Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Label-expansion efforts have failed, and mAb stands to lose provisional approval in breast cancer.

In the recent past oncology innovation in pharma companies has been driven by biotechnology company collaborations. About 75% of Phase II, III, and preregistration drugs originated from biotech firms. 

Such partnerships, however, have not rescued Roche’s anticancer pipeline. Setbacks over recent months forced the world’s leading supplier of cancer therapeutics to announce an “efficiency” drive to offset R&D disappointments.

Most notably, Roche’s latest hopes for Avastin (bevacizumab) in breast cancer have, at least for the present, hit the wall. Other setbacks include failure to expand use of Avastin to gastric cancer, inability to win priority review for T-DM1 in Her2+ metastatic breast cancer, and scrapping of ocrelizumab for RA. Approval of ocrelizumab in RA would potentially have produced $2 billion in annual sales.

As recently as last March Roche said it planned to strengthen its position in oncology and expand into areas such as metabolism and inflammation. It expected to introduce at least six new medicines by 2015.  In September, however, the company voiced concern over recent clinical failures and healthcare budget belt-tightening. It instituted a cost-cutting plan, which was billed by the company as a group-wide “Operation Excellence” initiative.

Breast Cancer Sanction Shaky

FDA’s 2008 green-light of Avastin in Her2-negative breast cancer faces suspension, as the Oncology Drugs Advisory Committee (ODAC) recommended that the provisional approval be revoked due to a lack of benefit when compared to the drug’s risks.

Avastin earned $6 billion in sales in 2009, accounting for 12.7% of Roche’s revenues last year. But ODAC’s July 20 recommendation could compromise that franchise. The company stands to lose $1 billion in sales if Avastin loses its breast cancer sanction. The drug retains approval for colon, lung, kidney, and brain cancer treatment.

When FDA gave Avastin the go-ahead for breast cancer it required the drug’s manufacturer, Genentech, to perform two additional clinical trials to establish its ability to keep the disease from worsening for at least five months. These studies indicated that the drug limited cancer growth by 2.9 months and found side effects including fatigue, abnormal white blood cell counts, and high blood pressure.

FDA was expected to make a decision about Avastin’s fate in September but extended the review until December 17 as Roche/Genentech submitted additional data to the agency. Roche/Genentech is convinced that study results showed Avastin improved progression-free survival (PFS).

While analysts are divided as to whether the agency will say yay or nay, they point to the highly charged political climate in which the December decision will be made. Last year, the Government Accountability Office criticized the agency for failing to effectively follow up on post-marketing studies required to grant full approval, pointing to the Roche-Avastin case as an example.

Outsiders Doubt Efficacy in Ovarian Cancer

As part of its franchise-extension plans for Avastin, in October Roche/Genetech reported full results of its ICON7 clinical trial testing the mAb’s efficacy as a first-line, postsurgical ovarian cancer treatment. Roche said that chemotherapy-naïve ovarian cancer patients who received Avastin in combination with standard chemotherapy and then continued Avastin alone had about 27% improvement in PFS compared to those women who received only chemotherapy. This corresponded to a 21% reduction in the risk of cancer progression or death.

Results from a previous Phase III study in 218 ovarian cancer patients, called GOG-0218, showed that Avastin, when combined with standard chemotherapy and then continued alone, improved PFS by up to 54% compared to those who received only chemotherapy.

Researchers have noted, however, that while Avastin helps women with ovarian cancer live longer without their disease getting worse, its effect peaks at 12 months and then diminishes. Overall, the drug extends the time patients live without their disease getting worse by 1.5 months, according to Tim Perren, M.D., from Leeds Teaching Hospitals NHS Trust.

At 12 months women taking Avastin on top of chemotherapy had a 15% reduced risk of their disease progressing compared to those on chemotherapy alone, Dr. Perren said. Beyond the first year, however, the effect dwindled, with a median time to progression of 19 months in the Avastin group and 17.3 months in the control group. After around two years the number of women alive without disease progression was lower in the Avastin arm.

Roche/Genentech presented a different analysis for ICON7, which will also be used for regulatory submissions. The company’s evaluation showed Avastin patients had a 21% reduction in the risk of disease progression. The firm plans to seek European ovarian cancer approval at the end of this year and submit a U.S. application in 2011. Mondher Mahjoubi, Roche’s head of oncology, said sanction in ovarian cancer could add between CHF 500 million and CHF 1 billion ($560 million to $1.04 billion) to annual sales.

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.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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