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Breast Cancer

Concurrent Trastuzumab with Chemotherapy Beats Sequential Use for HER2-positive Breast Cancer By Daniel M. Keller, PhD SAN ANTONIO—Interim analysis of a large trial of women treated with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer before or after surgery indicates that concurrent use with a taxane may improve overall survival (OS) and disease-free survival (DFS) compared with sequential administration. Previous trials have shown a large benefit of trastuzumab but left open the question of the optimal timing of its use. (See, eg, the HERA trial: Piccart-Gebhart MJ. N Engl J Med. 2005;353:1659-1672.)

trial randomized women to one of three treatment arms: doxorubicin/cyclophosphamide then paclitaxel (control), doxorubicin/cyclophosphamide, then paclitaxel, then trastuzumab for 52 weeks (sequential therapy), or doxorubicin/ cyclophosphamide, then paclitaxel plus trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (concurrent therapy). Compared with the control regimen (n = 1097), sequential therapy (n = 1087) was associated with a 30% benefit in DFS at a median of 5.5 years of follow-

Concurrent use with a taxane may improve overall survival and disease-free survival compared with sequential administration. At the San Antonio Breast Cancer Symposium in December 2009, Edith Perez, MD, director of the breast program at Mayo Clinic in Jacksonville, Florida, reported results of the N9831 trial that tested concurrent or sequential trastuzumab (San Antonio Breast Cancer Symposium; 2009. Abstract 80). The

up (estimated hazard ratio [HR], 0.70; log rank P = .0005). An additional 23% benefit in DFS occurred in the concurrent therapy group (n = 949) when compared with the sequential arm at a median follow-up of 5.3 years (estimated HR, 0.77; log rank P = .019). Based on the specific statistical methods designed for

interim analysis, however, this last differ- involved less than one half of the ence was not deemed to be significant. planned events for which the study was Perez presented results comparing powered to show a difference. She concontrol and concurrent theracluded that the results were py for a median follow-up of still strong enough to recomapproximately 3 years. Commend overlapping trastuzupared with the control arm, mab with a taxane. concurrent therapy was assoMark Pegram, MD, direcciated with a 52% benefit in tor of clinical research at DFS (adjusted HR, 0.48; P < the Sylvester Comprehen.00001) and a 35% benefit in sive Cancer Center of the OS (unadjusted HR, 0.65; P University of Miami Miller = .0007). School of Medicine in Edith Perez, MD Speaking with The OnFlorida, said, “While maybe cology Pharmacist before her not completely technically presentation, Perez said she thought the statistically significant…[the study is] N9831 trial results would change prac- so consistent with what was expected, tice patterns worldwide, especially in based on all of the science, that I think countries where the usual practice is it will be embraced fairly widely and sequential therapy. Most observers felt fairly quickly.” that the N9831 results made a good But Aman Buzdar, MD, of the M. D. case for using concurrent trastuzumab Anderson Cancer Center in Houston, with the taxane, although most said Texas, cautioned that physicians need using sequential therapy would not be to be familiar with using the drugs bad practice. together and have to follow patients Julie Gralow, MD, professor of med- closely. “Some of the toxicities are also ical oncology at the University of synergistic when you combine chemoWashington in Seattle, a coauthor of therapeutic agents with antibody treatN9831, noted that the interim results ment,” he warned. ●

Three New Drugs on the Horizon for HER2-positive Breast Cancer


hree new drugs are in the pipeline to treat human epidermal growth factor receptor (HER) type 2-positive metastatic breast cancer (MBC). Two appear to have the potential to provide incremental gains, and one looks like a game changer.

T-DM1 The one getting the most attention at recent oncology conferences is T-DM1, a first-in-class conjugate of the monoclonal antibody trastuzumab and DM1, a derivative of maytansine. Maytansine is an antimicrotubule agent that proved too toxic to use alone a couple of decades ago. The key to taming it for use today is a linker that attaches DM1 to trastuzumab and is cleaved once the drug has been internalized in cells overexpressing HER2, releasing the DM1 inside. The drug is almost undetectable in the circulation (LoRusso P, et al. San Antonio Breast Cancer Symposium; 2009. Abstract 5099). Ian Krop, MD, PhD, and coworkers reported on a phase 2 study of 110

patients with HER2-positive MBC previously treated with an anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab. Patients received singleagent T-DM1 at a dose of 3.6 mg/kg intravenously every 3 weeks. Even in this population of heavily pretreated patients with more than 2 years of HER2-directed therapy, the overall response rate (ORR) was 30%, more than 46% had stable disease, and the clinical benefit rate (CBR) was 40% to 45%. The median time to progression was 7.3 months (San Antonio Breast Cancer Sym posium; 2009. Abstract 5090). In another phase 2 study of 112 heavily pretreated patients with MBC, T-DM1 showed good efficacy and tolerability. The ORR was 26.7% by independent review and 38.9% by investigator assessment, with a median progression-free survival of 4.6 months (Vogel CL, et al. J Clin Oncol. 2009; 27[15S]:Abstract 1017). In the 66 patients in that trial who were previously treated with lapatinib and trastuzumab, T-DM1 produced very

similar response rates (24.2% and 34.8%, respectively). The main adverse effects, as exemplified in the Krop study, were fatigue, nausea, and brief, transient thrombocytopenia. Most have been grade 1 or 2. Phase 3 trials are ongoing, comparing TDM1 to other combined therapies. Carlos Arteaga, MD, professor of medicine at Vanderbilt University in Nashville, Tennessee, is very positive about T-DM1, especially for heavily pretreated patients. “The conjugate has shown remarkable activity as a third line in HER2-positive metastatic breast cancer,” he said. Harold Burstein, MD, PhD, of DanaFarber Cancer Institute in Boston, noted that T-DM1 may have efficacy as a single agent “because it is, in essence, chemotherapy plus trastuzumab.” And, he added, “It does not seem to cause significant alopecia, which is very exciting for patients.” Although some patients have done well on trial for more than 1 year, and in some cases 2 years, Eric Winer, MD,

director of breast oncology at DanaFarber, cautioned that “We have not treated a sufficient number of patients for years to know for certain that there isn’t a low level of cumulative toxicity.” Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh, remains very optimistic about T-DM1. “It will have a major role in clinical least be equivalent to capecitabine/lapatinib with probably fewer side effects,” he said. In a more general sense, the linker technology used to join DM1 with trastuzumab may be applicable to use with other monoclonal antibodies against other tumor types, “the so-called targeted chemotherapy concept that has been the Holy Grail for everybody for so many years,” according to Luca Gianni, MD, director of medical oncology and clinical pharmacology at Italy’s National Tumor Institute in Milan. Neratinib Another drug in development is neraContinued on page 13

June 2010 I VOL 3, nO 4


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