A phase II, open-label, neoadjuvant, randomized study of LCL161 with paclitaxel in patients with triple-negative breast cancer (TNBC).

Abstract

1014 Background: LCL161 is a small molecule that induces apoptosis by inactivating inhibitor of apoptosis proteins (IAPs). LCL161 preferentially synergizes with paclitaxel in TNBC models with a defined gene expression signature (GS) that reflects the biology of IAP antagonists. Here we present preliminary safety and efficacy data from a completed Phase II study of neoadjuvant LCL161 with paclitaxel in patients with GS+ and GS– TNBC (NCT01617668). Methods: Women with operable, newly diagnosed TNBC (T2, N0–N2, M0) were stratified into GS+ and GS– groups upfront, then randomized to receive paclitaxel (80 mg/m2/week) ± LCL161 (1800 mg/week) for 12 weeks. Patients then received surgery to assess pathological complete response (pCR), followed by investigator’s choice of adjuvant therapy. Primary objective: To assess whether LCL161 enhances the efficacy of paclitaxel in patients with GS+ or GS– TNBC, defined by a ≥ 7.5% increase in pCR rate after 12 weeks of combination treatment vs paclitaxel alone. Results: All 209 treated patients completed the study; 17/106 patients (16.0%) in the combination arm and 17/103 patients (16.5%) in the control arm achieved pCR. In the GS+ group (30.1% of patients), 13/34 patients (38.2%) in the combination arm and 5/29 patients (17.2%) in the control arm achieved pCR; the posterior probability of a ≥7.5% increase in pCR rate was 88.8%. In the GS– group, 4/72 patients (5.6%) in the combination arm and 12/73 patients (16.4%) in the control arm achieved pCR. The most frequent adverse events (AEs; ≥ 30% of patients, all grades) are shown in the table below. Serious AEs of pyrexia (combination 17.9%; control 1.0%), pneumonia (10.4%; 1.9%), and pneumonitis (9.4%; 0%) were significantly increased in the combination arm. Conclusions: Neoadjuvant LCL161 with paclitaxel shows promising signs of efficacy in a GS+ subset of TNBC (~30% of patients), but with notable toxicity at the 1800 mg/week dose. Clinical trial information: NCT01617668. LCL161 + paclitaxel (N = 106), % Paclitaxel (N = 103), % All grades G3/4 All grades G3/4 Diarrhea 71.7 5.7 22.3 1.0 Alopecia 67.9 – 67.0 1.0 Pyrexia 48.1 4.7 9.7 – Fatigue 45.3 3.8 36.9 – Nausea 42.5 0.9 31.1 – Rash 41.5 3.8 27.2 – Neutropenia 39.6 23.6 10.7 3.9 Headache 33.0 0.9 17.5 –