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Purpose The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) –overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. Patients and Methods This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. Results With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). Conclusion T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.

Purpose We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. Patients and Methods One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. Results In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Conclusion Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

1016 Background: The antibody-drug conjugate T-DM1 has shown encouraging efficacy in two phase II studies (4258g and 4374g) for pts with HER2-positive (HER2+) MBC who had progressed on prior HER2-d...

ABSTRACT WITHDRAWN: This abstract was withdrawn by the authors prior to the start of the Symposium. It was rescheduled to a Poster Discussion session and renumbered as Abstract 710. Background: T-DM1 combines the HER2-inhibiting properties of trastuzumab with targeted delivery of the anti-microtubule agent DM1. In a prior phase II 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 II 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).MethodsThis 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 positive 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 yr (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 positive 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 III 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.