Media Release

Basel, 13 February 2006

Recruitment temporarily suspended in an international phase III trial (AVANT) in post-surgical adjuvant colon cancer
Patients within this study continue treatment and the broad Roche-Genentech Oncology programme remains on track


Roche announced today that safety data from AVANT, a trial to study different combination treatments for post-surgical adjuvant colon cancer, will be further reviewed.

The review has been recommended by the AVANT independent Data Safety Monitoring Board (DSMB) and is supported by Roche. The DSMB’s recommendation is based on two reasons: a safety concern observed in one of the three study arms and the fast recruitment in the AVANT trial (more than 200 patients per month) which could prevent adequate and timely intervention. To enable the DSMB to undertake a review of 60-day safety data the recruitment of additional patients will be temporarily halted. Patients already enrolled into the AVANT trial will continue treatment as per the study protocol. The safety data from these patients will continue to be closely monitored by the DSMB. All ongoing Roche studies in the oncology area will continue as planned.

Professor Aimery de Gramont, Principal Investigator for AVANT stated: “The AVANT trial provides a unique opportunity to assess the effect of combining an anti-angiogenic agent with standard chemotherapy in the adjuvant colon cancer setting. The temporary halting of the recruitment is necessary because in the adjuvant setting, the threshold for concern is particularly low. However, we look forward to exciting findings that will hopefully confirm the efficacy benefits that we have already observed in the metastatic setting. This will open the avenue for new options for patients suffering from colon cancer”

Since the AVANT trial began recruitment in December 2004, almost two third of the target number of 3,450 patients have been enrolled and in January 2006 alone, more than 250 patients were recruited. The all cause mortality excluding deaths due to the recurrent colon cancer in the AVANT trial for FOLFOX-4 (Arm A) was 0.6% (4 cases), for FOLFOX-4 + Avastin (Arm B) 0.4% (3 cases) and for XELOX + Avastin (Arm C) 1% (7 cases). These rates are consistent with those reported in other adjuvant studies in colon cancer. An occurrence of sudden deaths (4), especially in three younger patients was noted in Arm C. Temporarily suspending recruitment will allow the DSMB to perform a full safety assessment. The DSMB will continue to monitor all adverse events in the study, including gastrointestinal perforations, a side effect observed in previous studies of Avastin plus chemotherapy, that has been observed in the AVANT study at a rate of 1%. This is less than what has been observed in the metastatic setting (up to 2%).

“We concur with the DSMB’s recommendation,” Ed Holdener, Head of Global Development at Roche said. “Patient safety is of utmost importance to us. Speed of recruitment in the AVANT trial is exceeding expectations and safety should be carefully monitored, especially in the adjuvant setting where the risk/benefit profile is different from that of the metastatic setting. As such, we are committed to continuous monitoring and evaluation of all safety data reported from the AVANT trial. Roche has an unprecedented clinical trial programme in place in Oncology.”

A second study of Avastin plus chemotherapy as an adjuvant treatment for early-stage colon cancer, called C-08, is continuing recruitment as scheduled. Conducted primarily in the U.S by the National Surgical Breast and Bowel Project (NSABP) in collaboration with the National Cancer Institute (NCI), C-08 will enroll 2,714 patients. Patients are being randomized into two arms:

• Arm 1: FOLFOX (control arm)
• Arm 2: FOLFOX+Avastin (experimental arm)

Like the AVANT study, the NSABP’s C-08 trial has an independent DSMB that reviews safety data on a regular basis. This study has enrolled more than 1,800 patients since the trial opened in 2004 and the DSMB has not made any changes to the study protocol.

Avastin was approved in February 2004 in the USA and in the EU in January 2005 for the treatment of patients with previously untreated metastatic colorectal cancer (mCRC) and has a well-established efficacy and safety profile demonstrated through its use in over 54,000 patients worldwide.

There are currently more than 9,000 patients taking part in Avastin clinical trials across several indications. At this time, the DSMB’s recommendation for AVANT does not affect ongoing and planned studies of Avastin in colorectal cancer or in other tumour types.

About AVANT
The AVANT trial is a 3-arm global study (308 centers from 33 countries) randomizing high-risk stage II and stage III patients with colon cancer to FOLFOX-4 (infused/bolus 5-FU/LV + oxaliplatin), FOLFOX-4 plus Avastin, or XELOX (capecitabine + oxaliplatin) plus Avastin (arms A, B and C respectively). The objectives of AVANT are to assess whether adding Avastin to the chemotherapy regimens FOLFOX-4 or XELOX can prolong disease-free survival (i.e. whether it can reduce the chance of the cancer recurring) in patients who had no evidence of macroscopic disease after curative surgery and to determine the safety profile of Avastin when used Avastin in combination with FOLFOX-4 or XELOX in the adjuvant setting.

About Avastin
Avastin is the first treatment that inhibits angiogenesis – the growth of a network of blood vessels that supply nutrients and oxygen to cancerous tissues. Avastin targets a naturally occurring protein called VEGF (Vascular Endothelial Growth Factor), a key mediator of angiogenesis, thus choking off the blood supply that is essential for the growth of the tumour and its spread throughout the body (metastasis).

In Europe, Avastin is approved for first-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with the chemotherapy regimens of intravenous 5-fluorouracil/folinic acid or intravenous 5-fluorouracil/folinic acid/irinotecan. Avastin received fast-track approval by the US Food and Drug Administration (FDA) and was launched in the US in February 2004.

In the pivotal Phase III study, the addition of Avastin to chemotherapy (irinotecan/5-fluorouracil/leucovorin) significantly extended survival by, on average, five months (20.3 months versus 15.6 months) for people with previously untreated metastatic colorectal cancer. Avastin also significantly increased the amount of time the cancer was not growing compared with patients receiving chemotherapy alone (10.6 months vs. 6.2 months). In a second Phase III study, conducted by the Eastern Cooperative Oncology Group (ECOG), Avastin was also shown to significantly improve survival when added to another widely prescribed chemotherapy regimen (oxaliplatin/5-fluorouracil/leucovorin). With Avastin, people who had previously failed one chemotherapy regimen for their advanced disease, lived nearly two months longer, on average, compared to those who received chemotherapy alone (12.5 months vs. 10.7 months).

People with very advanced colorectal cancer who are too unwell to tolerate traditional aggressive chemotherapy also benefit from Avastin. The addition of Avastin to a less aggressive form of chemotherapy increased the length of time the cancer was not growing, by four months, compared to chemotherapy alone (a 67 percent increase in progression-free survival).

Roche and Genentech are pursuing a comprehensive clinical programme investigating the use of Avastin in advanced colorectal cancer with other chemotherapies and also expanding into the adjuvant setting (post operation). As its mechanism may be relevant in a number of malignant tumours, Roche and Genentech are also investigating the potential clinical benefit of Avastin in breast, lung, pancreatic cancer, ovarian cancer, renal cell carcinoma and others. Approximately 15,000 patients are expected to be enrolled into clinical trials over the next years worldwide.

About Safety of Avastin
The safety profile of Avastin in metastatic colorectal cancer has been defined in the first line treatment (e.g. pivotal trial AVF2107 ¹,) and second-line treatment (E3200 trial ²,) settings through a large phase III programme where Avastin was tested in combination with 5-FU, irinotecan and oxaliplatin containing regimens. In general, Avastin appears to be well tolerated. The most common adverse effects observed in clinical trials of metastatic colorectal cancer that are attributable to Avastin therapy are: hypertension, proteinuria, arterial thrombosis, wound healing complications and bleeding. Rare cases (up to 2%) of GI perforations have also been observed. While higher incidences of these events were reported in patients receiving Avastin than in control patients, most of these adverse effects were manageable.

These safety findings have been confirmed with a US registry (BRITE) and a global Expanded Access Programme (FIRST BEAT) which include a total of almost 4,000 patients treated with Avastin.

About Safety of Xeloda
The safety profile of Xeloda in metastatic colorectal cancer has been defined in the first line treament (SO14695 and SO14796 ³) and adjuvant colon cancer (M66001 X-ACT ⁴). In general, Xeloda appears to be well tolerated. The most common adverse effects observed in clinical trials of metastatic colorectal cancer and adjuvant colon cancer that are attributable to Xeloda therapy are: diarrhea, nausea, vomiting, stomatitis and hand-foot syndrome. The safety data from the NO16968 XELOXA study in adjuvant colon cancer show that the combination Xeloda plus oxaliplatin (XELOX) combination appears to be well tolerated ⁵.

The safety data from the ongoing study in 1st line mCRC, NO16966 comparing XELOX+Avastin/placebo with FOLFOX+Avastin/placebo in a 2x2 factorial design have been continuously monitored by a DSMB and no safety signals leading to modification of the trial have been idenfied.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As a supplier of innovative products and services for the early detection, prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. In 2005 sales by the Pharmaceuticals Division totalled 27.3 billion Swiss francs, and the Diagnostics Division posted sales of 8.2 billion Swiss francs. Roche employs roughly 70,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Additional information about the Roche Group is available on the Internet (www.roche.com).

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1 The pivotal trial AVF2107 compared IFL with or without AVASTIN in first line treatment of patients with metastatic colorectal cancer.
2 E3200 investigated AVASTIN in combination with FOLFOX-4 in patients with relapsed metastatic colorectal cancer whose disease progressed following previous treatment with both a 5-FU and irinotecan based chemotherapy regimen, either alone or in combination.
3 SO14695 and SO14796, two trials with identical design comparing Xeloda with bolus 5-FU/LV in first line treatment of patients with metastatic colorectal cancer.
4 M66001 X-ACT comparing Xeloda with bolus 5-FU/LV in adjuvant treatment of patients with stage III colon cancer.
5 NO16968 XELOXA comparing Xeloda+oxaliplatin(XELOX) with bolus 5-FU/LV in adjuvant treatment of patients with stage III colon cancer