J. Cortés Castán

PURPOSE Human epidermal growth factor receptor 2 (HER2)–targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer. METHODS In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review. RESULTS In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points—clinical benefit rate, duration of response, and reduction in target lesion measurement—tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC). CONCLUSION Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

Selective inhibition of the mitogen activated protein kinase (MAPK) pathway with either BRAF or MEK inhibition has emerged as the key component for the treatment of BRAF-mutant metastatic melanoma. New evidence from several phase III trials suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival (PFS). Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma seen with the monotherapy treatment with a BRAF inhibitor are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for metastatic melanoma patients compared to single agent BRAF inhibitors.

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 –