Practice Update: Oncology

EDITOR’S PICKS 9

Neratinib Efficacy and ctDNA Detection of HER2 Mutations in HER2 Non-Amplified Metastatic Breast Cancer Clinical Cancer Research Take-home message • Patients with confirmed HER2-mutated non-amplified metastatic breast cancer were treated with neratinib to evaluate outcomes in this single-arm phase II trial. Of 381 tumors sequenced centrally, 9 demonstrated HER2 mutation. A further 13 cases were identified locally. Neratinib was administered to 16 patients. The clinical benefit rate was 31%, with 1 complete response, 1 partial response, and 3 patients with stable disease ≥24 weeks. The median progression-free survival was 16 weeks. Despite prophylactic administration of loperamide, the most prevalent grades 2 and 3 side effect was diarrhea, which affected 69% of patients. Baseline ctDNA sequencing had a sensitivity of 79% and a specificity of 100% for identifying the HER2 mutation. • Neratinib demonstrates activity in patients with HER2-mutated nonamplified metastatic breast cancer, and ctDNA sequencing is a noninvasive technique to effectively identify patients with HER2-mutated cancers who may be eligible to participate in clinical trials. T he availability of HER2-targeted therapies has dramatically improved outcomes for patients with HER2-positive breast cancer. Although ongoing studies such as NSABP B47 are addressing the role of trastuzumab in HER2-negative breast cancer, generally HER2-directed therapies are only administered to the roughly 20% of breast cancer patients who have HER2 amplification. However, in patients who are HER2-negative by immunohistochemistry (IHC) and fluorescence-in-situ-hybridization (FISH), breast cancer genome sequencing has identified HER2-activating mutations. Preclinical work has documented that the majority of these HER2 somatic mutations are activating mutations, which are likely driving tumorigenesis in a small percent- age of breast cancer patients overall (2%–4%). Furthermore, the presence of these mutations confers resistance to the reversible HER2 inhibitor lapatinib, but not to the irreversible HER2 inhibitor neratinib. In the current study, 22 patients of 381 were found to harbor HER2 mutations, and the authors report a CBR of 31% and PFS of 16 weeks when neratinib was administered as a single agent. Circulating tumor DNA (ctDNA) sequencing was found to be accurate in identifying the cases. These data add to data from other studies which have indicated that the identification of HER2 mutations may offer additional targeted approaches for a small subset of breast cancer patients. Ongoing basket-trial designs, such as the design of the SUMMIT trial, are investigating the clinical potential of neratinib in a broad spectrum of tumor types that harbor HER2 mutations. Data from these types of trials will hopefully lead to a more personalized approach to treatment in oncology. COMMENT By Reshma L. Mahtani DO

Abstract PURPOSE Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essen- tial for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. EXPERIMENTAL DESIGN This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemother- apy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-dig- ital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hyper- methylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronic- ity, and treatment line. RESULTS Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemo- therapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concen- tration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named “good” or “bad ctDNA respond- ers”). In multivariate analysis, patients belonging to the group called “good ctDNA responder” (n = 58) versus “bad ctDNA responder” (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001). CONCLUSION This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonam- plified metastatic breast cancer, Clin Cancer Res 2017 Aug 15;[EPub Ahead of Print], CX Ma, R Bose, F Gao, et al. www.practiceupdate.com/c/57071

Dr. Mahtani is Assistant Professor, Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System.

VOL. 1 • NO. 3 • 2017