IHS Global Insight Perspective | |
Significance | The U.S. FDA has confirmed that it will seek to withdraw all breast cancer indications for Avastin (bevacizumab). In Europe, the European Medicines Agency (EMA) has said that it will maintain the approval for Avastin in combination with paclitaxel, however it will revoke the use of the drug in combination with docetaxel, and it has also issued a non-recommendation for Avastin in combination with Xeloda (capecitabine). |
Implications | Roche's U.S. subsidiary is due to enter discussions with the FDA over its decision. |
Outlook | Roche will still be able to generate revenues from the drug in the European Union thanks to the EMA's decision to permit continued use of Avastin plus paclitaxel, although revenues in the United States appear to be less certain. |
FDA's Decision on Avastin
The U.S. FDA has issued a final decision on Swiss pharmaceutical company Roche's blockbuster oncology drug Avastin (bevacizumab) for the first-line treatment of metastatic HER2-negative breast cancer in combination with paclitaxel. The FDA informed Roche's U.S. subsidiary Genentech of its "Proposal to Withdraw Marketing Approval" for the drug. Genentech has also been issued a Notice of Opportunity for a Hearing (NOOH) which will give the company the opportunity to discuss the proposed withdrawal of the breast cancer licence with the regulatory agency.
The FDA has also issued complete responses related to AVADO, RIBBON1, and RIBBON2. AVADO looked at evaluated Avastin in combination with docetaxel in first-line HER2-negative breast cancer, RIBBON1 evaluated Avastin in combination with a taxane/anthracycline-based chemotherapy or Xeloda (capecitabine) also in first-line treatment, and RIBBON2 evaluated the drug in the second-line setting, in combination with a number of different chemotherapy regimens—taxanes such as paclitaxel, protein-bound paclitaxel or docetaxel; gemcitabine; Xeloda, or vinorelbine.
Roche has confirmed that its U.S. subsidiary will indeed request a NOOH with the FDA, and until the hearing process is complete Avastin will still be licensed for use in breast cancer.
EMA's Decision on Avastin
Separately, the European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP) has completed its review of Avastin in first-line breast cancer, focusing on the drug in combination with paclitaxel and docetaxel—the two currently approved combos for the drug in breast cancer.
According to the CHMP, the benefits of Avastin in combination with paclitaxel are positive in terms of improving progression-free survival (PFS), and as such the risk-benefit profile of the combination is favourable to justify continued approval. For Avastin in combination with docetaxel, the agency said that there remain uncertainties regarding the benefits, therefore it has decided to revoke the approval. The CHMP has also issued a non-recommendation on Avastin in combination with Xeloda. The European Commission will now make a final decision on the drug based on the recommendations of the EMA.
Timeline of Setbacks for Avastin 2009-2010 | ||
Indication | Details | Date |
Colon cancer | Avastin failed to meet its primary endpoint, defined as disease-free survival (DFS) benefits, in the NSABP C-08 (C-08) study. The Phase III study evaluated the benefits of Avastin in combination with FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin over stand-alone chemotherapy in the treatment of colon cancer patients immediately after surgery (adjuvant setting). | April 2009 |
Stomach cancer | Avastin failed to meet its primary endpoint in the Phase III AVAGAST study, which investigated the use of Avastin in combination with Xeloda or fluorouracil and cisplatin chemotherapy, in comparison with Xeloda or fluorouracil and cisplatin chemotherapy alone, for the treatment of advanced stomach cancer. | February 2010 |
Prostate cancer | Avastin failed to meet its primary endpoint in the Phase III CALGB 90401 trial, which evaluated the benefits of Avastin in combination with docetaxel and prednisone for late-stage prostate cancer. | March 2010 |
Diffuse large B-Cell lymphoma | Roche will no longer recruit patients into a Phase III clinical study investigating the use of a combination of Avastin with MabThera/Rituxan (rituximab) plus CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone). | June 2010 |
Breast cancer | The FDA's oncology drug advisory committee voted 12-1 in favour of removing the previously untreated, first-line, advanced, HER2-negative breast cancer indication for Avastin in combination with paclitaxel. The AVADO and RIBBON1 Phase III studies failed to confirm the drug's benefits in improving PFS. In AVADO, treatment with Avastin 7.5 mg/kg and 15 mg/kg plus docetaxel increased PFS by 30% and 39% respectively, while in the RIBBON1 study, Avastin in combination with taxane/anthracycline-based chemotherapy increased PFS by 36%, and Avastin in combination with capecitabine increased PFS by 31%. This data failed to match the original 52% improvement in PFS as per the results of the E2100 Phase III study which formed the basis of accelerated approval for Avastin in combination with paclitaxel back in 2008. | July 2010 |
Colon cancer | Results from the Phase III AVANT study, which evaluated Avastin in combination with Xeloda (capecitabine) and oxaliplatin (XELOX), or fluorouracil/leucovorin with oxaliplatin (FOLFOX-4), for the adjuvant treatment of early stage colon cancer, failed to meet its primary endpoint of improving DFS in patients with stage III colon cancer. | September 2010 |
Breast cancer | Following the FDA's Oncologic Drugs Advisory Committee (ODAC)'s damning verdict in July, and based on data from the RIBBON1 study, the EMA announced plans to initiate a review of current approvals for Avastin in combination with paclitaxel or docetaxel. | September 2010 |
Source: Roche, IHS Global Insight | ||
Outlook and Implications
The FDA was originally due to make a decision based on ODAC's recommendations on 17 September, however, this decision was delayed after further undisclosed information was provided by the company, thereby offering the company some temporary reprieve (see Switzerland: 23 September 2010: Avastin's Clinical Setbacks Persist, FDA Delays Final Decision on Breast Cancer Indication). It is now increasingly apparent that this information was not adequate to sway the FDA's opinion. While Roche has said that the breast cancer approval will remain in place until NOOH proceedings are complete, the outlook for the drug in breast cancer looks increasingly bleak, and it is highly likely that the company will be looking for an effective mitigation plan to address the revenue loss which will ensue. According to initial estimates, Roche could stand to lose as much as US$1 billion if Avastin's breast cancer revenue stream is cut. However,given the culture of off-label use for oncology drugs in the United States due to the private nature of the health system, Roche may still be able to generate some income from off-label use if the NOOH proceedings are not fruitful.
In contrast with the FDA, the EMA's position is crystal clear and Roche has not mentioned any plans to engage in further discussions with the EMA to salvage the drug in combination with docetaxel and Xeloda for the time being. The EMA's decision on Avastin/paclitaxel will therefore mean that European sales may still remain intact as the combination is more widely used than the Avastin/docetaxel combination.
Overall, it is fair to say that 2010 has been a challenging year for Roche: its star drug, Avastin, which generated 16% revenue growth to 6.2 billion francs (US$6.1 billion) in 2009, has encountered a string of clinical setbacks—colon cancer, stomach cancer, prostate cancer, and lymphoma—while an important revenue stream for the drug looks increasingly uncertain. In addition, the company has reported other setbacks for non-oncology drugs such as taspoglutide in type 2 diabetes, and ocrelizumab in rheumatoid arthritis. These setbacks have essentially served as the driving force behind the company's restructuring programme, which saw 4,800 jobs cut in various areas in a bid to save 1.8 billion Swiss francs in 2011, followed by 2.4 billion francs from 2012 onwards (see Switzerland: 17 November 2010: Roche Fully Outlines Restructuring Programme).
In terms of continued growth in the short-to-medium term, while the company's oncology drugs will continue to generate major revenues, the company faces challenges to diversify not just its portfolio and pipeline of innovative drugs, but also to look for wider growth beyond its core innovative pharma focus, as many of its competitors are now doing. Although the company has so far refrained from wider diversification—with the exception of its diagnostic-related activities, it is possible that it may seek to employ this type of strategy in the long term.