The biggest newsmaker at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) was a compound whose name and actions sound practically missilelike: T-DM1. Because of its highly targeted and potent effect that spares surrounding healthy tissue, T-DM1 not only has potent antitumor effects but is also very well tolerated.
Trastuzumab emtansine (T-DM1) is part of an emerging class of drugs called antibody-drug conjugates (ADCs) that link a monoclonal antibody (in this case, trastuzumab) to a cytotoxic agent (in this case, a potent antimicrotubule agent DM1 [a derivative of maytansine]).
“First and foremost, the design of an ADC centers on the selection of an antigen that is tumor specific and accessible to antibody binding at the tumor cell,” explained Howard A. Burris III, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
T-DM1, with its ability to bind HER2 with the same affinity as trastuzumab, maintains the activity of trastuzumab in addition to providing intracellular delivery of the antimicrotubule agent DM1. Presumably, the binding of T-DM1 to HER2 receptors leads to receptor internalization, followed by lysosomal degradation. Activated DM1 is then released from the lysosome into the cellular cytoplasm, which inhibits microtubule assembly and causes cell death, Burris explained at an educational session on ADCs.
Potent cytotoxic agents are necessary for maximizing the role of the drug conjugates, a requirement that maytansine fills; however, its toxicity was prohibitive. Researchers recently im proved the therapeutic index through conjugation with trastuzumab, leading to the development of its derivative, DM1. The in vitro cytotoxicity of DM1 is 10 to 200 times greater than that of taxanes. The compound also requires a highly stable linker: heterobifunctional reagent, Nsuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC).
EMILIA Shows the Drug’s Potential
At the ASCO plenary session, investigators reported early results of the international phase 3 EMILIA study of TDM1 in metastatic breast cancer patients (Abstract LBA1).
In a population of 991 advanced or metastatic patients who had already received trastuzumab and taxanes, treatment with T-DM1 was associated with an approximately 30% increase in progression- free survival (PFS) compared with a standard treatment regimen.
“For patients facing metastatic breast cancer, this is a breakthrough,” said lead author Kimberly L. Blackwell, MD, of Duke Cancer Institute at Duke University, Winston-Salem, North Carolina.
Louis Weiner, MD, director of the Georgetown-Lombardi Comp rehen sive Cancer Center in Washington, DC, the invited discussant of the study, commented, “Stated simply, T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.”
Patients received intravenous TDM1 or capecitabine plus lapatinib every 3 weeks until disease progression. Those getting T-DM1 had a median PFS of 9.6 months, compared with 6.4 months for those on capecitabine/lapatinib. This represented a 35% reduction in the risk of progression (P <.0001), Blackwell reported.
Median overall survival was not reached with T-DM1, and was 23.3 months with standard treatment, for a 38% reduction in mortality risk (P = .0005). This did not, however, meet the prespecified threshold for statistical significance for this end point at the first analysis.
Nevertheless, after 2 years, 65.4% of the T-DM1 patients were alive, compared with 47.5% of the conventionally treated group. “There is an apparent survival benefit with T-DM1,” Blackwell said. It is expected that further analyses will show a survival difference.
Tolerability was far better with T-DM1 as well. Dose reductions were required for 16.3% of this arm, compared with 53.4% for capecitabine and 27.3% for lapatinib. With T-DM1, the diarrhea, vomiting, hand–foot syndrome, and alopecia typically observed with the chemotherapy regimen were not seen.
The Future of T-DM1
Additional trials are now being conducted to evaluate T-DM1 as first-line treatment, including 2 randomized multicenter phase 3 trials of the drug in earlier lines of therapy. The MARIANNE trial is comparing the efficacy and safety of T-DM1 alone and in combination with pertuzumab—another drug with striking activity in breast cancer when combined with trastuzumab. The experimental combination will be compared with the standard trastuzumab/taxane regimen, Burris noted.
Burris concluded, “T-DM1 meets the criteria for a successful ADC by combining the targeted effect of trastuzumab with the cytotoxic potency of DM1 using a stable linker and minimizing systemic toxicity. In addition, other tumor histologies, such as gastrointestinal cancers that are HER2-positive, may be sensitive to this agent.…An aggressive portfolio of phase 2 and 3 clinical trials will help determine the role of T-DM1 in earlier lines of therapy or with combination of other targeted agents.”