By Laura Nikolaides, Director of Research and Quality Care Programs
I just got back from spending the weekend in Chicago at the annual meeting of the American Society of Clinical Oncology (ASCO). As you all know, this meeting always generates a flurry of headlines and media stories about new findings in the treatment of cancer. This year, it was T-DM1 for metastatic breast cancer that was given a top presentation spot at the meeting and created the biggest stir in the media.
But, as always, the facts or complexities of the results often get lost in the headlines and stories. The New York Daily News said the drug delivered “stunning results” in delaying progress of breast cancer. Huffington Post headlines called T-DM1 a “wonder drug.”
The truth is that the results of the Phase III trial of T-DM1 (named EMILIA by drugmaker and sponsor Genentech) were modest, but encouraging, and more time is needed before we know definitively if, and for how long, the drug increases survival in women with HER2+ metastatic breast cancer.
The study compared T-DM1 to a combination regimen of Xeloda and Tykerb (XT) in 991 women with HER2+ metastatic breast cancer that had progressed, despite treatment with Herceptin and taxanes and/or anthracyclines . The women receiving T-DM1 had an average time until disease progression of 9.6 months, compared to 6.4 months for those receiving XT. The final overall survival analysis is not yet complete, but an interim analysis fell short of the predetermined boundary for stopping the trial and allowing crossover, by just one patient.
At 12 months, 84% of those on T-DM1 were still alive, compared to 77% on XT, and at two years that gap had widened to an 18% difference, 65% alive on T-DM1, compared to 47% on XT. Statistically, it is still possible that the differences in survival could be due to chance and will need confirmation in the final analysis. There were five adverse events leading to death in the XT arm, compared to one in the TDM1 arm, cardiotoxicity was minimal, at less than 2% in both arms. The main T-DM1 toxicities were low platelet counts and abnormal liver function, which the investigators reported were reversible, while those on XT experienced more nausea, hand-foot disease, diarrhea and hair loss.
“These results left me feeling cautiously optimistic that this new agent does indeed deliver meaningful benefit to women with HER2+ metastatic breast cancer, with less toxicity.”
These results left me feeling cautiously optimistic that this new agent does indeed deliver meaningful benefit to women with HER2+ metastatic breast cancer, with less toxicity. And there is no doubt for me that the EMILIA results do represent a major victory for science, and may open the door to a long sought after goal for all cancer patients—being able to deliver toxic agents that kill malignant cells directly while avoiding damage to normal cells. According to an article in the New York Times, approximately 24 other similar agents, called antibody-drug conjugates, are in development. These antibody-drug conjugates, or hybrids, consist of antibodies that are linked to the chemotherapy agents. In the case of T-DM1, the monoclonal antibody Herceptin is attached to the chemotherapy emtansine, or DM1, a chemotherapy agent that is potent and intolerable if given directly to patients.
After decades of effort by scientists, the scientific victory for TDM1 was in the linking technology; the link used to combine the antibody and chemotherapy allows the drug to remain intact outside the cancer cell, but in an inactive state until it enters the cancer cell, thereby minimizing exposure of normal cells to the chemotherapy. After finding the cancer cells in the body by their over-expression of HER2 and attaching, T-DM1 is then absorbed into those cancer cells, and the potent DM1 is released to destroy the malignant cells.
I look forward eagerly to the final results of this trial, and to results of additional trials of T-DM1, including MARIANNE, a 3-arm, multicentre, phase III study comparing T-DM1 combined with pertuzumab, TDM1 alone, and the combination of Herceptin plus a taxane in patients with HER2-positive progressive or previously untreated metastatic breast cancer. And I look forward to ultimately seeing a translation of this new technology to create other agents that can target a wider group of breast cancer patients, giving more women the opportunity for less toxic treatment.
Genentech plans to submit an application for drug approval for T-DM1 to both the FDA and the European counterpart sometime this year. To avoid compromising the final results on overall survival, which could delay or prevent drug approval in the US or abroad, Genentech is not currently offering an early access program, but is actively recruiting metastatic HER2+ breast cancer into the TH3RESA trial at 210 sites, including 90 within the US. Women entering into this trial will be randomized at a 2 to 1 ratio to receive T-DM1 or physician’s choice for treatment.