutation and those with normal (vs. prediabetic/diabetic) metabolic status. Alpelisib in combination with nab-paclitaxel is under investigation in an ongoing biomarker-selected phase III clinical trial. The impact of metabolic status on response to alpelisib-based therapy merits further investigation.

Mutations and deregulations in the PI3K pathway are common in breast cancer (1). PI3K pathway activation frequently occurs as a result of mutation of the gene encoding the PI3K catalytic subunit p110α (PIK3CA). Activation of the PI3K pathway promotes tumor growth and progression, as well as resistance to anticancer therapies like taxanes (2, 3).

Activating mutations in PIK3CA are noted in approximately 40% of patients with hormone receptor–positive, HER2-negative breast cancer and in 8%–10% of patients with triple-negative breast cancer (TNBC; refs. 1, 4).

Alpelisib (BYL-719) is an oral, α-specific PI3K inhibitor (PI3Ki) that selectively inhibits the PI3Kα isoform (both wild-type and mutated p110α) and is significantly less active against the other class I isoforms β, δ, and γ (5). Targeting the alpha isoform of PI3K is expected to reduce the potential for treatment-related toxicity and improve the therapeutic window compared with inhibitors with less isoform specificity. Alpelisib has shown single-agent activity in patients with PIK3CA-altered advanced solid tumors (6). Recently, the phase III SOLAR-1 trial demonstrated that in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who had received previous endocrine therapy, the addition of alpelisib to fulvestrant significantly prolonged progression-free survival (PFS) compared with fulvestrant monotherapy (7). These findings led to approval of alpelisib to be used in combination with fulvestrant by both the FDA and European Medicines Agency.

The primary objective of this phase I/II trial was to determine the safety and efficacy of alpelisib in combination with nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).

Study design and participants

This was a single-arm, phase I–II trial (NCT2379247). Eligible patients were females aged ≥18 years with locally advanced or metastatic HER2-negative (per 2013 ASCO/CAP guidelines; ref. 8) breast cancer who had received at least one line of chemotherapy in either the advanced or neo/adjuvant setting, had measurable disease (per RECIST version 1.1), Eastern Cooperative Oncology Group performance status ≤2, and adequate organ and marrow function. Participants were excluded for uncontrolled diabetes mellitus [fasting plasma glucose (FPG) level >140 mg/dL (7.8 mmol/L) or glycosylated hemoglobin (HbA1C) >8%] or prior treatment with PI3Ki. Previous endocrine therapy was allowed (no limit on number of prior endocrine therapies), and previous taxanes (except nab-paclitaxel) were allowed if >6 months since exposure. Participants with treated brain metastases were eligible if free from central nervous system symptoms and at least 3 months had passed since brain metastasis treatment.

Participants were enrolled at the University of Kansas Medical Center (Kansas City, KS) and at the Vanderbilt-Ingram Cancer Center (Nashville, TN). The study was approved by each institution's human subjects research review board and was conducted in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services and in accordance with the U.S. Common Rule and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. All patients provided written informed consent.

Procedures and treatment

Nab-paclitaxel (100 mg/m2) was administered intravenously on days 1, 8, and 15 of each 28-day cycle. Phase I of the study was a 3+3 dose-escalation trial with three dose levels of alpelisib (250, 300, and 350 mg, administered orally once daily). Decision to escalate alpelisib dose was determined by safety evaluation (as described below). The dose of alpelisib identified as the recommended phase II dose (RP2D) in phase I was then administered in phase II. All patients were instructed to take second- or third-generation H1-antihistaminic prophylaxis for rash.

Toxicity was assessed using Common Toxicity Criteria for Adverse Events version 4.03. Response (investigator assessed) was evaluated according to RECIST version 1.1 every 8 weeks. During phase I, cycle 1 blood samples were collected predose and 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-alpelisib dose (oral alpelisib dosing occurred 1 hour prior to the start of 30-minute nab-paclitaxel infusion) for pharmacokinetics (Supplementary Materials and Methods).

Archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue (primary or metastatic site) was collected from all subjects. DNA and RNA isolated from FFPE tissue were subjected to next-generation sequencing (NGS) for assessment of PIK3CA mutation (see Supplementary Materials and Methods for details) and RNA gene expression profiling, respectively. RNA signature scores generated by claraT analysis and raw gene expression data (Xcel Array, Almac Diagnostic Services), as well as immune cell subpopulation gene expression data, were compared between PIK3CA-mutated and nonmutated groups (Supplementary Materials and Methods). Pretreatment blood samples were collected from all subjects. Circulating tumor DNA (ctDNA) isolated from plasma samples was subjected to NGS for PIK3CA mutation assessment (Supplementary Materials and Methods). Results of tissue or ctDNA analyses were not provided back to the treating physicians. Pretreatment FPG and HbA1C values were used to determine baseline metabolic status for each patient, per the 2019 Classification and Diagnosis Guidelines of the American Diabetes Association (9). Per these guidelines, normal metabolic status is defined as HbA1C < 5.7% and FPG < 100 mg/dL. Prediabetic status is defined as HbA1C 5.7%–<6.5% and/or FPG 100–<126 mg/dL. Diabetic status is defined as HbA1C ≥ 6.5% and/or FPG ≥ 126 mg/dL.

Endpoints

Primary objectives were to determine the RP2D of alpelisib plus nab-paclitaxel for phase I and the objective response rate (ORR) in subjects treated at the RP2D for phase II. Secondary objectives included safety, pharmacokinetics evaluation, clinical benefit rate (CBR), PFS, and overall survival (OS). Exploratory objectives included association of tumor/ctDNA PIK3CA alterations with response. ORR includes complete response (CR) plus partial response (PR). CBR includes CR, PR, plus stable disease (SD) ≥16 weeks.

Phase I was a 3+3 dose-escalation design (three dose levels of alpelisib: 250, 300, and 350 mg orally once daily, continuous dosing) with dose-limiting toxicities (DLT) assessed during the first treatment cycle. If 2 or more of the 6 patients experienced a DLT, dosing escalation would cease and maximum tolerated dose (MTD) would be reached. RP2D was the next lower dose at which <1 of 6 subjects experienced a DLT. Dose of alpelisib was not increased beyond 350 mg even if MTD was not reached (See Supplementary Materials and Methods for dose escalation details).

Phase II was designed according to Simon's two-stage minimax design to detect an improvement in ORR from 20% to 40%, with alpha 0.05 and a power of 80%. In the first stage, 18 participants were treated at the RP2D, with at least five responses necessary to proceed to the next stage. In the second stage, an additional 15 subjects were enrolled. If 11 or more subjects had an objective response among all 33 eligible subjects, the regimen would be considered promising.

Statistical analysis

Overall frequencies and percentages were summarized for baseline characteristics. ORR and CBR were estimated with 95% confidence intervals (CI). PFS was defined as the time in months from the date of enrollment to the date of progression or death, whichever was earlier. OS was defined as the time in months from the date of enrollment to death as a result of any cause. Survival curves were assessed by the Kaplan–Meier method and groups were compared by log-rank test. Cox regression modeling was used for multivariable analysis. All analyses were conducted using SPSS Statistics version 26 (IBM Corporation). P < 0.05 (two-sided) was considered significant, without correction for multiple comparisons.

Between April 2015 and May 2017, 43 patients were enrolled (n = 13, phase I and n = 30, phase II). Baseline characteristics of the study population are summarized in Table 1. Median age was 55 years, and 30% had triple-negative disease (defined as estrogen receptor and progesterone receptor IHC <10% and HER2 negative). A total of 84% of patients had visceral disease. The median lines of prior chemotherapy in the metastatic setting was one, and 30% of patients had received two or more lines of chemotherapy for metastatic disease.

Table 1.

Baseline patient demographics and clinical characteristics.

Characteristic, N (%)All patients (N = 43)
Age, years, median (range) 55 (34–72) 
Subtypea  
 ER and/or PgR positive 30 (70%) 
 Triple negative 13 (30%) 
Measurable disease 43 (100%) 
Visceral disease 36 (84%) 
Prior lines of chemotherapy for metastatic disease 
 0 10 (23%) 
 1 20 (47%) 
 ≥2 13 (30%) 
Prior taxane  
 Neo/adjuvant 26 (61%) 
 Metastatic 7 (16%) 
 Neo/adjuvant and metastatic 3 (7%) 
 None 7 (16%) 
Prior CDK4/6 inhibitor 12 (28%) 
Characteristic, N (%)All patients (N = 43)
Age, years, median (range) 55 (34–72) 
Subtypea  
 ER and/or PgR positive 30 (70%) 
 Triple negative 13 (30%) 
Measurable disease 43 (100%) 
Visceral disease 36 (84%) 
Prior lines of chemotherapy for metastatic disease 
 0 10 (23%) 
 1 20 (47%) 
 ≥2 13 (30%) 
Prior taxane  
 Neo/adjuvant 26 (61%) 
 Metastatic 7 (16%) 
 Neo/adjuvant and metastatic 3 (7%) 
 None 7 (16%) 
Prior CDK4/6 inhibitor 12 (28%) 

Abbreviations: CDK4/6, cyclin-dependent kinase 4/6; ER, estrogen receptor; PgR, progesterone receptor.

aER and/or PgR positivity defined as ≥10% by IHC.

Phase I results: no DLT occurred in the 3 patients treated at the first alpelisib dose level of 250 mg, in 3 patients treated at the second dose level of 300 mg, and in 7 patients treated at the third dose level of 350 mg (1/7 patients treated at the third level stopped treatment within 7 days due to progressive brain metastasis, thus not evaluable for DLT). MTD of alpelisib was not reached, and RP2D of alpelisib was defined as 350 mg orally daily in combination with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 28 days.

Toxicity

Diarrhea, hyperglycemia, fatigue, hematologic toxicity, and peripheral neuropathy were the most common toxicities (Table 2). Diarrhea was noted in 81% of patients, but was mainly grade 1 and 2 (5% grade 3 and 0% grade 4). Hyperglycemia was noted in 70% of patients (26% grade 3 and 0% grade 4). A total of 28% of patients required metformin for management of hyperglycemia. Rash was noted in 44% of patients and was mainly grade 1 and 2 (7% grade 3 and 0% grade 4). All patients received H1-antihistaminic prophylaxis for rash. A total of 12% (5/43) of patients discontinued treatment because of toxicity (two for pneumonitis and one each for infection, thrombocytopenia, and kidney dysfunction). No patients discontinued treatment because of hyperglycemia, rash, or diarrhea. Alpelisib dose reduction was required for 11 of 43 (26%) patients (n = 1 at the 250 mg dose and n = 10 at the 350 mg dose), and nab-paclitaxel dose reduction was required for 12 of 43 (28%) patients.

Table 2.

Treatment-related adverse events.

Event, N (%)All gradesGrade 1Grade 2Grade 3Grade 4
Diarrhea 35 (81%) 22 (51%) 11 (26%) 2 (5%) 0 (0%) 
Hyperglycemia 30 (70%) 8 (19%) 11 (26%) 11 (26%) 0 (0%) 
Nausea 28 (65%) 21 (49%) 7 (16%) 0 (0%) 0 (0%) 
Fatigue 27 (63%) 11 (26%) 14 (33%) 2 (5%) 0 (0%) 
Peripheral neuropathy 25 (58%) 15 (35%) 9 (21%) 1 (2%) 0 (0%) 
Anorexia 22 (51%) 16 (37%) 6 (14%) 0 (0%) 0 (0%) 
Electrolyte imbalance 22 (51%) 10 (23%) 7 (16%) 5 (12%) 0 (0%) 
Anemia 21 (49%) 12 (28%) 4 (9%) 5 (12%) 0 (0%) 
Mucositis 21 (49%) 14 (33%) 6 (14%) 1 (2%) 0 (0%) 
Neutropenia 20 (47%) 3 (7%) 4 (9%) 10 (23%) 3 (7%) 
Dysgeusia 19 (44%) 17 (40%) 2 (5%) 0 (0%) 0 (0%) 
Rash 19 (44%) 14 (33%) 2 (5%) 3 (7%) 0 (0%) 
Infection 13 (30%) 1 (2%) 10 (23%) 2 (5%) 0 (0%) 
Edema 12 (28%) 8 (19%) 4 (9%) 0 (0%) 0 (0%) 
Vomiting 11 (26%) 6 (14%) 5 (12%) 0 (0%) 0 (0%) 
Myalgia 10 (23%) 7 (16%) 3 (7%) 0 (0%) 0 (0%) 
Nail changes 10 (23%) 7 (16%) 3 (7%) 0 (0%) 0 (0%) 
Liver enzyme increase 9 (21%) 8 (19%) 1 (2%) 0 (0%) 0 (0%) 
Alopecia 8 (19%) 3 (7%) 5 (12%) 0 (0%) 0 (0%) 
Arthralgia 8 (19%) 6 (14%) 1 (2%) 1 (2%) 0 (0%) 
Dry skin/mouth 8 (19%) 7 (16%) 1 (2%) 0 (0%) 0 (0%) 
Dyspepsia 8 (19%) 5 (12%) 3 (7%) 0 (0%) 0 (0%) 
Dyspnea 8 (19%) 6 (14%) 1 (2%) 1 (2%) 0 (0%) 
Cough 7 (16%) 4 (9%) 3 (7%) 0 (0%) 0 (0%) 
Weight loss 7 (16%) 2 (5%) 5 (12%) 0 (0%) 0 (0%) 
Musculoskeletala 7 (16%) 4 (9%) 2 (5%) 1 (2%) 0 (0%) 
Creatinine imbalance 5 (12%) 2 (5%) 2 (5%) 1 (2%) 0 (0%) 
Flatulence 4 (9%) 4 (9%) 0 (0%) 0 (0%) 0 (0%) 
Watering eyes 4 (9%) 4 (9%) 0 (0%) 0 (0%) 0 (0%) 
Blurred vision 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Decreased lymphocyte count 3 (7%) 1 (2%) 2 (5%) 0 (0%) 0 (0%) 
Dizziness 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Dry eyes 3 (7%) 2 (5%) 1 (2%) 0 (0%) 0 (0%) 
Fever 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Gait disturbance 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Gastrointestinal, otherb 3 (7%) 2 (5%) 1 (2%) 0 (0%) 0 (0%) 
Headache 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Pneumonitis 3 (7%) 1 (2%) 2 (5%) 0 (0%) 0 (0%) 
Abdominal pain 2 (5%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) 
Lymphedema 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Prolonged corrected QT interval 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Pulmonary, otherc 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Thrombocytopenia 2 (5%) 1 (2%) 1 (2%) 0 (0%) 0 (0%) 
Otherd 20 (47%) 17 (40%) 2 (5%) 1 (2%) 0 (0%) 
Event, N (%)All gradesGrade 1Grade 2Grade 3Grade 4
Diarrhea 35 (81%) 22 (51%) 11 (26%) 2 (5%) 0 (0%) 
Hyperglycemia 30 (70%) 8 (19%) 11 (26%) 11 (26%) 0 (0%) 
Nausea 28 (65%) 21 (49%) 7 (16%) 0 (0%) 0 (0%) 
Fatigue 27 (63%) 11 (26%) 14 (33%) 2 (5%) 0 (0%) 
Peripheral neuropathy 25 (58%) 15 (35%) 9 (21%) 1 (2%) 0 (0%) 
Anorexia 22 (51%) 16 (37%) 6 (14%) 0 (0%) 0 (0%) 
Electrolyte imbalance 22 (51%) 10 (23%) 7 (16%) 5 (12%) 0 (0%) 
Anemia 21 (49%) 12 (28%) 4 (9%) 5 (12%) 0 (0%) 
Mucositis 21 (49%) 14 (33%) 6 (14%) 1 (2%) 0 (0%) 
Neutropenia 20 (47%) 3 (7%) 4 (9%) 10 (23%) 3 (7%) 
Dysgeusia 19 (44%) 17 (40%) 2 (5%) 0 (0%) 0 (0%) 
Rash 19 (44%) 14 (33%) 2 (5%) 3 (7%) 0 (0%) 
Infection 13 (30%) 1 (2%) 10 (23%) 2 (5%) 0 (0%) 
Edema 12 (28%) 8 (19%) 4 (9%) 0 (0%) 0 (0%) 
Vomiting 11 (26%) 6 (14%) 5 (12%) 0 (0%) 0 (0%) 
Myalgia 10 (23%) 7 (16%) 3 (7%) 0 (0%) 0 (0%) 
Nail changes 10 (23%) 7 (16%) 3 (7%) 0 (0%) 0 (0%) 
Liver enzyme increase 9 (21%) 8 (19%) 1 (2%) 0 (0%) 0 (0%) 
Alopecia 8 (19%) 3 (7%) 5 (12%) 0 (0%) 0 (0%) 
Arthralgia 8 (19%) 6 (14%) 1 (2%) 1 (2%) 0 (0%) 
Dry skin/mouth 8 (19%) 7 (16%) 1 (2%) 0 (0%) 0 (0%) 
Dyspepsia 8 (19%) 5 (12%) 3 (7%) 0 (0%) 0 (0%) 
Dyspnea 8 (19%) 6 (14%) 1 (2%) 1 (2%) 0 (0%) 
Cough 7 (16%) 4 (9%) 3 (7%) 0 (0%) 0 (0%) 
Weight loss 7 (16%) 2 (5%) 5 (12%) 0 (0%) 0 (0%) 
Musculoskeletala 7 (16%) 4 (9%) 2 (5%) 1 (2%) 0 (0%) 
Creatinine imbalance 5 (12%) 2 (5%) 2 (5%) 1 (2%) 0 (0%) 
Flatulence 4 (9%) 4 (9%) 0 (0%) 0 (0%) 0 (0%) 
Watering eyes 4 (9%) 4 (9%) 0 (0%) 0 (0%) 0 (0%) 
Blurred vision 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Decreased lymphocyte count 3 (7%) 1 (2%) 2 (5%) 0 (0%) 0 (0%) 
Dizziness 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Dry eyes 3 (7%) 2 (5%) 1 (2%) 0 (0%) 0 (0%) 
Fever 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Gait disturbance 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Gastrointestinal, otherb 3 (7%) 2 (5%) 1 (2%) 0 (0%) 0 (0%) 
Headache 3 (7%) 3 (7%) 0 (0%) 0 (0%) 0 (0%) 
Pneumonitis 3 (7%) 1 (2%) 2 (5%) 0 (0%) 0 (0%) 
Abdominal pain 2 (5%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) 
Lymphedema 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Prolonged corrected QT interval 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Pulmonary, otherc 2 (5%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 
Thrombocytopenia 2 (5%) 1 (2%) 1 (2%) 0 (0%) 0 (0%) 
Otherd 20 (47%) 17 (40%) 2 (5%) 1 (2%) 0 (0%) 

aGrade 3 generalized muscle weakness (n = 1); grade 2 muscle weakness lower limb (n = 2); and grade 1 events (n = 1 each): muscle weakness lower limb, left arm pain, generalized muscle weakness, and toe pain.

bGrade 2 colitis (n = 1); grade 1 stomach tightness (n = 1); and grade 1 unspecified gastrointestinal disorder (n = 1).

cGrade 2 pleural effusion (n = 1) and grade 2 stridor (n = 1).

dGrade 3 thromboembolic event (n = 1); grade 2 epistaxis (n = 1); grade 2 hot flashes (n = 1); grade 1 fall (n = 2); grade 1 allergic rhinitis (n = 2); and grade 1 events (n = 1 each): anxiety, bone pain, epistaxis, flu-like symptoms, hoarseness, hot flashes, hypertension, hypoalbuminemia, postnasal drip, sore throat, urinary incontinence, urinary urgency, and visual disturbance.

Efficacy

In the primary efficacy analysis among 33 patients treated at the RP2D, ORR was 52% (95% CI, 34%–70%; CR, n = 2; PR, n = 15). Objective responses were noted at all dose levels of alpelisib and were maintained over time (Fig. 1A–C). In an intention-to-treat analysis including all 42 evaluable patients treated in phase I and II portions of the trial (1/43 patients not evaluable for response), ORR was 59% (95% CI, 44%–75%), with an additional 21% demonstrating SD for ≥16 weeks, for CBR of 80% (95% CI, 69%–93%). Among patients with triple-negative and hormone receptor–positive disease, ORR was 58% (7/12; 95% CI, 26%–91%) and 60% (18/30; 95% CI, 41%–79%), respectively. Table 3 provides additional ORR details by line of treatment, taxane exposure, and breast cancer subtype. A total of 29% (12/42) of patients received prior cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy; of these, 58% (7/12) had an objective response (CR, n = 2 and PR, n = 5).

Figure 1.

Antitumor activity of alpelisib plus nab-paclitaxel based on RECIST v1.1. A, Best percentage change from baseline in the sum of longest diameters of target lesions. B, Longitudinal change from baseline in the sum of longest diameters of target lesions. C, Durability of response. A and B include patients who received at least one cycle of alpelisib and had available at least one postbaseline tumor assessment (n = 39). C includes all patients evaluable for response (N = 42).

Figure 1.

Antitumor activity of alpelisib plus nab-paclitaxel based on RECIST v1.1. A, Best percentage change from baseline in the sum of longest diameters of target lesions. B, Longitudinal change from baseline in the sum of longest diameters of target lesions. C, Durability of response. A and B include patients who received at least one cycle of alpelisib and had available at least one postbaseline tumor assessment (n = 39). C includes all patients evaluable for response (N = 42).

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Table 3.

Objective response by prior treatment and subtype.

Prior lines of chemotherapy in metastatic settingPrior taxane exposureSubtype
01≥2YesNoER/PgR+aTNBC
Response, N (%)All evaluable (N = 42)(n = 9)(n = 20)(n = 13)(n = 36)(n = 6)(n = 30)(n = 12)
ORR 25 (59%) 6 (67%) 13 (65%) 6 (46%) 22 (61%) 3 (50%) 18 (60%) 7 (58%) 
 CR 3 (7%) 0 (0%) 2 (10%) 1 (8%) 3 (8%) 0 (0%) 1 (3%) 2 (17%) 
 PR 22 (52%) 6 (67%) 11 (55%) 5 (38%) 19 (53%) 3 (50%) 17 (57%) 5 (42%) 
SD ≥16 weeks 9 (21%) 1 (11%) 4 (20%) 4 (31%) 7 (19%) 2 (33%) 9 (30%) 0 (0%) 
CBRb 34 (80%) 7 (78%) 17 (85%) 10 (77%) 29 (81%) 5 (83%) 27 (90%) 7 (58%) 
Prior lines of chemotherapy in metastatic settingPrior taxane exposureSubtype
01≥2YesNoER/PgR+aTNBC
Response, N (%)All evaluable (N = 42)(n = 9)(n = 20)(n = 13)(n = 36)(n = 6)(n = 30)(n = 12)
ORR 25 (59%) 6 (67%) 13 (65%) 6 (46%) 22 (61%) 3 (50%) 18 (60%) 7 (58%) 
 CR 3 (7%) 0 (0%) 2 (10%) 1 (8%) 3 (8%) 0 (0%) 1 (3%) 2 (17%) 
 PR 22 (52%) 6 (67%) 11 (55%) 5 (38%) 19 (53%) 3 (50%) 17 (57%) 5 (42%) 
SD ≥16 weeks 9 (21%) 1 (11%) 4 (20%) 4 (31%) 7 (19%) 2 (33%) 9 (30%) 0 (0%) 
CBRb 34 (80%) 7 (78%) 17 (85%) 10 (77%) 29 (81%) 5 (83%) 27 (90%) 7 (58%) 

Abbreviations: CBR, clinical benefit rate; CR, complete response; ER, estrogen receptor; ORR, overall response rate; PgR, progesterone receptor; PR, partial response; SD, stable disease; TNBC, triple-negative breast cancer.

aER and/or PgR positivity defined as ≥10% by IHC.

bCR + PR + SD ≥16 weeks.

At the time of data cutoff (October 16, 2019), 1 patient remained on study, and the median duration of follow-up was 17.3 months (range, 1.8–40). Median duration of response was 5 months (range, 2–40), and 21% (7/34) of patients had response lasting >12 months. Median PFS and OS were 8.7 months (95% CI, 5.5–11.9 months) and 18.5 months (95% CI, 9.6–27.4 months), respectively (Fig. 2A; Supplementary Fig. S1A). Seven patients discontinued nab-paclitaxel and continued alpelisib monotherapy (after 24, 19, 8, 6, 6, 5, and 4 cycles of the combination therapy, respectively). Progressive disease was noted for patients on monotherapy after a median of 15 weeks (range, 8–43).

Figure 2.

Kaplan–Meier estimates of PFS. A, All evaluable patients. B, All evaluable patients, by PIK3CA mutation status.

Figure 2.

Kaplan–Meier estimates of PFS. A, All evaluable patients. B, All evaluable patients, by PIK3CA mutation status.

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Efficacy by PIK3CA status

Tumor tissue PIK3CA mutation status was available for 34 of 42 (81%) patients (inadequate tissue = 6 and assay failure = 2), and ctDNA PIK3CA status was available for all 42 patients. Overall, 40% (17/42) of patients had PIK3CA mutation detected in tumor tissue and/or ctDNA (n = 9 detected in both tissue and ctDNA, n = 4 detected in tissue only, n = 1 detected in ctDNA only, and n = 3 detected in ctDNA, but tissue not available). CBR was higher in the PIK3CA-mutated subgroup compared with those without tumor/ctDNA PIK3CA mutation (CBR, 100% vs. 68%; OR, 1.47; P = 0.013).

Median PFS was 11.9 months (95% CI, 6.2–17.6) in the PIK3CA-mutated subgroup compared with 7.5 months (95% CI, 2.3–12.6) in those without tumor/ctDNA PIK3CA mutation (HR, 0.44; 95% CI, 0.21–0.93; P = 0.027; Fig. 2B). Median OS was numerically higher in the PIK3CA-mutated subgroup compared with those without tumor/ctDNA mutation (26.7 vs. 14.9 months; HR, 0.59; 95% CI, 0.27–1.29; P = 0.19; Supplementary Fig. S1B).

Metabolic status and efficacy

Among 42 patients, 38% had normal metabolic status, 52% were prediabetic, and 10% were diabetic. Patients with normal metabolic status had longer PFS compared with those who were prediabetic or diabetic; median PFS was 12 months (95% CI, 7.9–16.1) for those with normal metabolic status and 7.5 months (95% CI, 4.8–10.2) for prediabetic/diabetic patients (HR, 0.36; 95% CI, 0.16–0.84; P = 0.014; Supplementary Fig. S2A). The impact of metabolic status on PFS was more pronounced in the PIK3CA-mutated subgroup (n = 17), where median PFS was 25.8 months (95% CI, 7.7–43.9) for patients with normal metabolic status (n = 6) versus 5.8 months (95% CI, 5.5–6.1) for prediabetic/diabetic patients (n = 11; HR, 0.10; 95% CI, 0.01–0.78; P = 0.008; Supplementary Fig. S2B). In the patient subgroup without PIK3CA mutation (n = 25), median PFS for patients with normal (n = 10) versus prediabetic/diabetic (n = 15) metabolic status was similar (6.4 vs. 7.5 months; P = 0.29; Supplementary Fig. S2C).

On multivariable analysis (variables included: PIK3CA status, breast cancer subtype, baseline metabolic status, and prior lines of chemotherapy 0 vs. ≥1), presence of PIK3CA mutation and normal metabolic status was significantly associated with longer PFS (HR, 0.43; 95% CI, 0.20–0.91; P = 0.027 and HR, 0.36; 95% CI, 0.15–0.82; P = 0.016, respectively).

Gene expression signatures

Tumor samples adequate for RNA extraction were available for 30 patients, and RNA sequencing was successful for 19 patients (n = 7 with PIK3CA mutation and n = 12 without mutation). Analysis of published gene expression signatures revealed that angiogenesis (10) was upregulated, whereas MYC targets, tumor necrosis (11), and TP53 deficiency (12) pathways were downregulated in the PIK3CA-mutated group compared with the nonmutated group (Supplementary Fig. S3A). On CIBERSORTx analysis, PIK3CA-mutated tumors appeared to exhibit lower imputed abundance of monocytes and naïve B cells (Supplementary Fig. S3B).

Pharmacokinetics

The study included limited pharmacokinetics analysis for 13 patients (phase I). Plasma samples were analyzed for alpelisib concentration for cycle 1 predose and 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours postdose. For alpelisib, obtained values for Tmax, Cmax, and AUC (0–8 hours) and the dose proportionality observed for the latter two parameters were consistent with reports published previously (Supplementary Table S1A; ref. 6). Paclitaxel was measured in both plasma and ultrafiltered plasma (to quantify total and free paclitaxel, respectively) at end of infusion (EOI), and at 0.5, 1, 1.5, 2, 4, and 6 hours post-EOI. Plasma concentration profiles, Cmax, and AUC values were consistent with previous reports of paclitaxel monotherapy at all alpelisib doses (Supplementary Table S1B and S1C; ref. 13). We thus conclude that no significant pharmacokinetics interactions were detected for the coadministration of alpelisib and nab-paclitaxel.

In this phase I/II study, the combination of alpelisib and nab-paclitaxel demonstrated encouraging efficacy with a manageable safety profile in patients with HER2-negative MBC. More than two thirds of the patients in our study had received prior chemotherapy for metastatic disease, and one third had received more than two lines of chemotherapy. We noted an ORR of 59% and CBR of 80% in this pretreated patient population, with efficacy maintained in patients receiving treatment in the second line or beyond, where ORR was 61%. The majority (84%) of patients in this study had prior taxane exposure (for early or metastatic disease), and efficacy was noted in patients with prior taxane exposure. Although numbers are small to draw definitive conclusions, efficacy appeared similar in hormone receptor–positive breast cancer (ORR, 58%) and TNBC (ORR, 60%). Importantly, 21% of patients had response lasting longer than 1 year, suggesting durability of response in some patients. In the 29% of patients who had received prior CDK4/6 inhibitor therapy, response rate was 67%.

Although further development of older generation PI3Kis was hampered by the toxicity profile of these agents, there were hints of efficacy in PIK3CA-mutated disease in previous studies (14, 15). SOLAR-1 results have now validated PIK3CA mutation as a required selection criterion for efficacy of alpelisib, which is an α-specific PI3Ki. SOLAR-1 showed statistically significant and clinically meaningful prolongation of PFS with alpelisib plus fulvestrant compared with placebo plus fulvestrant in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer (PFS, 11 vs. 5.7 months; HR, 0.65; P < 0.001; ref. 7). In our study, 40% of patients had PIK3CA-mutated disease. The PIK3CA-mutated subgroup of our study demonstrated higher CBR (100% vs. 68%) and longer PFS (11.9 vs. 7.5 months) than those without mutation. The longest duration of response (40 months, ongoing) was observed in a patient with TNBC with PIK3CA mutation. Clinical studies do not show differential efficacy of taxanes based on PIK3CA mutations in HER2-negative MBC (16). On the contrary, efficacy of alpelisib, at least in combination with endocrine therapy, is related to PIK3CA mutations. Thus, the observed higher activity of the alpelisib plus nab-paclitaxel combination in the PIK3CA-mutated subgroup of our study is likely being driven by alpelisib. It should, however, be acknowledged that given the single-arm nature of our trial, the relative contribution of each drug in the entire study population or in the PIK3CA-mutated subgroup cannot be determined.

The efficacy seen in our study compares very favorably with what has been reported for single-agent nab-paclitaxel in phase II/III trials, where ORR ranges from 37%–64% (in first-line setting) to 14%–21% (in second line or greater; refs. 17–19). Previous studies of nab-paclitaxel show median PFS ranging from 3 to 6.1 months (17–19). In this context, our observed PFS of almost 12 months in the PIK3CA-mutated group appears very promising. This combination of alpelisib and nab-paclitaxel should be investigated further in randomized studies.

In the phase I portion of our trial, the RP2D of alpelisib was determined without observing any DLTs at the three dose levels, and responses were noted at all three dose levels of alpelisib. The most common toxicities were gastrointestinal, hyperglycemia, and hematologic. Overall incidence of diarrhea was 81%, majority of which was grade 1 or 2, with only 5% reporting grade 3 diarrhea. Rash was noted in 63% of patients and was also mainly grade 1 and 2 in severity (7% grade 3 and no grade 4). All patients in our study received second-/third-generation H1-antihistaminic prophylaxis for rash, which probably contributed to low rates of grade 3–4 rash. It is to be noted that nab-paclitaxel is also associated with some risk of diarrhea and rash, which likely contributed to higher overall rates of diarrhea and rash we observed compared with SOLAR-1 (20). The incidences of grade 3 diarrhea and rash in our study were similar to SOLAR-1 (20). Hyperglycemia is an on-target effect of alpelisib, and grade 3 hyperglycemia was noted in 26% of the patients in our study (no grade 4 hyperglycemia events). One quarter of patients required metformin for management of hyperglycemia. No patient discontinued treatment because of hyperglycemia, rash, or diarrhea. A total of 26% of patients required alpelisib dose reductions for toxicity management. Hematologic toxicity, peripheral neuropathy, and musculoskeletal adverse events are expected toxicities related to nab-paclitaxel, although the rate of grade 3 or higher peripheral neuropathy (2%) was lower than what has been reported previously with this agent. No new toxicity signals associated with either alpelisib or nab-paclitaxel were observed.

It has been shown that hyperglycemia induced by PI3K inhibition leads to an increase in insulin levels, and this glucose-insulin feedback can reactivate PI3K signaling in mouse models even in the presence of PI3Ki (21). Dietary/pharmacologic measures (e.g., ketogenic diet and sodium-glucose cotransporter inhibitors) can diminish this insulin feedback, thus increasing treatment efficacy of PI3Ki (21). Patients with normal metabolic status in our study experienced longer PFS compared with prediabetic/diabetic patients. This effect was remarkably pronounced in the PIK3CA-mutated subgroup. It is plausible that baseline insulin resistance in prediabetic/diabetic patients may have played a role in decreasing the efficacy of the alpelisib. A somewhat similar observation was made in the international SANDPIPER trial, where differences in taselisib efficacy were observed according to geographic distribution (lesser efficacy in patients enrolled in Latin America/Eastern Europe compared with other parts of the world; ref. 15). Possible differences in degree of insulin resistance, diet, and perhaps hyperglycemia management in patients from different geographic regions may have contributed to these findings. These observations highlight the potential role of insulin resistance and glucose-insulin feedback on optimizing clinical efficacy of PI3Kis. The impact of metabolic status/insulin resistance and diet on effectiveness of PI3Kis should be evaluated further in ongoing studies.

Upon gene expression analysis, PIK3CA mutation was associated with enhanced angiogenesis and MYC downregulation. These findings are not surprising, because hyperactivity of PI3K is known to increase tumor angiogenesis and The Cancer Genome Atlas pan-cancer analysis has shown MYC and PIK3CA mutations to be mutually exclusive (22–24). PIK3CA-mutated cancers may be less likely to have oncogenic dysregulation of the MYC axis; however, evasion of PI3K-targeted therapy can occur via MYC/eIF4E amplification, thus this pathway remains potentially important for acquired resistance to PI3K-directed therapy (24). Using CIBERSORTx analysis, we found lower imputed frequency of monocytes and naïve B lymphocytes in PIK3CA-mutated cancers. A small sample size and lack of direct immune cell quantification preclude any definitive conclusions, but several previous preclinical reports have suggested that PI3K hyperactivity blunts tumor immunogenicity (25, 26). If confirmed in other clinical studies, these findings may inform future trial design of PI3Ki combinations (immunotherapy, MYC-targeting agents, VEGF inhibitors, etc.).

In addition to PI3K inhibition, AKT inhibition is also currently being explored as a way to target the PI3K pathway in breast cancer. Two phase II trials have demonstrated that the addition of oral AKT inhibitors to first-line paclitaxel therapy improves PFS in patients with PIK3CA/AKT1/PTEN-altered metastatic TNBC (4, 27). A phase II trial in patients with hormone receptor–positive MBC has also demonstrated improvement in PFS with addition of an AKT inhibitor (capivasertib) to fulvestrant (28). The recently reported IPATunity130 (cohort A) trial, however, failed to show improvement in PFS with addition of the oral AKT inhibitor ipatasertib to first-line paclitaxel in PIK3CA/AKT1/PTEN-altered metastatic TNBC (29). The clinical efficacy of AKT inhibitors in breast cancer, especially the ability of these agents to target altered PIK3CA and PTEN, which are upstream of AKT in the PI3K/AKT pathway, is being investigated in ongoing studies. OS results from IPATunity130 are awaited, and another ongoing phase III trial (NCT03997123) is assessing capivasertib in combination with first-line paclitaxel chemotherapy in patients with metastatic TNBC.

Although the results are intriguing, our study has limitations. As a single-arm trial, the relative contribution of alpelisib versus nab-paclitaxel toward efficacy cannot be determined. The small number of patients in subgroup analyses similarly limits our ability to draw conclusive links between PIK3CA mutation or metabolic status and benefit from alpelisib. Our study does, however, raise important hypotheses to be explored in future work. This combination warrants further investigation in randomized trials. Indeed, an ongoing phase III clinical trial (EPIK-B3, NCT04251533) is assessing alpelisib plus nab-paclitaxel as first- or second-line treatment for patients with advanced TNBC and PIK3CA mutation or PTEN loss. A phase II trial (NCT04216472) evaluating alpelisib plus nab-paclitaxel as neoadjuvant treatment for anthracycline-refractory early-stage TNBC with PIK3CA or PTEN alterations is also currently enrolling patients. Results of these ongoing trials will address the role of alpelisib in TNBC. Other ongoing studies are also evaluating alpelisib in combination with HER2-targeted therapy, antiandrogen therapy, and antiestrogen therapy in biomarker-selected patient populations (NCT03207529, NCT04208178, and NCT03056755).

P. Sharma reports grants and nonfinancial support from Novartis during the conduct of the study; grants and personal fees from Novartis and Merck; grants from Genentech, Celgene, GlaxoSmithKline, and Bristol-Myers Squibb; and personal fees from Pfizer, Puma Biotechnology, Myriad Inc, Exact Life Sciences, Seattle Genetics, Almac Diagnostics, Epic Biosciences, and AstraZeneca outside the submitted work. V.G. Abramson reports grants from Genentech and other from Eisai and Daiichi Sankyo outside the submitted work. A. O'Dea reports personal fees from PUMA Biotechnology, Pfizer, Novartis, AstraZeneca, and Daiichi Sankyo outside the submitted work. I. Mayer reports personal fees from Novartis during the conduct of the study; personal fees from Novartis, Lilly, AstraZeneca, GlaxoSmithKline, AbbVie, Puma, Immunomedics, MacroGenics, Seagen, Cyclacel, and Blueprint; and grants and personal fees from Pfizer and Genentech outside the submitted work. M. Hoffmann reports personal fees from Janssen and Pharmacyclics outside the submitted work. S.K. Williamson reports grants from Novartis and BMS during the conduct of the study and outside the submitted work. Q.J. Khan reports grants from Novartis outside the submitted work. A.K. Godwin reports grants from NIH/NCI and NIGMS during the conduct of the study and personal fees from Sinochips Diagnostics and NanoString outside the submitted work. No disclosures were reported by the other authors.

The funding sources of the study had no role in the design of the study; collection, analysis, or interpretation of the data; or in the writing of this article.

P. Sharma: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. V.G. Abramson: Resources, supervision, investigation, project administration, writing–review and editing. A. O'Dea: Resources, investigation, writing–review and editing. L. Nye: Resources, investigation, writing–review and editing. I. Mayer: Resources, investigation, writing–review and editing. H.B. Pathak: Data curation, formal analysis, investigation, writing–review and editing. M. Hoffmann: Resources, investigation, writing–review and editing. S.R. Stecklein: Formal analysis, investigation, visualization, writing–review and editing. M. Elia: Resources, investigation, writing–review and editing. S. Lewis: Writing–review and editing. J. Scott: Supervision, project administration, writing–review and editing. J.A. De Jong: Supervision, project administration, writing–review and editing. Y.Y. Wang: Data curation, formal analysis, visualization, writing–review and editing. R. Yoder: Data curation, formal analysis, visualization, writing–original draft, project administration, writing–review and editing. K. Schwensen: Data curation, writing–review and editing. K. Finke: Data curation, visualization, writing–review and editing. J. Heldstab: Resources, investigation, writing–review and editing. S. LaFaver: Resources, investigation, writing–review and editing. S.K. Williamson: Resources, Investigation, methodology, writing–review and editing. M.A. Phadnis: Methodology, writing–review and editing. G.A. Reed: Resources, formal analysis, investigation, methodology, writing–review and editing. B.F. Kimler: Data curation, formal analysis, writing–review and editing. Q.J. Khan: Resources, supervision, investigation, writing–review and editing. A.K. Godwin: Conceptualization, resources, supervision, funding acquisition, investigation, methodology, project administration, writing–review and editing.

This work was supported by Novartis, the Cancer Center Support Grant (to the University of Kansas Cancer Center, P30 CA168524, Biospecimen Repository Core Facility, Clinical Pharmacology Shared Resource), University of Kansas Cancer Center, and the National Institute of General Medical Sciences (P20 GM130423 to A.K. Godwin).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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