Toxicity issues taint Kadcyla approval.
Kadcyla’s approval will strengthen Roche’s position in HER2-positive breast cancer market, but initial uptake could be limited due to toxicity concerns.
Kadcyla (T-DM1, trastuzumab emtansine; Genentech/Roche) has received FDA approval for the treatment of HER2-positive metastatic breast cancer. Kadcyla’s approval will enhance Roche’s portfolio of HER2-targeted therapies, but a boxed warning detailing associated toxicity could restrict the drug’s potential market.
Kadcyla’s approval is based on results from the Phase III EMILIA trial, which enrolled 980 first-, second-, and third-line HER2-positive metastatic breast cancer patients who had previously received Herceptin (trastuzumab; Roche/Chugai)-based therapy. Patients randomized to receive Kadcyla demonstrated median progression-free survival of 9.6 months and median overall survival of 30.9 months, surpassing the control arm of Xeloda (capecitabine; Roche/Genentech/Chugai) plus Tykerb (lapatinib; GlaxoSmithKline) by 3.2 months and 5.8 months, respectively.
Kadcyla is an antibody-drug conjugate (ADC), combining the biological component of the humanized monoclonal antibody Herceptin with the microtubule inhibitor drug maytansinoid 1 (DM1). Kadcyla utilizes Herceptin’s targeting nature, which internalizes the cytotoxic within the breast cancer tumor and selectively releases the drug inside the tumor cells.
Kadcyla is currently enrolled in two late-stage trials for the treatment of HER2-positive breast cancer. The MARIANNE trial is comparing three different treatment regimens (Kadcyla alone, Kadcyla in combination with Perjeta [pertuzumab; Genentech/Roche/Chugai], and Herceptin plus taxane chemotherapy) in treatment-naïve patients with HER2-positive metastatic breast cancer. In addition, the TH3RESA trial is comparing Kadcyla to the physician’s choice of treatment in the third-line treatment of HER2-positive metastatic breast cancer.
While Kadcyla is likely to gain uptake in HER2-positive breast cancer patients who relapse following Herceptin treatment, its commercial prospects could be impacted by concerns regarding its safety. Kadcyla’s approval has come with a black box warning, detailing treatment-associated hepatotoxicity, cardiac toxicity, and embryo-fetal toxicity. As the targeted nature of ADCs is thought to minimize treatment-related adverse events, the toxicity associated with Kadcyla could restrict its potential patient population.
Kadcyla’s approval adds weight to Roche’s portfolio of HER2-directed therapies. In June 2012, the FDA approved Perjeta in combination with Herceptin and docetaxel for the treatment of HER2-positive metastatic breast cancer. The approvals of both Kadcyla and Perjeta represent a determined effort by Roche to counteract the approaching patent expiry of its blockbuster Herceptin. However, Kadcyla’s ability to replicate Herceptin’s success will hinge on the results of the MARIANNE study, which directly compares the efficacy of both drugs in the first-line setting.