Richard Bryce

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. METHODS We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. FINDINGS Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. FUNDING Wyeth, Pfizer, Puma Biotechnology.

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial

Importance Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. Objective To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. Design, Setting, and Participants In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Interventions Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. Main Outcome and Measures The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. Results The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed. Conclusions and Relevance In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm. Trial Registration clinicaltrials.gov Identifier: NCT00915018.

Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

Abstract S5-02: Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET)

Background: Neratinib (Puma Biotechnology Inc), an irreversible pan-HER tyrosine kinase inhibitor, was evaluated in a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET) to assess for improved invasive DFS (iDFS) in women with early-stage HER2+ breast cancer (BC) after trastuzumab-based therapy (clinicaltrials.gov NCT00878709). Primary efficacy analysis at 2-yrs demonstrated iDFS of 93.9% and 91.6% neratinib and placebo, respectively (HR 0.67, 95% CI 0.50–0.91; P=0.009). Greater benefit was observed in hormone-receptor (HR)-positive and centrally- confirmed HER2 subsets – HR 0.51, p=0.001 and HR 0.51 p=0.002, respectively [Chan et al. ASCO 2015]. We report an exploratory analysis of efficacy after 3-yrs of follow-up. Methods: Women with HER2+ BC were randomly assigned to oral neratinib 240 mg/day or matching placebo for 1 year, stratified by nodal status, HR-status and prior trastuzumab regimen. The study was initiated in April 2009 with recruitment ceased in October 2011, limiting follow-up to 2 years. In January 2014, follow-up was restored to 5 years. During year 1, physical examinations were performed at 3-monthly intervals, at 4-monthly intervals in year 2 and then 6-monthly to 5-years; with mammography performed annually. Patients were asked to re-consent following ethics approval of the January 2014 protocol amendment. During years 3 to 5, disease-free survival (DFS) and survival events were identified from medical records. A descriptive analysis of iDFS, to investigate the durability of neratinib effect was performed after 3-yrs of follow-up. Data for overall survival remains blinded until 248 events have occurred. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using stratified Cox proportional-hazards models. Results: The intention-to-treat population included 2840 patients (neratinib, N 1420; placebo, P=1420). Central HER2 testing has now been performed in 2041 pts (72%) - HER2-positive 1709 (84%) and HER2-negative 332 (16%). Pts were randomized within 12-months of completion of prior adjuvant trastuzumab in 2297 (81%) pts. Three-yr iDFS for ITT population demonstrated HR 0.74, [95% CI 0.56-0.96]. In the ITT pts who were randomized within 1-yr of trastuzumab completion, iDFS HR 0.72 [0.54-0.95]. For pts who had centrally-confirmed (cc) HER2-positive disease , iDFS HR 0.70 [0.50-0.98]. Pts with HR-positive disease had 3-yr iDFS HR 0.57 [0.39-0.82] and HR-negative pts HR 0.96 [0.67-1.45]. Overall survival data are not yet mature. Conclusions: Exploratory analysis at 3-years supports the significant benefit seen in the primary analysis of 12-months of neratinib following adjuvant trastuzumab-based therapy. Patients who consistently derived the greatest benefit were 1) patients who received neratinib within 12 months of completing adjuvant trastuzumab; 2) centrally confirmed HER2 positive patients and 3) HR positive patients. Citation Format: Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harker G, Masuda N, Neskovic Konstantinovic ZB, Petrakova K, Guerrero Zotano AL, Iannotti N, Rodriguez GI, Tassone P, von Minckwitz G, Ejlertsen B, Chia SKL, Mansi J, Barrios CH, Buyse M, Wong A, Bryce R, Ye Y, Martin M. Neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis from a phase 3 randomized, placebo-controlled, double-blind trial (ExteNET). [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 S5-02.

Abstract PD2-08: Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial

Background: Somatic mutations in ERBB2 are a new class of oncogenic drivers in HER2–non amplified MBC. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits the growth of ERBB2-mutant breast tumors in preclinical models and has encouraging single-agent clinical activity in patients (pts) with ERBB2-mutant, HER2–non amplified MBC. Bi-directional signaling between HER2 and ER may limit the effectiveness of endocrine and HER2 directed therapy, if each is given alone, in ER+ MBC with ERBB2 amplifications/mutations. Preclinical data suggest that dual blockade of ER and HER2 signaling results in enhanced anti-tumor activity in ER+ HER2+ MBC. SUMMIT, a multicenter multi-histology phase II 9basket9 trial, is investigating the efficacy of neratinib monotherapy (in ER+ and ER– pts) and neratinib + fulvestrant (ER+ pts only) in ERBB2-mutant MBC. Methods: MBC pts with ERBB2 mutations documented by local testing were eligible and received oral neratinib 240 mg qd. Pts with ER+ MBC received fulvestrant 500 mg, a selective ER degrader, in addition to neratinib on d1 & 15 of month 1 then on d1 q4w. Patients received high dose loperamide prophylaxis during cycle 1. Primary endpoint is objective response rate (ORR) at 8w, defined using RECIST 1.1 and/or modified PERCIST assessments. Secondary endpoints include ORR, clinical benefit rate (CBR), progression free survival (PFS), and safety. Mutation profiling and central confirmation of ERBB2 mutation(s) from available fresh or archival tumor tissues and plasma DNA were performed retrospectively by next-generation sequencing (MSK-IMPACT). Clinicaltrials.gov: NCT01953926. Results: As of 23 Sep 2016, 35 efficacy-evaluable ERBB2-mutant MBC pts received neratinib, either as monotherapy (n=24) or in combination with fulvestrant (n=11). Efficacy findings are shown in the table. The overall safety profile of neratinib + fulvestrant was similar to that previously reported with neratinib monotherapy. Grade 3 diarrhea rate was 24% with neratinib monotherapy and 18% with neratinib + fulvestrant. Conclusions: Encouraging clinical activity has been observed with neratinib + fulvestrant in heavily pretreated pts with ERBB2-mutant, ER+ MBC. Clinical efficacy in the ER+ MBC cohort met pre-specified efficacy requirements; a confirmatory trial of neratinib + fulvestrant for targeting ERBB2 mutations in ER+ MBC is warranted. The safety profile of neratinib was acceptable and diarrhea was manageable with loperamide prophylaxis. Citation Format: Hyman D, Piha-Paul S, Saura C, Arteaga C, Mayer I, Shapiro G, Loi S, Lalani A, Xu F, Cutler R, Butturini A, Bryce R, Meric-Bernstam F, Baselga J, Solit D. Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-08.

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

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 9basket9 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 study9s pre-specified efficacy requirements according to a Simon9s 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, Rodon 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.

Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.

117 Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer (BC). ExteNET is an ongoing multicenter randomized placebo-controlled phase III trial evaluating the efficacy and safety of a 1-year course of neratinib in patients with early-stage HER2+ BC after trastuzumab-based adjuvant therapy (clinicaltrials.gov: NCT00878709). METHODS Women with locally-confirmed early-stage HER2+ BC were randomly assigned to oral neratinib 240mg/day or matching placebo for 1 year. Archived diagnostic tumor samples were submitted for HER2 gene amplification testing at a central laboratory. Primary endpoint: invasive disease-free survival (iDFS). Secondary endpoints: DFS including ductal carcinoma in situ (DFS+DCIS); distant disease-free survival (DDFS); time to distant recurrence (TDR). Stratified Cox proportional-hazards models were used to estimate hazard ratios (HR) for the ITT and amended ITT (aITT) populations; unstratified models were used for the centrally confirmed HER2 population. Treatment groups were compared using 2-sided log-rank tests. RESULTS The ITT population included 2840 patients (neratinib, N=1420; placebo, N=1420). The higher-risk aITT population (i.e. node-positive disease and randomized ≤1 year of completing prior trastuzumab) included 1873 patients (neratinib, N=938; placebo, N=935). Of the tumor samples analyzed, 1463 (86%) were centrally confirmed (neratinib, N=741; placebo, N=722). CONCLUSIONS Neratinib significantly improves iDFS in trastuzumab-treated early-stage HER2+ BC patients. An enhanced treatment effect is observed with neratinib in women with centrally confirmed HER2+ tumors. CLINICAL TRIAL INFORMATION NCT00878709. [Table: see text].