Updated Data Confirm Survival Benefits with T-DM1 in Breast Cancer and with Regorafenib in Colon Cancer

October 2012, Vol 3, No 7

Vienna, Austria—The updated analyses of 2 major studies of drugs that were recently approved by the US Food and Drug Administration (FDA) confirm the benefits of trastuzumab emtansine (T-DM1) in patients with advanced HER2-positive breast cancer and of regorafenib (Stivarga) in patients with metastatic colorectal cancer (mCRC). Both studies were presented at the 2012 European Society for Medical Oncology (ESMO) Congress. Regorafenib was approved by the FDA for the treatment of mCRC during the ESMO meeting (see article here).

The latest findings from the EMILIA clinical trial that were presented at the meeting showed that T-DM1 prolonged survival versus treatment with lapatinib (Tykerb) plus capecitabine (Xeloda) in women with HER2-positive metastatic breast cancer. Women assigned to T-DM1 had a 32% lower mortality rate compared with those assigned to the lapatinib and capecitabine combination.

The median overall survival (OS) was 30.9 months with T-DM1 versus 25.1 months with lapatinib plus capecitabine, a significant (P <.001)
6-month difference. To date, a median OS of approximately 31 months is the best reported survival rate in a randomized trial in patients with HER2-positive metastatic breast cancer. The full report of the EMILIA trial was simultaneously published online (Verma S, et al. N Engl J Med. Epub 2012 Oct 1) to coincide with the ESMO 2012 presentation.

Lead investigator Sunil Verma, MD, Assistant Professor, University of Toronto, Ontario, Canada, and a medical oncologist at Sunnybrook Odette Cancer Center, Toronto, noted that the survival benefit and safety of T-DM1 in EMILIA, “suggest that T-DM1 should be an important therapeutic option in the treatment of metastatic HER2-positive breast cancer.”

The global EMILIA trial randomized 991 patients with HER2-positive metastatic breast cancer to T-DM1 or to lapatinib and capecitabine in a 1:1 ratio. Participants were previously treated with trastuzumab and with a taxane. Patients were stratified according to their geographic region, the number of previous chemotherapy regimens for metastatic breast cancer or unresectable locally advanced disease, and the presence of visceral disease.

Grade 3 or higher adverse events (AEs) were more frequent (57%) in the lapatinib plus capecitabine arm than in the T-DM1 arm (41%). Patients in the T-DM1 arm had a higher incidence of thrombocytopenia and increased serum aminotransferase levels, whereas the combination group had higher rates of diarrhea, nausea, vomiting, and hand-foot syndrome. Cardiac dysfunction rates were low and similar in both arms.

According to updated results of the CORRECT trial, which was the basis for the FDA approval, regorafenib achieved a sustained survival benefit in patients with heavily pretreated mCRC who had a good performance status score (ie, 0 or 1). Regorafenib benefited all of the prespecified subgroups. The drug’s safety was as expected, with no new safety concerns emerging at the extended follow-up.

The study was stopped at the first interim analysis, because of a clear OS difference between the 2 arms, with a median of 6.4 months (95% confidence interval [CI], 5.8-7.0) for regorafenib versus 5 months (95% CI, 4.4-5.9) for placebo.

A final updated OS analysis presented at ESMO 2012 confirmed the benefits of regorafenib by demonstrating a 21% reduced risk of death. At 6 months, 52.2% of the patients in the regorafenib group were alive versus 43% of the patients receiving placebo; and 24% of those receiving regorafenib were alive at 1 year compared with 17% of those receiving placebo.

“Regorafenib is the first oral multitargeted TKI [tyrosine kinase inhibitors] with proven activity in metastatic colorectal cancer….The drug represents a new potential standard of care for patients with chemorefractory metastatic disease,” stated lead author Eric van Cutsem, MD, PhD, Professor, University of Leuven, and Head of the Division of Digestive Oncology at University Hospital Gasthuisberg in Leuven, Belgium.

The CORRECT clinical trial included 760 patients with mCRC who progressed despite previous treatment with several lines of standard therapies. Patients were randomized in a 2:1 ratio to oral regorafenib 160 mg daily or to placebo for 3 weeks on and 1 week off; both groups got best supportive care. Patients were treated until disease progression, unacceptable toxicity, or until the investigator’s decision to withdraw treatment.

Regorafenib-related AEs included hand-foot syndrome in 46% (all grades; grade 3, 16%); fatigue, 47.4% (all grades; grade 3, 9.2%); hypertension, 27.8% (all grades; grade 3, 7.2%); diarrhea, 38% (all grades; grade 3, 7%); and rash or skin desquamation in 26% (all grades; grade 3, 5.8%). A subgroup analysis showed no major differences in AEs between the 2 treatment arms.

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