Carla Falkson

Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003)

PURPOSE Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes. PATIENTS AND METHODS Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. RESULTS Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). CONCLUSION Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.

TBCRC 003: Phase II trial of trastuzumab (T) and lapatinib (L) in patients (pts) with HER2+ metastatic breast cancer (MBC).

527 Background: In heavily pre-treated pts, L+T is associated with improved outcomes compared to L alone (Blackwell et al, 2009). We evaluated the safety and efficacy of L+T in pts with 0-2 prior lines of chemotherapy (CT) for HER2+ MBC. We also explored mechanisms of resistance and predictors of response to anti-HER2 therapy. METHODS Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT for MBC, and > 1 yr from adjuvant T, if received. Cohort 2: 1-2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Baseline (BL) research biopsy was required. FDG-PET/CT was performed at BL, Wk 1, and Wk 8. Circulating tumor cells and plasma were collected at BL, Wk 4, and off-study. Staging studies were done at BL and every 2 cycles (1 cycle = 4 wks). The primary endpoint was objective response rate (ORR) by RECIST 1.0. The study was designed to distinguish between ORR 25% vs. 45% in Cohort 1 (>/= 5/17 pts to enter 2nd stage; 14 responses in 36 evaluable (eval) pts needed to be promising) and between ORR 10% vs. 25% in Cohort 2 (>/=3/22 pts to enter 2nd stage; responses in 8/40 pts needed to be promising). Secondary endpoints included clinical benefit rate (CBR; CR+PR+SD >/= 6 months), toxicity, and radiologic/biomarker correlates. RESULTS Enrollment was completed 10/28/2010 (Cohort 1, n=40; Cohort 2, n=47). 14 pts in Cohort 1 remain on protocol therapy. In Cohort 2, all pts have come off study; median number of cycles was 6 (range 1-18). Of the 1st 36 eval pts in Cohort 1, confirmed objective responses were observed in 41.7% (95% CI 23.0%-67.1%; 3 CR, 12 PR; 4 unconfirmed PR). Of the 1st 40 eval pts in Cohort 2, confirmed ORR was 25% (95% CI 11.2%-45.6%; 0 CR, 10 PR; 2 unconfirmed PR). CBR was 47.2% (95% CI 30.4%-64.5%) and 40% (95% CI 24.9%-56.7%), respectively. Grade 3/4 treatment-related toxicities were uncommon (grade 3 diarrhea, 7%; all others < 3%). No biopsy-related SAEs were reported. CONCLUSIONS L+T is an active regimen in HER2+ MBC. The study met its pre-specified primary endpoint in each cohort. Updated efficacy data will be presented. Imaging and tissue-based correlative analyses are underway.

An evidence-based systematic review of bilberry (Vaccinium myrtillus) by the Natural Standard Research Collaboration.

An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer A Clinical Trial

Importance Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. Objective To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor–positive, human epidermal growth receptor 2–negative advanced breast cancer. Design, Setting, and Participants In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Interventions Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator’s discretion upon initial disease progression. Main Outcomes and Measures The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. Results A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). Conclusions and Relevance The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Trial Registration clinicaltrials.gov Identifier: NCT01698918

Abstract P4-14-19: ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets)

Background: The risk of CNS involvement in patients with HER2+ metastatic breast cancer (MBC) is high. The natural history of HER2+ CNS metastases (mets) is different from other breast cancer subtypes; there is a longer time from metastatic diagnosis to CNS relapse, greater control of extracranial disease at the time of CNS relapse, and longer median overall survival from the time of CNS relapse. Local treatments, i.e., surgery and/or radiation, remain the mainstay of treatment for HER2+ CNS disease as standard systemic therapy options have limited efficacy. ONT-380, a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects, has been associated with increased survival compared to lapatinib or neratinib in an animal model of HER2+ CNS disease. Here, we describe 24 pts from two studies with response-evaluable CNS mets treated with ONT-380 in combination with other systemic therapies. Methods: Pts with asymptomatic untreated or post-treatment progressive CNS mets were enrolled in ongoing phase 1b studies of ONT-380 + ado-trastuzumab emtansine (T-DM1) or ONT-380 ± trastuzumab (T) ±capecitabine (C). All pts received treatment in 21 day cycles including ONT-380 300 mg PO BID and approved doses of either T-DM1, T or C alone, or T+C. Eligibility criteria for all pts included prior treatment with T and a taxane, and for pts receiving T and/or C, prior T-DM1. Prior lapatinib was allowed. Assessments included safety, systemic tumor response per RECIST 1.1, and CNS tumor response by MRI every 2 cycles per modified RECIST 1.1. Results: 24 pts (10 with untreated CNS mets and 14 with progressive CNS mets after local therapy) received ONT-380 plus T-DM1 (n =14), C (n=1), T (n = 5) or T+C (n = 4) for 1-8 cycles. Of these 24 pts, 14 are evaluable for response in the CNS (at least one follow-up MRI); 7 pts have not yet been rescanned, and 3 are non-evaluable. In the 14 response-evaluable pts, best CNS response has been: 1 CNS CR (T-DM1), 4 CNS PR (T-DM1 n = 2; T+C n = 1; C n=1) and 9 CNS SD (T-DM1 n = 5; T n = 3; T+C n=1). Pts with CR or PR (prior lapatinib n=2; prior pertuzumab n=2; prior T-DM1 n=2) all had > 50% decrease in CNS target lesions. One CNS non-evaluable pt (T) had a 15% increase in their target lesion and underwent surgical resection; pathology, however, revealed no viable tumor with only necrotic tissue present. Two additional CNS non-evaluable pts (T-DM1 n=1; C+T n=1) were taken off study due to systemic PD after treatment was held for AEs (Gr 3 AST/ALT elevation [n=1]; Gr 4 edema in thalamic lesion [n=1]). No other ≥ Gr 3 ONT-380 related events were reported. Systemic disease control was also seen, with a best response in 17 evaluable pts of 6 PR, 9 SD, and 2 PD. Conclusions: This case series demonstrates early clinical signs of activity of ONT-380 against HER2+ CNS mets in combination with other systemic agents. Further study of the CNS activity of ONT-380 is ongoing and further studies are being planned. Updated results will be reported. Clinical trial information: NCT01983501, NCT02025192. Citation Format: Murthy RK, Hamilton E, Borges VF, Moulder S, Aucoin N, Welch S, Chaves J, Falkson CI, Walker L, Ferrario C. ONT-380 in the treatment of HER2+ breast cancer central nervous system (CNS) metastases (mets). [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 P4-14-19.

Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial

Importance Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer. Objective To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Design, Setting, and Participants In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018. Interventions Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days. Main Outcomes and Measures Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles. Results Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). Conclusions and Relevance In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Trial Registration ClinicalTrials.gov Identifier: NCT01983501

P2-09-07: Metabolic Response by FDG-PET in Patients (pts) Receiving Trastuzumab (T) and Lapatinib (L) for HER2+ Metastatic Breast Cancer (MBC): Correlative Analysis of TBCRC 003.

Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.