Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer.

Abstract

143 Background: Activation of the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways has been implicated in endocrine therapy resistance in pts with advanced HR+ breast cancer (BC). BYL719 (BYL), an α-isoform selective PI3K inhibitor and LEE011 (LEE), a CDK4/6 inhibitor have demonstrated clinical activity in pts with advanced HR+ BC and advanced solid tumors, respectively. In preclinical HR+ BC models, the combination of LEE, BYL, and letrozole (LET) had enhanced antitumor activity vs either agent alone. Here we report results from Arm (A)1 (LEE + LET) and A2 (BYL + LET) of the Ph Ib part of a Ph Ib/II, 3-arm study of LEE, BYL, and LET in pts with advanced ER+ BC (CLEE011X2107/NCT01872260). Methods: Postmenopausal women with advanced ER+, HER2− BC receive daily oral doses of LEE (3-wks on/1-wk off; A1) or BYL (continuous; A2), plus fixed, daily LET (2.5 mg, continuous), as part of a 28-day cycle. Primary objective: determine the MTD and/or RP2D of A1 and A2. Dose escalation is guided by a Bayesian Logistic Regression Model using the escalation with overdose control principle and real-time PK. Safety and preliminary efficacy are also assessed. Results: As of March 28, 2014, 10 pts have been treated with 600 mg LEE + LET (A1), and 7 pts with 300 mg BYL + LET (A2). One DLT was observed (A1: Grade [G]4 neutropenia; data cut-off: May 15). Common (all grade >30%) study drug-related AEs (all grade/G3–4) were: A1: neutropenia (90%/50%) and nausea (40%/0%); A2: hyperglycemia (57%/14%), decreased appetite, diarrhea, and nausea (43%/0% each). PK for LEE and BYL on Days 1 and 21, and LET on Day 1, are comparable to historic single-agent data. PK of LET at steady state is being evaluated. In A1, 6 pts had known responses: 1 PR, 2 SD, 1 NCRNPD, and 2 PD. In A2 5 pts had known responses: 2 SD, and 3 NCRNPD. Conclusions: LET plus LEE or BYL had an acceptable safety profile and preliminary signs of clinical activity have been observed. Upon determination of the MTD/RP2D in A1 and A2, enrollment into A3 (LEE + BYL + LET) will commence. The randomized Ph II part of the trial will compare LET + LEE or BYL with LET + LEE + BYL. MONALEESA-2 (CLEE011A2301/NCT01958021), a Ph III, randomized, double-blind, placebo-controlled study of LEE + LET in untreated advanced HR+ BC is currently recruiting pts. Clinical trial information: NCT01872260.

Cell cycle proteins as promising targets in cancer therapy

“…The first clinical phase I trial involving various advanced RB-positive cancers reported partial responses in a patient with CCND1 -amplified, PIK3CA -mutated breast cancer and a patient with CCND1 -amplified melanoma; the major dose-limiting toxicities were neutropaenia and thrombocytopaenia 163 . Ribociclib was then studied in combination with hormonal therapy for postmenopausal women with ER+ HER2- advanced breast cancer and exhibited preliminary signs of clinical activity (TABLE 2) 164 . These phase Ib results await validation in a large phase III study (MONALEESA-2) (see Supplementary Information S1 (table)).…”

“…Indeed, combination of PI3Kα and CDK4/6 inhibition caused synergistic tumour regression in several PIK3CA -mutant breast cancer xenograft models 176 . The efficacy of combining ribociclib with a PI3Kα inhibitor (BYL719) and an aromatase inhibitor (letrozole) is currently being investigated in a phase Ib study for advanced ER+ breast cancer 164 . Finally, following an increase in efficacy revealed in preclinical studies, combination of ribociclib with an mTOR inhibitor (everolimus) and an aromatase inhibitor (exemestane) is also currently under clinical investigation in ER+ breast cancer 177 .…”

Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

“…The dose expansion phase will further explore tolerability of the triplet in patients naïve to CDK4/6 therapy and of the exemestane/ribociclib doublet in patients with prior CDK4/6 inhibitor therapy. Similarly, phase I data for the doublet combinations of ribociclib/letrozole and ribociclib/apelisib have been presented (Munster et al 2014). Both arms demonstrated acceptable safety profiles, with neutropenia observed as expected with ribociclib.…”

CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

“…Another preclinical study assessed the combination of ribociclib, endocrine therapy (letrozole or fulvestrant) and alpelisib or the PI3K-pan class I-inhibitor BKM120. Profound tumor regression was noted in all four murine ER-positive breast cancer models tested (78). Clinical trials of ribociclib as monotherapy or in combination with targeted therapies and/or hormonal therapy are ongoing in the preoperative and metastatic setting (Table 3).…”

“…Clinical trials of ribociclib as monotherapy or in combination with targeted therapies and/or hormonal therapy are ongoing in the preoperative and metastatic setting (Table 3). Preliminary results from a phase I study of ribociclib combined with exemestane and everolimus suggested that triplet therapy was tolerable, therefore a phase II trial is ongoing (78). Furthermore, the combination of ribociclib, letrozole and alpelisib is currently being tested and results are pending.…”