Antibody-drug conjugates: not exactly “smart bombs” for cancer
I only have a quick post today because I really want you to spend your reading energy on a superb C&EN cover story by my colleague here, Lisa M. Jarvis.
The media frenzy that normally follows the American Society of Clinical Oncology (ASCO) meeting each June focused this year on cancer cell-directed antibodies conjugated to highly-cytotoxic compounds. The most ballyhooed of these is T-DM1, the anti-HER2 trastuzumab antibody (Herceptin) covalently linked to the microtubule-inhibiting maytansine analog, DM1 (meeting abstract, Genentech press release). When the conjugate is internalized by breast cancer cells overexpressing the HER2 protein, the highly-toxic DM1 drug is released intracellularly.
The study population was 991 breast cancer patients whose disease was previously treated with plain old trastuzumab and a taxane (such as paclitaxel or docetaxel). In this, the EMILIA study, patients were randomized to receive T-DM1 or a combination of capecitabine (Xeloda) and lapatinib (Tykerb). Relative to the latter group, the DM-1-treated patients had a 35 percent increase in "progression-free survival," the time from treatment to worsening of the disease or death (9.6 months vs. 6.4 months). The T-DM1-treated patients also experienced a reduction in serious adverse effects (40.8 percent vs. 57.0 percent).
Large media organizations promoted this drug as a "smart bomb" or "wonder drug." The truth, as Jarvis reports, is that this promising technology is still in the experimental phase following the 2010 withdrawal of the first FDA-approved ADC, Mylotarg, due to severe liver toxicity and poor treatment response in acute myeloid leukemia (AML).
Don't get me wrong. The ADC field is fascinating and full of promise. But mainstream-media editors who simplify headlines have oversold the findings, potentially misleading patients who might not read all of the study details. Moreover, the T-DM1 findings are in abstract form at this point.
The comprehensive article by Lisa Jarvis details some of the technical challenges in creating ADCs but the high promise of these therapies based on the breadth of companies with ADCs currently in development. Go and read.
Disclosure: The primary author of the ASCO report, Duke oncologist Dr. Kim Blackwell, is a family friend and colleague. I also had a professional interest in antibody-drug conjugates while working at RTI and was co-author on a paper with investigators from Seattle Genetics in this regard.
Jarvis, Lisa M. Rethinking antibody-drug conjugates. Chemical & Engineering News 90(25): 12-18 (18 June 2012).
Antibody-drug conjugates are the cover story in the 18 June 2012 issue of C&EN. Illustration credit: ImmunoGen.