Polly Niravath

Interventions to improve endocrine therapy adherence in breast cancer survivors: what is the evidence?

PurposeEndocrine therapy reduces the risk of breast cancer recurrences and mortality in hormone receptor-positive (HR+) breast cancer survivors. However, non-adherence to treatment remains a significant problem. The aim of this study was to review current literature and ongoing trials to identify interventions employed to improve adherence to adjuvant endocrine therapy (AET) in breast cancer survivors.MethodsWe searched PubMed and the National Library of Medicine registry of clinical trials using the terms “breast cancer” and “adherence” or “compliance” and “intervention” and “medication” or “endocrine therapy” or “hormone therapy” to identify published studies as well as ongoing clinical trials.ResultsThree hundred and sixty-three studies were identified; five studies met the inclusion criteria. Most studies enrolled postmenopausal women diagnosed with early stage HR+ breast cancer. Providing educational materials was the most common intervention implemented to improve adherence to one or more aromatase inhibitors. None of the studies found a significant improvement in adherence with the intervention evaluated. Twelve clinical trials investigating various interventions, mostly based on technology, to improve AET adherence were also identified.ConclusionsImproving adherence to AET in HR+ breast cancer survivors is an urgent medical need. While newer clinical trials are overcoming some of the limitations seen with published studies, tailored interventions led by clinicians need further investigation.Implications for cancer survivorsOur study highlights the unmet clinical need to develop and test feasible interventions to improve AET adherence in HR+ breast cancer survivors to extend their long-term survival.

Abstract OT1-1-11: TBCRC 022: Phase II Trial of Neratinib for Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast cancer and Brain Metastases

Background: 1/3 of women with metastatic HER2+ breast cancer will develop central nervous system (CNS) metastases yet evidence-based treatments for women with progressive CNS disease are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4 which has promising activity in HER2+ breast cancer. Preclinical evidence suggests it may cross the blood brain barrier. Trial Design: This is a multicenter, phase II, open-label study of neratinib for patients with HER2+ breast cancer and brain metastases. Neratinib is administered at 240 mg orally daily during a 28 day cycle. Two cohorts will be enrolled: Cohort 1 will enroll 40 patients with progressive CNS disease; cohort 2 will enroll ≤5 patients who are candidates for surgical excision of intracranial disease. Surgical candidates receive neratinib 7–21 days preoperatively and resume postoperatively. All patients are re-staged every 2 cycles. Those who develop non-CNS progression have an option to extend therapy with trastuzumab+neratinib. Circulating tumor cells (CTC) are collected at baseline and progression; neurocognitive testing, HADS and EORTC QLQ30/BN20 measures are administered at baseline, cycle 2, cycle 3, and progression (cohort 1). Intracranial tumor, cerebrospinal fluid (CSF), and plasma are collected at surgery (cohort 2). Specific Aims: The primary endpoint is CNS objective response rate (ORR) by composite criteria. Additional endpoints include: non-CNS ORR, progression-free survival, overall survival (OS), site of 1st progression, and toxicity. Correlative and exploratory endpoints include association of CTC count and OS and longitudinal neurocognitive function and quality of life. In an exploratory analysis (cohort 2), we will quantify neratinib concentrations in CSF, intracranial tissue, and plasma and examine associations with response. Eligibility: Patients must have confirmed HER2+ metastatic disease with ≥1 parenchymal brain lesion measuring ≥10 mm that is new or progressed after completing ≥1 line of standard CNS-directed treatment (cohort 1) or CNS disease that is amenable for surgery, including those without prior CNS treatments (cohort 2). Additional eligibility criteria (cohorts 1,2) include: adequate performance status and end organ/marrow function, and ejection fraction ≥50%. Any number of prior lines of therapy is allowed, including prior lapatinib. Statistical Methods: Cohort 1 has a 2-stage design with up to 40 patients. CNS ORR is defined as ≥50% reduction in sum volume of CNS target lesions, without evidence of new lesions, progression of non-target CNS lesions, non-CNS disease progression, worsening neurological symptoms, or increase in corticosteroids. CNS lesion measurements are performed centrally by the Harvard Tumor Imaging Metrics Core. If 1/18 patients have a CNS response in the 1st stage, another 22 patients will enroll. With this design, if ≥5 of 40 patients achieve a CNS response, the drug will be deemed worthy of future study. This 2-stage design has 92% power to distinguish between a true CNS ORR of 20% and a null of 6% (one-sided type I error rate=9%). Accrual: Accrual has begun. Target=45 (cohort 1=40, cohort 2=5) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-11.

Progression-free survival with endocrine-based therapies following progression on non-steroidal aromatase inhibitor among postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: a network meta-analysis

Abstract Objective: To quantify the comparative efficacy of currently available endocrine-based therapies (ETs) for postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2−) metastatic breast cancer (mBC) after non-steroidal aromatase inhibitor (NSAI) progression. Design: Network meta-analysis (NMA). Methods: Randomized clinical trials of ETs for HR+/HER2− mBC were identified via a systematic literature review using MEDLINE, Embase, Cochrane Library and key conference proceedings. All trials met the following inclusion criteria: (1) included women with HR+/HER2− mBC; (2) previous treatment with ETs or chemotherapy as first-line therapy; (3) treatment with ET as monotherapy or in combination with targeted therapy; (4) progression-free survival (PFS) was reported; and (5) published in 2007 (when HER2 testing became standardized) or later. Regimens were compared using pairwise hazard ratios (HRs) and 95% credible intervals (CrIs) of PFS obtained from a Bayesian NMA. Treatments with different approved dosages were pooled into the same arm; anastrozole and exemestane were pooled as aromatase inhibitors (AIs) due to clinical similarities. Results: A total of 4 trials and 6 regimens (palbociclib + fulvestrant, everolimus + fulvestrant, everolimus + AI, fulvestrant + AI, fulvestrant and AI) were eligible for inclusion. Palbociclib + fulvestrant and everolimus + AI had 50% and 55% reduced hazard of progression or death vs. AI (95% CrI upper bound ≤1), respectively. Palbociclib + fulvestrant, everolimus + AI and everolimus + fulvestrant had 54%, 58% and 40% reduced hazard vs. fulvestrant (95% CrI upper bound ≤1), while palbociclib + fulvestrant and everolimus + AI had 52% and 55% reduced hazard vs. fulvestrant + AI (95% CrI upper bound ≤1), respectively. Conclusion: Postmenopausal women with HR+/HER2− mBC who had previously failed an NSAI and received palbociclib + fulvestrant, everolimus + AI or everolimus + fulvestrant had longer PFS compared to those who received fulvestrant or AI alone.

Abstract P5-20-15: Dosing patterns and economic burden of drug wastage among postmenopausal women with HR+/HER2- metastatic breast cancer receiving palbociclib

Background: Dose modification related to adverse event is common in the treatment of metastatic breast cancer (mBC). Based on the dosage form and strengths available, dose modification may lead to drug wastage when the dose cannot be split or saved for later use. This study aimed to describe dosing patterns and to estimate the economic burden of drug wastage associated with dose modifications in postmenopausal women with HR+/HER2- mBC receiving palbociclib. Methods: Postmenopausal adult women diagnosed with HR+/HER2- mBC were identified from the Truven administrative claims database (2006Q1–2015Q4). Regimens received following mBC diagnosis were identified – patients who received a palbociclib-based regimen during one of their first three lines of therapy for mBC were included in the study. Palbociclib starting daily dose, average daily dose, and dosing patterns (dosing modifications and sequences) were reported. A dose modification was defined as a change (decrease/increase) of ≥25mg daily compared to the preceding dose. The economic burden of drug wastage was estimated by multiplying the number of days with drug wastage (i.e., days with overlapping palbociclib prescriptions due to dosage change) by the average cost reimbursed by payers for one unit of palbociclib. Descriptive analyses were conducted separately by line of therapy for mBC. Results: A total of 473 patients received palbociclib in first (214), second (157), or third (120) line of therapy for mBC. Patients were observed to receive palbociclib for an average of 4.3 months in first line and 4.1 months in second and third line of therapy. The majority of patients started palbociclib on the recommended 125 mg dose and remained on that dose until the end of observation. Dosing patterns and sequences are summarized in Table 1. Among the 214 patients who used palbociclib in first line, 38 (17.8%) had a dose modification – among these, 6 (15.8%) patients had an overlap in prescription fills (average overlap of 9.2 days). This potential drug wastage resulted in an average cost of

Monitoring of Hematologic, Cardiac, and Hepatic Function in Post-Menopausal Women with HR+/HER2− Metastatic Breast Cancer

4,376 per patient over a period of approximately 4 months following treatment initiation. Results were consistent in second and third lines of therapy, with higher proportions of patients with drug wastage in later lines of therapy. Conclusion: Over a short observation period, dose modifications, mostly dose reductions, were relatively frequent, and potential resulting drug wastage was associated with a substantial economic burden. Citation Format: Dalal AA, Gagnon-Sanschagrin P, Burne R, Guerin A, Gauthier G, Small T, Niravath P. Dosing patterns and economic burden of drug wastage among postmenopausal women with HR+/HER2- metastatic breast cancer receiving palbociclib [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-15.

TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM).

IntroductionIn the treatment of metastatic breast cancer (mBC), regular monitoring is key in helping physicians to make informed clinical decisions, managing treatment side effects, and maintaining patients’ quality of life. Therefore, we investigated the monitoring frequency in post-menopausal women with HR+/HER2− mBC stratified by first-line regimen.MethodsTreatment monitoring was assessed using two complementary data sources: a medical chart review (chart review analysis) and a commercial claims database (claims analysis). Women with post-menopausal HR+/HER2− mBC who initiated first-line therapy for mBC were selected and classified under three cohorts, based on treatment received: cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (i.e., palbociclib—the only CDK4/6 approved at the time of the study), endocrine therapy (ET), and chemotherapy. Frequency of monitoring [complete blood count (CBC), electrocardiogram (EKG), and liver function test (LFT)] and laboratory abnormalities detected during the first line of therapy were analyzed.ResultsIn the chart review analysis, 64 US oncologists abstracted medical information on 401 eligible patients, including 210 CDK4/6 users, 121 ET users, 51 chemotherapy users; 19 patients used other regimens. All patients had ≥ 1 CBC; between 8.3% (ET users) and 39.5% (CDK4/6 users) had ≥ 1 EKG; and over 98% of patients had ≥ 1 LFT across all three cohorts. Among monitored patients, 64.6% had a CBC abnormality, with anemia (39.9%), leukopenia (27.4%), and neutropenia (26.7%) being the most common. Abnormal EKG readings were detected in 8.4, 0.0%, and 7.7% of CDK4/6, ET, and chemotherapy users, respectively. LFT abnormalities were detected in 14.1–26.0% of CDK4/6 and chemotherapy users, respectively. Similar frequency of monitoring was observed in the claims analysis, with the exception of EKG monitoring, for which the proportion of patients tested was higher.ConclusionPost-menopausal women with HR+/HER2− mBC receiving first-line therapy with CDK4/6, ET, or chemotherapy were regularly monitored regardless of the first-line regimen received.FundingNovartis Pharmaceuticals Corporation.