Will a Herceptin-Based ADC Save the Firm?
In what looked like much better news for Roche in the breast cancer arena, Roche and ImmunoGen reported in October initial findings from a randomized Phase II trial testing T-DM1 as a first-line treatment of Her2+ metastatic breast cancer in 137 patients with no prior chemotherapy. This antibody-drug conjugate (ADC) combines trastuzumab, the active ingredient in Herceptin, with a chemotherapy agent called maytansine (DM1).
The objective response rate for patients treated with T-DM1 was 47.8% compared to 41.4% for patients treated with Herceptin plus chemotherapy, with a minimum of 5.9 months of patient follow-up. Longer follow-up is required for analysis of PFS, the primary endpoint of the study, and for final, mature objective response-rate data. Final PFS data is expected to be available in the second quarter of 2011.
Particularly noteworthy trial results showed that the incidence of serious side effects reported with T-DM1 was about half of that reported with trastuzumab plus docetaxel (37% vs. 75%, respectively), with no increased risk of cardiotoxicity. For example, the rates of hair loss and neutropenia in the Herceptin-docetaxel arm were 66% and 57%, respectively. By comparison, hair loss and neutropenia were 1.5% and 7.5% of TDM-1-treated patients, respectively.
Roche and Immunogen had hoped that the promising Phase II data would form the basis of a BLA submitted in July with the FDA but instead received a refuse to file letter on August 21. The agency said that the trial failed to meet the standard for accelerated approval because all available treatment choices for metastatic breast cancer, regardless of Her2 status, had not been exhausted in the study population.
Questions of Avastin’s efficacy in treating breast cancer, given the antibody’s relative cost and associated toxicities, are one thing. It’s tougher, though, to figure out why the agency would oppose a drug that appears to show efficacy among 60–70% of Her2+ patients studied in the trial who didn’t respond to Herceptin. It also had an infinitely more tolerable side-effect profile than the usual suspects.
“Most of us are still shaking our heads and trying to understand what happened here,” analyst David Miller, president of Biotech Stock Research, told GEN. “What it comes down to is that the medical community believes that there is a fundamentally different treatment paradigm for Her2-positive patients and Her2-negative patients.
“For the former group, if you have a new therapy directed toward Her2, like T-DM1, once other treatment modalities considered options for treating positive patients are exhausted, the situation constitutes an unmet medical need with no available therapies. So, under that line of thinking, the Phase II single-arm study that Roche/ImmunoGen ran would have been suitable for approval. That is what the medical community believes.
“But the FDA believes that once you cycle Her2-positive patients through all the treatments they usually receive and those fail, they should receive the same treatment as Her2-negative patients. So, fundamentally, what the FDA said was that even though these patients didn’t respond to seven prior therapies, they are not really treatment refractory because they didn’t get the last two drugs, gemcitabine and ixabepilone.
“There’s a disconnect between what clinicians do and what FDA labels are for breast cancer patients. Theoretically those two drugs are last-line treatments for any kind of breast cancer, but in practice Her2-positive patients would never get those things if there was another Her2-specific drug available.”
Why didn’t Roche/Genentech figure this out before submitting their BLA to the FDA? Miller thinks that the issue was never a regulatory one but a clinical question, saying that the Phase II results would have been suitable for an advisory panel. “There is no question about the data, it’s fabulous with much fewer onerous side effects. The FDA made another regulatory decision that hurts patients.”
Roche and ImmunoGen are proceeding with the Phase III trial MARIANNE, which commenced in July. It is comparing T-DM1 and T-DM1 plus pertuzumab (an antibody that inhibits Her2 receptor dimerization with other Her receptors) to Herceptin plus taxane in patients with advanced Her2+ breast cancer not previously treated for advanced disease. They hope that their persistence and the trial results will, ultimately, provide an effective, less toxic treatment for women with breast cancer.