Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial

PURPOSE: In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS: Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS: There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; CONCLUSION: In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial

Abstract CT173: Sunitinib (S) in patients (pts) with metastatic breast cancer (mBC) with FGFR1 mutations or amplifications: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. S is an oral multi-kinase inhibitor that inhibits Fibroblast Growth Factor Receptor family members 1-4 (FGFR1-4) in biochemical and cellular assays and is FDA approved in several tumor types. Results in a cohort of mBC pts with FGFR1 mutations (mut) or amplifications (amp) treated with S are reported. Methods: Eligible pts had mBC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received S 50 mg orally daily for four weeks followed by two weeks off, until tumor progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Thirty pts with mBC with FGFR1 mut (1 pt), amp (28 pts), or both (1 pt) were enrolled from Oct 2016 to June 2019. 3 were not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table 1. Two partial responses (PR) and 5 SD16+ (FGFR1 amp only) were observed for DC and OR rates of 29% (95% CI: 13%, 42%) and 7% (95% CI: 1%, 24%), respectively, and the null DC rate of 15% was rejected (p=0.09). S related grade 3-5 TAEs (Table 1) were consistent with the product label for S except encephalopathy. Conclusions: Monotherapy S showed modest anti-tumor activity and clinically significant TAEs in heavily pre-treated pts with mBC with FGFR1 amplification. Table 1.Demographics, Efficacy (N=27) and Toxicity Outcomes (N=30)Median age, yrs (range)61 (28, 81)Female, %97ECOG PS, %047137217Prior systemic regimens, %1-210≥390Hormone Receptor (HR) & HER2 Status, %HR (+) HER2 (-)77HR (-) HER2(-)13HR (+) HER2 (+)7Not reported3DC rate, % (OR or SD16+) (95% CI)29 (13, 42)OR rate, % (95% CI)7 (1, 24)Median PFS, wks (95% CI)8.7 (8.1, 15.7)Median OS, wks (95% CI)33.9 (23.0, 49.0)Number of Pts with Treatment-related AEs/SAEs (TAEs, maximum grade reported)Grade 211Grade 329Grade 4321Skin infection (SAE)2Cytopenia, encephalopathy (SAE), febrile neutropenia (SAE), increased alkaline phosphatase, Palmar-plantar erythrodysesthesia syndrome, vomiting3Cytopenia, hypertension Citation Format: Carmen Calfa, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Eugene Ahn, Keerthi Gogineni, Nitin Rohatgi, Monika L. Burness, Anu Gaba, Omid Hamid, Tareq Albaghdadi, Alison Conlin, Philip Gold, Jordi Rodon, Ramya Thota, Richard L. Schilsky. Sunitinib (S) in patients (pts) with metastatic breast cancer (mBC) with FGFR1 mutations or amplifications: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT173

A phase Ib study of pre-operative, locoregional IRX-2 cytokine immunotherapy to prime immune responses in patients with early stage breast cancer.

PURPOSE: To evaluate the safety and feasibility of pre-operative locoregional cytokine therapy (IRX-2 regimen) in early stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. EXPERIMENTAL DESIGN: Sixteen patients with stage I-III early stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive pre-operative locoregional immunotherapy with the IRX-2 cytokine biologic (2mL subcutaneous x 10 days to peri-areolar skin). The regimen also included single-dose cyclophosphamide (300mg/m RESULTS: Pre-operative locoregional cytokine administration was feasible in 100% (n=16/16) of subjects and associated with increases in stromal tumor-infiltrating lymphocytes (p CONCLUSIONS: IRX-2 is safe in early stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early stage breast cancer and other malignancies

Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial.

PurposeIn the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs.Patients and methodsPatients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease.ResultsThere were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03).ConclusionIn patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial

Detectable clonal mosaicism and its relationship to aging and cancer

10.1038/ng.2270Nature Genetics446651-658NGEN