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Background:Androgen receptor (AR) expression has been observed in up to 77% of human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC).References:1 Enzalutamide (ENZA) is a potent AR inhibitor approved for patients (pts) with metastatic castration-resistant prostate cancer. In vitro, ENZA enhances antitumor activity of trastuzumab in HER2+ AR+ cell lines and inhibits proliferation in trastuzumab-resistant HER2+ cell lines.2 Methods:Pts with metastatic or locally advanced BC that was HER2+ AR+ by local or central laboratory assessment were enrolled in a single-arm, Simon 2-stage phase 2 study (NCT02091960). Key eligibility criteria included availability of a tissue sample, presence of measurable or evaluable disease per RECIST v1.1, progression on prior trastuzumab and ≥1 prior line of anti-HER2 therapy as the most recent regimen. Brain metastases and history of seizure were exclusionary. Evaluable pts were those with centrally confirmed nuclear AR expression≥10% by immunohistochemistry who received ≥1 dose of ENZA and had ≥1 postbaseline tumor assessment. Pts received ENZA 160 mg daily and trastuzumab 6 mg/kg every 21 days until disease progression. The primary objective was clinical benefit rate at 24 weeks (CBR24), defined as complete or partial response (CR or PR) or stable disease (SD) for ≥24 weeks in evaluable pts. Additional endpoints included safety and progression-free survival (PFS). CBR24 in ≥3 of 21 evaluable pts was required to continue to stage 2 and enrollment of up to 66 evaluable pts total. This design yields a 1-sided type 1 error of 5% and 90% power when the true response is 25%. Results:Here we present results from stage 1 (data cutoff: Mar 23, 2016), with 22 evaluable pts enrolled (pts 21 and 22 enrolled simultaneously); 18 had received ≥4 prior lines of therapy. Median duration of ENZA exposure was 144 days (range, 22-495), mean number of complete trastuzumab infusions was 6.5. CBR24 was 27.3% (95% confidence interval [CI], 10.7-50.2); 2 confirmed PR and 4 SD ≥24 weeks. Median PFS was 108 days (95% CI, 56-144). All pts experienced ≥1 adverse event (AE) any grade; 5 pts experienced AEs grade ≥3. ENZA-related AEs were reported in 16 pts (72.7%), the most common (in ≥10% of pts) were fatigue (22.7%), nausea (18.2%), diarrhea (13.6%) and arthralgia (13.6%). Serious AEs were reported in 6 pts (27.3%; 2 each of infection and back pain, 1 each of abdominal pain, nausea, vomiting, pyrexia, urinary retention and pulmonary edema). Two pts discontinued due to drug-related AEs: 1 related to both drugs, 1 related to trastuzumab. One on-study death from pulmonary edema was reported, which was not considered related to either drug. Conclusion:Stage 1 met its primary objective. No new safety signals were identified, and the safety profile in this study was similar to that in men with prostate cancer and women with other BC subtypes treated with ENZA. These results are encouraging for a heavily pretreated population with advanced HER2+ AR+ BC. Enrollment in stage 2 continues with the combination of ENZA and trastuzumab. 1. Micello D et al. Virchows Arch. 2010;457:467-476. 2. Richer J. Presented at AACR Advances in Breast Cancer, San Diego, CA, 2013. Citation Format: Krop I, Cortes J, Miller K, Huizing MT, Provencher L, Gianni L, Chan S, Trudeau M, Steinberg J, Sugg J, Liosatos M, Paton VE, Peterson A, Wardley A. A single-arm phase 2 study to assess clinical activity, efficacy and safety of enzalutamide with trastuzumab in HER2+ AR+ metastatic or locally advanced breast cancer [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 P4-22-08.
Background: NKTR-102, a topoisomerase 1 inhibitor-polymer conjugate with reduced peak concentrations and a continuous concentration profile, demonstrated evidence of anti-tumor activity in a broad range of tumors in phase 1 (Von Hoff; EORTC-NCI-AACR 2008, abstract #595), including three patients (pts) with triple negative breast cancer (one confirmed PR by RECIST, one 20% reduction in tumor burden and one 50%+ reduction in CA 27.29). We now report data of a randomized phase 2 study in pts with MBC following progression to taxane-based therapy. Methods: This open-label, phase 2 study enrolled pts to receive NKTR-102 intravenously (IV) at a target dose of 145 mg/m2. Eligible patients had progressive MBC following taxane therapy, ECOG PS 0-1, adequate renal, hepatic, and marrow function. The study randomized pts to receive NKTR-102 q14d or q21d; each schedule followed a two-stage Simon design to ensure adequate response rate prior to proceeding to full enrollment. The primary endpoint was objective response rate (ORR) by RECIST v1.0; secondary endpoints were safety and PFS. Results: 70 pts were randomized from Feb09 to Apr10 and treated (35 on each schedule); 20 patients remain active on study as of 14Jun2010. Median age was 55 (range 33-83); all but 1 pt was female. ECOG PS 0/1 equaled 40%/60%. Prior neo-adjuvant and adjuvant therapy had been administered in 15 and 39 patients respectively; 23 pts had received prior hormonal therapy. Median number of prior non-hormonal regimens for metastatic disease was 2 (range 0-4). All pts had received prior taxane therapy; 11 in the adjuvant setting and 60 in the metastatic setting). 45 pts had received only prior anthracycline/taxane therapy (“AT”); an additional 14 pts had received prior AT/capecitabine therapy (“ATC”). 42 were estrogen or progesterone receptor positive and 20 pts had triple negative disease. Best RECIST response rate (confirmed and unconfirmed) equaled 27% (9 pts; 2 awaiting confirmation) and 24% (8 pts; 4 awaiting confirmation) for the q14d and q21d schedules (n=33 and 34, respectively; 3 patients had not undergone first on-study CT exam). As ORR results were similar for each schedule, the combined best RECIST ORR for in AT/ATC pts equaled 23%/29%, respectively and in pts with triple negative disease, this equaled 25%. Common related Grade 3/4 toxicities (q14d/q21d schedules; n=67 pts with AE data available): diarrhea (15%/12%), neutropenia (15%/9%),fatigue (12%/3%), and dehydration (6%/3%). One pt in each schedule died due to septic shock and acute renal failure secondary to hypovolemia. Conclusion: Single-agent NKTR-102 demonstrates significant anti-tumor activity in pts with MBC, including pts having tumor progression after ATC-based therapy and pts with triple negative disease, with a tolerable toxicity profile. Mature ORR and median PFS will be available by December 2010. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-01.
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