Roche's T-DM1 Early Filing Strategy Backfires As FDA Refuses To File BLA
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
FDA issued a refusal to file letter for Roche's BLA for trastuzumab-DM1 (T-DM1) for accelerated approval because all the available treatment choices approved for metastatic breast cancer had not been exhausted in the study population, Roche said Aug. 27
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FDA issued a refusal to file letter for Roche's BLA for trastuzumab-DM1 (T-DM1) for accelerated approval because all the available treatment choices approved for metastatic breast cancer had not been exhausted in the study population, Roche said Aug. 27. The decision appears to have more to do with the statutory standards for accelerated approval than with concerns about the pioneering antibody-drug conjugation technology used in the product, an "armed antibody" version of Roche's blockbuster Herceptin linked to the cytotoxic drug DM1 that delivers the chemotherapeutic directly to cancer cells. The conjugation technology is licensed from ImmunoGen. FDA appears to be taking a stringent approach to defining cancer patient populations eligible for accelerated approval, a regulatory pathway that allows for conditional approval based on surrogate markers in patients with life-threatening diseases who have no remaining medical options. GSK and Genmab's Arzerra (ofatumumab) was denied accelerated approval in one of the populations in the BLA because the agency determined other treatment options existed (see related story, "1 (Also see "Review Challenge: Deduce Efficacy From One Subset Of One Single-Arm Trial" - Pink Sheet, 1 Sep, 2010.)"). Roche's filing was based solely on the results of a single-arm 110-patient Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2-positive breast cancer who had received an average of seven prior medicines, including two HER2-targeted agents. During Roche's investor meeting in March, the company admitted the accelerated approval strategy had a lower probability of success than one based on significantly more data. "If we file early, we file on early data and the risk of not succeeding there is higher," acknowledged Jean-Jacques Garaud, head of research and early development. Accelerated approval also carries the risk of losing marketing clearance if a required confirmatory trial fails to confirm the clinical benefit suggested by the surrogate or interim data. Pfizer, for example, pulled Mylotarg (gemtuzumab) for acute myeloid leukemia from the market in June, 10 years after it received accelerated approval, when it failed in a confirmatory trial (2 (Also see "Pfizer Pulls Mylotarg For Safety 10 Years After Accelerated Approval" - Pink Sheet, 28 Jun, 2010.)). While the T-DM1 Phase II data were positive, it's not surprising that FDA would want to see more. The agency is taking a harder look at progression-free survival as an endpoint for breast cancer and how it relates to clinical outcomes, as suggested by the controversial June advisory committee review of Genentech's application to convert the accelerated approval of Avastin (bevacizumab) for first-line treatment of metastatic breast cancer to full approval. The committee's rejection of full approval was based largely on concerns that the drug did not delay disease progression long enough to be clinically meaningful (3 (Also see "Avastin Breast Cancer Approval Debate Pits Clinical Benefit Versus Statistics" - Pink Sheet, 26 Jul, 2010.)). "We can't speculate if the Avastin decision had anything to do with this decision" not to accept the accelerated approval BLA for T-DM1, a Genentech representative said. "But FDA continues to make it clear that they want randomized data and overall survival data for approval of new breast cancer drugs." "We continue to believe in the potential for T-DM1 and don't see FDA's decision as a reflection on that," ImmunoGen CEO David Junius said during a same-day conference call. "This appears to be a technical issue, not a fundamental one." The refusal to file action pushes a potential re-filing and launch out two years, pending the results of an ongoing Phase III trial. Dubbed EMILIA, the trial compares T-DM1 to GlaxoSmithKline's Tykerb (lapatinib) in combination with capecitabine in people with advanced HER2 positive breast cancer whose disease has worsened after initial treatment. Roche said it expects to resubmit the BLA in mid-2012, which would position the drug for a launch in 2013. Genentech has also partnered with another antibody-drug conjugate developer, Seattle Genetics, which isn't concerned that the T-DM1 RTF action will derail such programs. "We do not believe the FDA's decision on T-DM1 has broader implications for antibody-drug conjugates," the firm said. "In our view, the decision appears to relate to the treatment landscape for metastatic breast cancer rather than more generally applicable principles." Its lead program, SGN-35, which combines a CD30 antibody with its ADC technology, is in Phase III for relapsed and refractory Hodgkin's lymphoma patients under a Special Protocol Assessment with FDA. The firm said FDA has agreed the trial design meets the requirements for accelerated approval. - Jessica Merrill ( 4 [email protected] ) |