Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial

Abstract

Purpose There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)–based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial. Patients and Methods Women with localized TNBC (T2/N0–2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS. Results Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. Conclusion This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

“…The reported preclinical studies and clinical trials reported the observation that high anticancer efficacy of PTX/LCL161 co-therapies (including breast and lung cancers) [47][48][49]. Our discovery of the essential role of memTNF-mediated cell death in these effects defines the mechanistic rationale that can explain how this observed synergism actually occurs.…”

“…Given that IAP proteins block apoptosis caused by TNF, and considering that IAP antagonists have profound effects in potentiating solTNF-induced apoptosis [44][45][46], we hypothesized a combination treatment with IAP antagonists Smac mimetics (S) would further sensitize cancer cells to MTA-induced apoptosis. Currently, several Smac mimetics are being evaluated in clinical trials (https://clinicaltrials.gov) and combination of LCL161 with PTX has shown synergistic effects on several cancers [47][48][49], but the mechanism remains largely unknown.…”

Future Therapeutic Directions for Smac-Mimetics

“…As discussed above, the chemotherapy paclitaxel has been shown to potentiate LCL161 mediated killing in solid tumors, including Triple Negative Breast Cancer (TNBC) [124,[134][135][136]. Phase II clinical trials were initiated [137], following Phase I trials that indicated that LCL161 plus paclitaxel therapy is well tolerated [134]. Interestingly, for this study the TNF-based Gene expression Signature (GS) was determined for each patient and used as a predictor of sensitivity to SM-mediated cell death [137].…”

“…Phase II clinical trials were initiated [137], following Phase I trials that indicated that LCL161 plus paclitaxel therapy is well tolerated [134]. Interestingly, for this study the TNF-based Gene expression Signature (GS) was determined for each patient and used as a predictor of sensitivity to SM-mediated cell death [137]. Bardia and colleagues conducted a global trial incorporating molecular pre-screening to investigate the neoadjuvant treatment of LCL161 and paclitaxel in TNBC patients assigned as GS-positive (more likely to respond to SM treatment) vs. GS-negative (less likely to respond) [137].…”

“…Interestingly, for this study the TNF-based Gene expression Signature (GS) was determined for each patient and used as a predictor of sensitivity to SM-mediated cell death [137]. Bardia and colleagues conducted a global trial incorporating molecular pre-screening to investigate the neoadjuvant treatment of LCL161 and paclitaxel in TNBC patients assigned as GS-positive (more likely to respond to SM treatment) vs. GS-negative (less likely to respond) [137]. Of 207 patients, 30.4% had a GS-positive score and combination treatment was more effective than paclitaxel alone treatment.…”