The antibody-drug conjugate trastuzumab emtansine, T-DM1 (Kadcyla®), is composed of the antibody trastuzumab and the chemotherapeutic agent DM1 and is currently being investigated for the treatment of HER2-positive cancers. It specifically suppresses HER2 signaling, which is relevant for tumor growth, and places the cell-killing substance DM1 directly in the HER2-positive tumor cells. Furthermore, it appears to cause the body to fight the cancer cells itself via the immune system. Results on this new agent as well as on rituximab subcutaneously were presented at the DGHO Congress in Vienna.
(ag) “Preclinical studies show higher activity compared with trastuzumab alone, an effect that specifically affects only HER2, and activity even in trastuzumab-refractory tumors [1],” said Prof. Peter Schmid, MD, Brighton.
A 2011 phase II study [2] reexamined efficacy after results from an earlier phase I study showed that T-DM1 was well tolerated at the maximum dose of 3.6 mg/kg bw every three weeks and worked concurrently in patients with HER2-positive metastatic breast cancer (MBC) previously taking trastuzumab.
Methods: 112 patients with HER2-positive MBC who had progression on trastuzumab and chemotherapy were studied. The dose was 3.6 mg/kg bw every three weeks.
Results: T-DM1 demonstrated robust activity in these heavily pretreated patients. The response rate was better in patients with higher HER2 expression.
Therapy landscape today and tomorrow
“Before T-DM1 and pertuzumab, the treatment landscape was as follows: First-line chemotherapy plus trastuzumab was the standard of care, second-line capecitabine plus lapatinib, and third-line there was no widely accepted treatment pathway,” Prof. Schmid said. “There is now a comparative study with T-DM1 at each of these levels.”
- In the first-line setting , a phase II study [3] compared T-DM1 with trastuzumab plus docetaxel. It concludes that the new agent provides significantly longer progression-free survival than the comparator drug in first-line HER2-positive MBC patients. The safety profile was positive.
- Also in the first-line setting, the phase III MARIANNE trial is currently comparing three different treatments: T-DM1 alone, T-DM1 plus pertuzumab, and trastuzumab plus taxane chemotherapy.
- In the second-line setting, the phase III EMILIA trial is comparing T-DM1 to capecitabine plus lapatinib. Preliminary results show that T-DM1 significantly increased progression-free survival, as assessed by an independent review panel, compared with the other arm. It also improved overall survival and showed less frequent adverse events of severity ≥3 than the comparator medication.
- In the third-line setting , the TH3RESA trial is comparing T-DM1 to physician-selected therapy in patients already treated with Herceptin and lapatinib. Initial results show that T-DM1 significantly improved progression-free survival compared to other trastuzumab combinations. The safety profile was positive.
“Thus, T-DM1 has significant activity in all treatment indications based on initial evidence and is superior to alternative standard therapies in the second- or third-line setting. The effect is dependent on HER2 expression, but otherwise consistent across subtypes. The agent also has a more favorable toxicity profile compared to standard therapies and the incidence of cardiac toxicity is low,” Prof. Schmid concluded.
Subcutaneous rituximab
Clemens Wendtner, MD, Munich, spoke about the novel formulation of the anti-CD20 antibody rituximab subcutaneous plus hyaluronidase: Potentially, subcutaneous offers the following advantages over i.v. administration:
- faster application
- thus shorter stay of the patient in the hospital/day clinic/practice
- increased compliance
- Time, resource and cost savings for physicians.
Subcutaneous hyaluronidase also increases the distribution of the co-injected drug. By allowing rituximab to be given subcutaneously possibly at a fixed dose, fewer dosing errors occur. Intravenous formulations of antibodies such as rituximab and trastuzumab require dosages based on body surface area or body weight. This makes them more prone to error and associated with high pharmacokinetic variability. Moreover, they do not adequately reflect actual exposure to a drug.
“Initial clinical studies then show good efficacy compared with rituximab i.v.: the phase III SABRINA study met the first endpoint of non-inferiority to intravenous administration (375 mg/m2). Furthermore, switching to the subcutaneous route of administration (1400 mg fixed dose) does not appear to affect the anti-lymphoma activity of rituximab but does appear to increase the Absolute Risk Reduction (AAR). Medically relevant, new safety signals that might have been associated with the higher dose did not appear. Accordingly, approval for subcutaneous rituximab is expected in the first quarter of 2014 in the indication follicular lymphoma and diffuse large B-cell lymphoma (DLBCL),” Dr. Wendtner concluded his presentation.
Source: “Antibodies reloaded: new applications and antibody-drug conjugates”, Satellite Symposium of Roche Pharma AG at the DGHO Congress, October 18-22, 2013, Vienna.
Literature:
- Lewis Phillips GD, et al: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008 Nov 15; 68(22): 9280-9290. doi: 10.1158/0008-5472.CAN-08-1776.
- Burris HA, et al: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011 Feb 1; 29(4): 398-405. doi: 10.1200/JCO.2010.29.5865. epub 2010 Dec 20.
- Hurvitz SA, et al: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 2013 Mar 20; 31(9): 1157-1163. doi: 10.1200/JCO.2012.44.9694. epub 2013 Feb.
CongressSpecial 2014; 6(1): 15-16
InFo Oncology & Hematology 2014; 2(2): 39-40.
