Third-line bevacizumab disappoints in colorectal cancer trial

No third-line advantage seen with 5-FU/LV/bevacizumab combination

Combining bevacizumab (Avastin) with fluorouracil/leucovorin produced little response in 100 patients who had tumor progression after receiving at least two previous chemotherapy regimens for locally ad-vanced or metastatic colorectal cancer, according to the results of a National Cancer Institute (NCI) study (Treatment Referral Center protocol TRC-0301).

When Helen Chen, MD, reported the disappointing results at the 40th annual meeting of American Society of Clinical Oncology (ASCO) in June, at the median follow-up of 7.7 months (range, 7.2–9 months), she noted that the median time to disease progression was 15.1 weeks. Participating sites reported that just four patients had a partial response to treatment; the NCI’s independent review confirmed one response and listed the other three as stable disease. However, survival data were not considered to be mature.

Dr. Chen, a senior investigator at the NCI’s Cancer Therapy Evaluation Program (CTEP), would not completely dismiss further clinical evaluation of bevacizumab after the early stage of metastatic colorectal cancer, however. “Adding it to an inactive chemotherapy agent doesn’t seem to work,” she said in an interview. “However, it is unclear at this time whether bevacizumab may had any added value when combined with anti-tumor agents that are active in the second- or third-line setting.

This multicenter trial was unusual, since it was organized by the NCI’s CTEP and involved the Treatment Referral Center network of NCI-designated cancer centers and selected community cancer centers to achieve geographic coverage. It was conducted in collaboration with Genentech, Inc. and in consultation with patient advocacy groups.

Dr. Chen said that the trial was initiated in response to tremendous public interest in bevacizumab after the ASCO 2003 meeting, when Dr. Herbert I. Hurwitz, assistant professor of medicine at Duke University Medical Center, Durham, North Carolina, reported the pivotal trial results in the first-line setting, which demonstrated a 5-month survival advantage conferred by the addition of bevacizumab to fluorouracil-based therapy. At the time, bevacizumab was not commercially available. The CTEP trial was designed to provide rapid and widely available access to bevacizumab in the setting of a clinical trial for third-line patients who had exhausted standard treatment options.

Explaining why fluorouracil/leucovorin were chosen for the combination with bevacizumab, Dr. Chen said, “Given the lack of data to support bevacizumab monotherapy, it was considered important to use bevacizumab in a combination regimen. How-ever, there were no standard agents for
this setting. Cetuximab [Erbitux], which was also investigational at the time, was the only [agent] that has shown efficacy in the third line, but we did not have safety data for the combination [with bevacizumab] to be used in a multicenter trial of this nature. On the other hand, there were extensive safety data for bevacizumab and fluorouracil/leucovorin.” Eligibility cri--teria for the trial included tumor progression after or intolerance to tolerate both irinotecan (Camptosar) and oxaliplatin (Eloxatin).

Patient enrollment in this trial was brisk. Between July 14, 2003, and October 7, 2003, 100 patients evaluable for response were enrolled in this study. At the recommendation of patient advocacy groups, CTEP extended enrollment for 2 weeks, admitting an additional 250 patients who already were being screened. The average age for all patients involved was 61 years. Over 90% of patients in both groups had an Eastern Cooperative Oncology Group performance status of 0–1.

In all, 337 patients received at least one dose of the combination, which included 5 mg/kg of bevacizumab via infusion every 2 weeks and either the Roswell Park or de Gramont fluorouracil/leucovorin regimen. By May 17, 2004 (at a median follow-up of 7 months; range, 5.4–10 months), however, 264 patients had left the study—64% of them due to progressive disease. Half of the treated patients experienced at least one adverse event that was of grade 3 or higher, and 13% came off study because of adverse events. Data received thus far have contributed to the response data for the first 100 patients.

On the basis of these results, Dr. Chen’s team concluded, “In the third-line setting of [colorectal cancer], bevacizumab should only be used in additional clinical trials with other agents.” Dr. Chen pointed out that a combination regimen of great interest is bevacizumab with cetuximab. Cetuximab, a monoclonal antibody, has been shown to shrink colorectal tumors when used alone and with irinotecan. She noted that Leonard Saltz, MD, of the Memorial Sloan-Kettering Cancer Center, is conducting a CTEP-sponsored study with bevacizumab/cetuximab with and without irinotecan in patients who have irinotecan-refractory colorectal cancer. This trial is actively accruing, and the results are eagerly awaited, she added.

From the Fall 2004 edition of The Oncology Report, published by Elsevier/BioLink Communications.
© 2004 Elsevier Inc. All rights reserved.