PURPOSE Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab. PATIENTS AND METHODS In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally. RESULTS Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell–free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue. CONCLUSION We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.

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Background Statins are established as first line therapy in patients with hypercholesterolemia and are thought to have pleiotropic effects including inhibition of signaling pathways known to drive cell proliferation and survival responses. Numerous preclinical and observational studies have demonstrated activity and improved outcomes in breast cancer patients who received statins, particularly lipophilic statins, as part of their adjuvant therapy. In the Life After Cancer Epidemiology (LACE) Study, 1,945 early-stage breast cancer survivors were shown to have a 33% decreased risk of breast cancer recurrence with post-diagnosis statin use, an effect that was magnified with increasing duration of statin use. We hypothesized that statin use concurrent with trastuzumab based chemotherapy in patients treated for non-metastatic HER2 positive breast cancer would be associated with improved outcomes. Methods We performed a retrospective review of all patients (n = 300) with HER2+ breast cancer who received trastuzumab from 2006-2012 at UM/SCCC. We identified two groups of patients for comparison - those who received statins (ST) during adjuvant chemotherapy (n = 45) or no statins during chemotherapy (NST) during adjuvant chemotherapy (n = 200). Patients with unclear documentation of concurrent statin use, men, patients with de-novo-metastatic breast cancer or prior primary cancer, bilateral breast cancers, and patients without follow-up were excluded. 5-year disease free (DFS) and overall survival (OS) were calculated. A univariate analysis was performed. Multivariate analysis for time-to-event data, using the Cox and extended Cox regression model will be performed and reported. Results The median age at diagnosis was 58 and 48, in the ST and NST groups, respectively. The most commonly used statin was lipophilic simvastatin (34.1%). The average baseline and post chemotherapy total cholesterol level in the ST group was 200.8 and 218.1mg/dL, respectively. Descriptive characteristics of the ST and NST groups respectively are as follows: postmenopausal (77.8% vs. 43.5%) tumor size <2cm (48.9% vs. 41.0%), node-negative disease (40.0% vs. 40.0%), HR+ status (64.4% vs. 60.5%), diabetes mellitus (26.7% vs. 9.0%), baseline BMI >30 (40.0% vs. 27.0%), and concomitant metformin (28.9% vs. 11.5%). The NST group was more likely to have a reduction of greater than 10% in their EF (9.0% vs. 6.7%). At a median follow-up of 32 and 26 months, the estimated 5-year DFS was significantly improved in the ST group (81.8% vs. 51.5%, p = 0.046). Meanwhile, the estimated 5-year OS was not significantly different between both groups (93.4% vs. 91.6%, p = 0.121). Metformin was not associated with a significant improvement in DFS or OS. Conclusion Our study demonstrated that statin use concurrent with trastuzumab-based chemotherapy for non-metastatic HER2 breast cancer was associated with improved estimated 5-year DFS, but not OS. The retrospective nature of our study does not allow for a definitive answer but further research needs to be done to define the role of statins in HER2+ breast cancer treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-03.

Background gpNMB is an internalizable transmembrane protein overexpressed in ˜40% of TNBC, and associated with a worse prognosis. Preclinical data implicates gpNMB in tumor invasion and metastasis. GV is a novel ADC designed to deliver monomethyl auristatin E (MMAE) to gpNMB-overexpressing cells. Prior phase 1/2 studies suggested promising activity of GV in gpNMB-overexpressing TNBC. Methods In the METRIC trial (NCT#01997333), patients (pts) with mTNBC were randomized 2:1 to GV (1.88 mg/kg IV q21 days) or capecitabine (2,500 mg/m2 PO daily d1-14 q21 days) until disease progression or intolerance. Key eligibility criteria included: gpNMB over-expression (>25% tumor cells positive by central immunohistochemistry of archival tissue); estrogen and progesterone receptor expression <10% and HER2 negative; ECOG 0-1; prior taxane; prior anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC. The primary endpoint was progression-free survival (PFS) per independent, blinded central review using RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), safety, and pharmacokinetics. The trial had 85% power to detect a PFS hazard ratio of 0.64 with two-sided α = 0.05. Results From Feb 2014 to Aug 2017, 327 women were randomized at 120 institutions to GV (n=218) or capecitabine (n=109). Pretreatment characteristics were well balanced between arms: median age of 55 years; 77% visceral disease; 2.4 years median duration of disease at study entry; 1 median prior anticancer regimen for metastatic disease. At the cut-off for final data analysis (Nov 30, 2017), 21 pts remained on treatment and 98 pts were alive. For GV vs. capecitabine based on independent central review, median PFS was 2.9 (95% CI: 2.8, 3.5) vs. 2.8 (95% CI: 1.6, 3.2) months (HR=0.95; p=0.76); median OS was 8.9 (95% CI: 7.9, 10.5) vs. 8.7 (95% CI: 6.9, 10.8) months (HR=1.06; p=0.73); ORR was 16% (95% CI: 11.1, 22.4) vs. 15% (95% CI: 8.6, 23.5); and median DOR was 5.6 (95% CI: 3.0, 7.8) vs. 4.2 (95% CI: 3.0, 12.2) months. A post-hoc subgroup analysis suggested the greatest benefit from GV was in potentially taxane-sensitive disease (i.e., not previously rechallenged or >6 months progression-free interval following last taxane). The incidence of grade ≥ 3 treatment-related adverse events (TRAEs) was 58% in the GV arm and 37% in the capecitabine arm. The most common grade ≥ 3 TRAEs were neutropenia (27%), rash (15%), and leukopenia (9%) in the GV arm, and diarrhea (14%) and palmar-plantar erythryodysesthesia (8%) in the capecitabine arm. There was 1 fatal TRAE of neutropenic sepsis in the GV arm and none in the capecitabine arm. Conclusion The METRIC study evaluating GV in mTNBC did not meet the primary efficacy endpoint of improved PFS over capecitabine. While anticancer activity was seen with GV, it was comparable to capecitabine with no therapeutic advantage of GV in terms of ORR, PFS, or OS. The safety profile of GV was consistent with prior experience with no new safety signals identified. Citation Format: Vahdat LT, Forero-Torres A, Schmid P, Blackwell K, Telli ML, Melisko M, Holgado E, Moebus V, Cortes J, Fehrenbacher L, Montero AJ, Ma C, Nanda R, Wright GS, He Y, Bagley RG, Halim A, Turner CD, Yardley DA. METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-01.