Issue 1 - San Antonio Breast Cancer Symposium

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8 Abstract 44 A double-blind, randomized, placebo-controlled, phase 2b study evaluating the efficacy and safety of sorafenib (SOR) in combination with paclitaxel (PAC) as a first-line therapy in patients (pts) with locally recurrent or metastatic breast cancer (BC) William J. Gradishar, Feinberg School of Medicine, Northwestern University, Chicago, IL; Virginia Kaklamani, Northwestern University, Chicago, IL; Tarini Prasad Sahoo, Jawaharlal Nehru Cancer Hospital, Bhopal-1, M.P, India; D. Lokanatha, Kidwai Institute of Oncology, Bangalore, India; Vinod Raina, Institute Rotary Cancer Hospital, New Delhi, India; Shailesh Bondarde, Shatabadi Hospital, Nashik, India; Minish Jain, Ruby Hall Clinic, Pune, India; Lee Schwartzberg, West Clinic, Memphis, TN Introduction: SOR is a targeted therapeutic agent indicated for advanced renal cell carcinoma and hepatocellular carcinoma. SOR targets multiple kinases involved in tumor growth and angiogenesis. The TIES (Trials to Investigate the Effects of Sorafenib in BC) program includes 4 phase 2b randomized, double-blind, placebo-controlled screening trials in HER2-negative BC. Recently, the first of these trials, SOR+capecitabine (CAP) vs placebo (PL)+CAP demonstrated a significant progression-free survival (PFS) benefit in pts with advanced BC. Here we present initial results from the second of the 4 trials. This study evaluated the efficacy and safety of SOR in combination with PAC as a first-line regimen for pts with advanced BC. Methods: Pts with HER2-negative, locally recurrent or metastatic BC were eligible for first-line treatment for advanced BC. Previous cytotoxic (non-metastatic), endocrine, or radiation therapy was allowed. Pts were randomized 1:1 (stratified by visceral vs non-visceral metastatic disease) to SOR (400 mg, orally, twice daily, continuously) or PL in combination with PAC (90 mg/m 2 weekly, IV, 3 weeks on/1 week off). The primary endpoint was PFS. Secondary endpoints included overall survival (OS), time to progression (TTP), overall response rate (ORR), and safety. A sample size of 220 pts was planned to detect a targeted HR of 0.65 (90% power and 1-sided a=0.14). The study is registered at ClinicalTrials.gov (NCT00499525). Results: From January 2008 to January 2009, 237 pts were randomized to SOR+PAC (n=119) vs PL+PAC (n=118), with 170 pts in India (74% vs 69%), 52 pts in the United States (21% vs 23%), and 15 pts in Brazil (5% vs 8%). Treatment groups were balanced for age (mean, 51.9 y), ECOG performance 0 (45%) and 1 (53%), stage IV disease (85%), visceral metastatic disease (75%), and previous non-metastatic chemo (58%). Results of the study were as follows for SOR+PAC vs PL+PAC: median PFS 6.9 vs 5.6 mos (HR 0.788; 95% CI, 0.558-1.112; 1-sided log rank P=0.0857), median TTP 8.1 vs 5.6 mo (HR 0.674; 95% CI, 0.465-0.975; 1-sided log rank P=0.0171), and ORR of 67% vs 54% (1-sided Cochran-Mantel-Haenszel P=0.0234). OS data are pending. Discontinuation of study treatment due to adverse events occurred in 23 pts (19%) in the SOR+PAC vs 5 pts (4%) in the PL+PAC. Grade 3/4 toxicities (SOR+PAC vs PL+PAC) included hand-foot skin reaction (30% vs 3%), asthenia (7% vs 3%), peripheral neuropathy (6% vs 7%), neutropenia (13% vs 7%), and anemia (11% vs 6%). Treatment-related deaths occurred in 2 pts (malaria and liver dysfunction), both in the SOR+PAC arm. Conclusions: Results of the primary endpoint, PFS, demonstrated a trend favoring SOR+PAC over PL+PAC in the treatment of advanced BC (HR 0.788; P=0.0857). In addition, significant improvements in TTP and ORR were observed. OS data are pending. There were no new toxicities observed with the combination and AEs were manageable. These data indicate that SOR provides added benefit when combined with PAC compared with single-agent PAC in the first-line treatment of advanced BC.
Abstract 710 A phase 2 study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody–drug conjugate, in HER2+ metastatic breast cancer (MBC) patients previously treated with conventional chemotherapy, lapatinib and trastuzumab Ian Krop, Dana Farber Cancer Institute, Boston, MA; Patricia LoRusso, Karmanos Cancer Institute, Detroit, MI; Kathy D. Miller, Indiana University Melvin-Bren Simon Cancer Center, Indianapolis, IN; Shanu Modi, Memorial Sloan-Kettering Cancer Center, New York, NY; Denise Yardley, Sarah Cannon Research Institute, Nashville, TN; George Rodriguez, South Texas Oncology/Hematology, San Antonio, TX; Sam Agresta, BioOncology, Genentech, South San Francisco, CA; Maoxia Zheng, BioOncology, Genentech, South San Francisco, CA; Lukas Amler, BioOncology, Genentech, South San Francisco, CA; Hope Rugo, UCSF Comprehensive Cancer Center, San Francisco, CA Background: T-DM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of the anti-microtubule agent DM1. In a prior phase 2 study, single agent T-DM1 was well tolerated and had significant activity (objective response rate [ORR] of 26% by independent review [IRF]) in 112 patients (pts) with pre-treated HER2+ MBC (Vogel CL et al, J Clin Oncol, 27:15s, 2009 [suppl; abstr 1017]). To confirm and extend these findings, we conducted a phase 2 study that enrolled a more homogenous population of HER2+ MBC pts who had all received prior anthracycline, taxane, capecitabine, trastuzumab, and lapatinib therapy and progressed on the last regimen received (at least 2 HER2-directed regimens had to be given for metastatic disease). Methods: This is an open-label, single-arm study of T-DM1 given at 3.6 mg/kg IV q3w. Primary objectives are to assess ORR by IRF and evaluate the safety of T-DM1. Key secondary objectives assess the clinical benefit rate (CBR = ORR + stable disease [SD] at 6 months), duration of response (DoR) and progression-free survival (PFS). Pts remain on study until disease progression or unmanageable toxicity. Key exploratory objectives were the assessment of ORR and clinical benefit rate (CBR) by IRF in retrospectively tested, centrally confirmed HER2+ patients. Results: The study completed enrollment of 110 patients. This analysis has a median follow-up of 8.3 months (range 0.7-13.1). Median age was 52.5 y (range 34–77). Pts received a median of 7 agents for metastatic disease (range 1–15). Median durations of prior trastuzumab and lapatinib treatment in metastatic setting were 19.4 and 6.9 months respectively. The ORR was 32.7% and the CBR was 44.5% by IRF. Median DoR and PFS have not reached maturity. In retrospectively tested, centrally confirmed HER2+ patients, the ORR was 39.5% and the CBR was 52.6% by IRF. T-DM1 was well tolerated, with no dose-limiting cardiotoxicity. One pt with pre-existing non-alcoholic fatty liver disease died with hepatic dysfunction. The most common adverse events were fatigue (59.1% of pts), nausea (37.3%), and thrombocytopenia (29.1%); 41.8% of pts experienced at least one grade 3 or above adverse event. Conclusions: In this study, single agent T-DM1 demonstrates a 32.7% ORR with an acceptable safety profile in a well defined, homogeneous, and extensively pretreated population that has not been previously studied. Centrally confirmed HER2 positivity strongly correlated with objective response. These results confirm the activity of T-DM1 in treatment resistant HER2+ MBC. An ongoing global randomized phase 23 study is evaluating T-DM1 compared with lapatinib plus capecitabine in pts with advanced HER2+ who have been previously treated with a taxane and trastuzumab. 9
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Issue 1 - San Antonio Breast Cancer Symposium

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