Javier Cortés

Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PURPOSEnThe combination of pertuzumab and trastuzumab resulted in a clinical benefit rate (CBR) of 50% in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer whose disease progressed during prior trastuzumab-based therapy. To define whether this previously observed encouraging activity was a result of the combination of pertuzumab and trastuzumab or of pertuzumab alone, we recruited a third cohort of patients who received pertuzumab without trastuzumab. We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on pertuzumab monotherapy.nnnPATIENTS AND METHODSnTwenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) until progressive disease or unacceptable toxicity. Seventeen patients with disease progression continued to receive pertuzumab (at the same dose), with the addition of trastuzumab (4 mg/kg loading dose and then 2 mg/kg weekly or 8 mg/kg loading dose and then 6 mg/kg every 3 weeks).nnnRESULTSnAll 29 patients enrolled for pertuzumab monotherapy experienced disease progression. The objective response rate (ORR) and CBR were 3.4% and 10.3%, respectively, during pertuzumab monotherapy. With the addition of trastuzumab, the ORR and CBR were 17.6% and 41.2%, respectively. Progression-free survival was longer with combination therapy than pertuzumab monotherapy (17.4 v 7.1 weeks, respectively). Treatment was well tolerated with minimal cardiac dysfunction.nnnCONCLUSIONnAlthough pertuzumab has some activity in patients with HER2-positive breast cancer that progressed during therapy with trastuzumab, the combination of pertuzumab and trastuzumab seems to be more active than monotherapy.

Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial

Background: PI3K pathway activation is a hallmark of hormone receptor-positive (HR+) BC cells resistant to endocrine therapy (ET). Preclinical and early clinical data suggest that combining the pan-PI3K inhibitor BUP (BKM120) with ET may provide clinical benefits in this setting. BELLE-2 (NCT01610284) is the first randomized Phase III trial to assess the efficacy and safety of a PI3K inhibitor combined with FULV in HR+ advanced BC, including a prospective analysis of whether PI3K pathway activation status measured in archival tumor tissue and ctDNA is predictive of clinical benefit. Methods: Postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to aromatase inhibitor therapy were enrolled. After a 14-day run-in with FULV (500 mg), patients (pts) were randomized (1:1) to receive oral BUP (100 mg/day) or placebo (PBO) with FULV (500 mg per standard of care). Randomization of all pts was stratified by PI3K pathway status measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, non-activated, unknown) and visceral disease status (present, absent). Baseline PIK3CA mutation status in ctDNA was assessed in a subset of 587 pts at trial entry. The primary endpoint was locally-assessed progression-free survival (PFS; RECIST v1.1) in the full population and PI3K pathway-activated group. Secondary endpoints included overall survival, safety, overall response rate (ORR), and clinical benefit rate (CBR). Results: 1147 pts received FULV with BUP or PBO, with 187 (16%) ongoing at data cut-off. Baseline characteristics were well balanced between the two arms: median age was 62 years, 98% had ECOG performance status of 0/1, 61% had visceral disease, 69% were sensitive to prior ET, 28% had received prior chemotherapy for metastatic BC. BELLE-2 met its primary endpoint in the full population (Table). In pts with PI3K pathway-activated tumor tissue, PFS increase for BUP+FULV vs PBO+FULV did not meet the planned endpoint. Among pts with PIK3CA status measured in ctDNA, median PFS, ORR, and CBR were significantly improved for BUP+FULV vs PBO+FULV in pts with PIK3CA-mutant tumors but not pts without. The most common Grade 3/4 adverse events (AEs; ≥5% of pts; BUP+FULV vs PBO+FULV) in all pts were increased alanine aminotransferase (26 vs 1%), increased aspartate aminotransferase (18 vs 3%), hyperglycemia (15 vs 0.2%), and rash (8 vs 0%). The most common reasons for treatment discontinuation were disease progression (54 vs 73%) and AEs (13 vs 2%). Conclusions: BELLE-2 met its primary endpoint in the full population. Prespecified analyses showed that characterizing PIK3CA mutation in ctDNA at trial entry identifies pts with endocrine- resistant HR+/HER2–advanced BC, for whom BUP+FULV results in meaningful clinical benefits. Citation Format: Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortes J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Hachemi S, Le Mouhaer S, Di Tomaso E, Urban P, Massacesi C, Campone M. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-01.

Abstract OT1-03-14: SANDPIPER: Phase III study of the PI3-kinase inhibitor taselisib (GDC-0032) plus fulvestrant in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer enriched for patients with PIK3CA-mutant tumors

Background:PIK3CA mutations are one of the most frequent genomic alterations in breast cancer (BC), being present in ∼40% of estrogen receptor (ER)-positive, HER2-negative breast tumors. PIK3CA mutations promote growth and proliferation of tumors and mediate resistance to endocrine therapies in BC. Taselisib is a potent and selective PI3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα. Taselisib has enhanced activity against PIK3CA-mutant BC cell lines, and clinical data include confirmed partial responses in patients with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Trial design: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate efficacy and safety of taselisib plus fulvestrant in patients with ER-positive, HER2-negative locally advanced or metastatic BC. Patients will be randomized 2:1 to receive either taselisib (4 mg daily) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Randomization will be stratified by visceral disease, endocrine sensitivity, and geographical region. The study enriches for patients with PIK3CA-mutant tumors who will be randomized separately from patients with non-mutant tumors. Eligibility: Postmenopausal women with ER-positive, HER2-negative, locally advanced or metastatic BC are eligible if they have disease recurrence or progression during or after aromatase inhibitor treatment. A valid PIK3CA-mutation result via central assessment is required prior to enrollment. Aims: The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) in patients with PIK3CA-mutant tumors. Other endpoints include overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Efficacy in patients without PIK3CA-mutant tumors will be an exploratory endpoint. Statistical methods: The primary efficacy analysis population will include all randomized patients with PIK3CA-mutant tumors. Patients will be grouped according to treatment arm assigned at randomization. Median PFS and OS will be estimated using Kaplan-Meier methodology in each treatment arm. Cox proportional-hazards models will be used to estimate the hazard ratio with 95% confidence intervals (CIs). ORR, CBR, and their 95% CIs will be estimated by treatment arms. Duration of objective response will be estimated by treatment arms using the Kaplan-Meier methodology. Quality of life will be analyzed and summarized by treatment arms. Safety will be analyzed for all treated patients according to actual treatment received. Accrual: Target enrollment is 600 pts from ∼165 sites and ∼23 countries. The study is open for enrollment and 11 patients have been enrolled as of May 31, 2015. Clinicaltrials.gov ID: NCT02340221. Contact information: For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Citation Format: Baselga J, Cortes J, De Laurentiis M, Dieras V, Harbeck N, Hsu J, Jin H, Schimmoller F, Wilson TR, Im Y-H, Jacot W, Krop IE, Verma S. SANDPIPER: Phase III study of the PI3-kinase inhibitor taselisib (GDC-0032) plus fulvestrant in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer enriched for patients with PIK3CA-mutant tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-14.

Abstract OT2-3-09: Phase III randomized study of the oral pan-PI3K inhibitor BKM120 with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer resistant to aromatase inhibitor – BELLE-2

Background: The PI3K/AKT/mTOR pathway has been reported altered in up to 40% of hormone receptor-positive (HR+) breast cancers (BC). Furthermore, pathway activation has been implicated in resistance to endocrine therapy, including aromatase inhibitors (AI). BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In combination with fulvestrant, BKM120 has demonstrated pro-apoptotic effects in vitro, and achieved near-complete tumor regression in HR+ PIK3CA-mutated estrogen-independent xenografts. Preliminary clinical activity was observed with BKM120 in patients with BC, both as a single agent and in combination with letrozole (Mayer, et al. ASCO 2012: #510) or trastuzumab (Saura, et al. SABCS 2011: #PD09-03). Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic BC that progressed on or after AI treatment (BELLE-2; CBKM120F2302; NCT01610284). After a 14-day fulvestrant run-in phase to allow determination of tumor PI3K pathway activation status, patients are randomized (1:1) to receive continuous BKM120 (100 mg/d) or placebo, and fulvestrant 500 mg at C1D15, and D1 of all cycles thereafter; 1 cycle=28 days. Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by IHC), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason. Eligibility criteria include: postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to AI (progression while on AI, or within 4 wks [metastatic] or 12 mos [adjuvant] of last AI dose); no more than 1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers. Co-primary endpoints: PFS in the full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints: PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate (both in full, PI3K-activated, PI3K non-activated/unknown populations), safety (CTCAE 4.03), pharmacokinetics of BKM120 and fulvestrant, and patient-reported quality of life (EORTC QLQ-C30 and QLQ-BR23). Statistical methods: PFS and OS will be estimated using the Kaplan–Meier method for both full and PI3K pathway activated populations. Both primary and key secondary endpoints will be tested using a stratified log-rank test at levels α governed by a graphical gate-keeping procedure. A stratified Cox regression will be used to estimate the hazard ratio, along with two-sided 95% confidence interval. Target accrual: Estimated enrollment for BELLE-2 is 842 patients. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe, Asia and Africa. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-09.