Abstract PD5-05: Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial

Abstract

Background: Somatic ERBB2 (HER2) mutations occur in approximately 2% of patients with breast cancer and are found in a predominantly mutually exclusive manner with ERBB2 amplification. These mutations result in increased signaling and oncogenic transformation. Neratinib, a pan-ERBB irreversible tyrosine kinase inhibitor, potently inhibits growth of ERBB2 mutant tumor cell lines and xenografts. An ongoing signal-seeking phase II 'basket' study is evaluating neratinib in patients with multiple histologies harboring ERBB2 mutations (NCT01953926). Novel mutations identified in enrolled patients were characterized for biologic activity in a variety of in vitro model systems. A preliminary analysis of the HER2 non-amplified metastatic breast cancer cohort is presented. Methods: Patients with ERBB2 mutant metastatic breast cancer documented by local testing methods received single-agent oral neratinib 240 mg once daily until progression or intolerable toxicity. High-dose loperamide prophylaxis was mandatory during cycle 1. The primary endpoint was the objective response rate at 8 weeks, defined using anatomic (RECIST 1.1) and/or metabolic (PET Response Criteria) assessments. Secondary endpoints were best overall response rate, clinical benefit rate, progression-free survival, duration of response, and safety. Results: 17 patients with metastatic breast cancer were enrolled and received neratinib (13 patients are evaluable for efficacy to date). Patients had a median of 3 prior anticancer regimens. Other baseline characteristics were: median age 59 years; bone involvement 71%; visceral disease 82%. Tumor characteristics were: ductal/lobular 76%/24%; ERBB2 mutation single nucleotide variants/indels 82%/18%; HER2 amplified/non-amplified 0%/100%; hormone receptor positive/negative 82%/18%. Five patients (39%) had an objective response at 8 weeks (95% CI 14–68%). In the patients who responded, ERBB2 mutations were: 1 complete response (L755S); 4 partial responses (L755S, V777L, V777L, and L869R). The most common all-grade adverse events (in ≥15% of patients) across all cohorts (n=93) were: diarrhea (62%), fatigue (28%), nausea (36%), vomiting (30%), anemia (15%), and constipation (29%). The most common grade 3/4 adverse event was diarrhea (14%, all grade 3). Updated efficacy results, centralized genomic analyses on archival tumor samples, and in vitro characterization of novel ERBB2 mutants will be presented. Conclusions: Single-agent neratinib shows encouraging signs of clinical activity in patients with heavily pretreated, ERBB2 mutant, HER2 non-amplified metastatic breast cancer. The breast cancer cohort demonstrated sufficient activity to meet the study's pre-specified efficacy requirements according to a Simon's two-stage design, and suggests that a confirmatory trial of neratinib for targeting ERBB2 driver mutations in metastatic breast cancer is warranted. Safety was acceptable and diarrhea was manageable with loperamide prophylaxis. Citation Format: Hyman DM, Piha-Paul SA, Rodón J, Saura C, Puzanov I, Shapiro GI, Loi S, Joensuu H, Hanrahan AJ, Modi S, Lalani AS, Xu F, Garza SJ, Cutler RE, Bryce R, Meric-Bernstam F, Baselga J, Solit DB. Neratinib for ERBB2 mutant, HER2 non-amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, multi-histology phase II basket trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-05.

Implementing Genome-Driven Oncology

“…Indeed, AKT inhibitors have recently shown marked efficacy in AKT1 E17K-mutation-positive solid tumors in a basket study, and clinical development is now progressing toward regulatory approval (Hyman et al, 2015b). Similarly, a basket study of the pan-HER kinase inhibitor neratinib in solid tumors harboring activating mutations in ERBB2 and ERBB3 , which also occur infrequently across a large number of cancer types, has reported promising preliminary results (Bose et al, 2013; Hyman et al, 2016). …”

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations

“…In the HER2 mutation-positive breast cancer cohort (n=19), an objective response at week 8 was documented in 6 (32%) patients, with clinical benefit in 8 (42%) patients. Median PFS was 4.0 (range, 2.0-4.0) months [79]. Tumors were HER2 nonamplified in all cases and patients had received a median of 4 (range, 0-11) previous treatments in the metastatic setting.…”

“…An interim analysis from one of these trials (SUMMIT) has recently been presented [79]. SUMMIT is an international open-label, phase II study evaluating neratinib in multiple cohorts of patients with solid tumors with activating HER2, HER3 or EGFR mutations or with EGFR gene amplification.…”

“…In vitro data suggest that cells harboring these mutations are highly sensitive to neratinib [25], and early clinical data with neratinib in patients with breast cancers carrying HER2 mutations are promising [79]. Although these activating mutations are rare (approximately 2% of patients with breast cancer), this patient population could constitute a very interesting niche for the development of neratinib.…”

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

“…Data is emerging that targeting some of these alterations, such as AKT and HER2 mutations, indeed may have antitumor efficacy. 1,2 Most proof-of-principle genomically-selected trials are conducted in the metastatic setting, while many molecular characterization efforts such as The Cancer Genome Atlas (TCGA) were performed in operable breast cancer. 3 In order to effectively design and interpret genotype-selected trials, it is critical to determine the genomic profile of patients with metastatic breast cancer (MBC), the frequency of genomic alterations as well as co-alterations, and to determine the impact of common alterations on prognosis.…”