Single-agent bevacizumab (Avastin) may be an appropriate option for maintenance therapy in patients with metastatic colorectal cancer, instead of continuing treatment with bevacizumab and chemotherapy, according to a phase III study presented at the 2010 ASCO Annual Meeting. However, the data remain to be confirmed, and the investigators' conclusions were strongly debated at this Gastrointestinal Cancer Oral Abstract Session.

Lead author Josep Tabernero, MD, presented the findings of the Maintenance in Colorectal Cancer (MACRO) trial, conducted by the Spanish Cooperative Group for the Treatment of Digestive Tumors.¹ Dr. Tabernero, Chairman of the Medical Oncology Department at Vall d'Hebron University Hospital in Barcelona, Spain, said the optimal duration of treatment of metastatic colorectal cancer after maximal response is still under debate.

Using a noninferiority design, he and his colleagues compared maintenance treatment with single-agent bevacizumab vs that with bevacizumab plus continued standard chemotherapy. The aim of using bevacizumab alone was to "avoid cumulative toxicity without reducing the efficacy of treatment," Dr. Tabernero said.

"Noninferiority cannot be confirmed [yet for bevacizumab alone], but we can reliably exclude a detriment of larger than 3 weeks in median progression-free survival," he said, noting that longer follow-up is needed.

The investigators compared the two regimens after administering six cycles of induction chemotherapy-a classic regimen of capecitabine (Xeloda) plus oxaliplatin (XELOX)-and bevacizumab. Treatment continued until disease progression, toxicity, or withdrawal from the study. Dosages for induction therapy were 7.5 mg/kg of IV bevacizumab on day 1, 1,000 mg/m² of oral capecitabine twice daily on days 1 to 14, plus 130 mg/m² of IV oxaliplatin on day 1 every 3 weeks for six cycles.

Of the 480 patients enrolled in the study, 239 were randomly assigned to receive bevacizumab plus chemotherapy maintenance (arm 1) and 241 received the experimental treatment, bevacizumab alone (arm 2). Patient characteristics did not differ significantly for the two groups, Dr. Tabernero reported. The median duration of follow-up was 21.1 months for arm 1 and 20.4 for arm 2.

Progression-free survival (PFS), the primary endpoint, was a median of 10.4 months in arm 1 vs 9.7 months in arm 2 (Fig. 1). The difference was not statistically significant.

Secondary Endpoints Similar Between Regimens

The secondary endpoints of overall survival (OS) and objective response rate also showed no significant differences between the treatment arms, according to the authors. Median OS in arm 1 was 23.4 months and in arm 2 was 21.7 months. The confirmed response rate was 46% in arm 1 and 49% in arm 2.

The experimental arm completed one more cycle of maintenance treatment than did the control arm (median of four vs three, respectively).

In terms of safety, another secondary endpoint, the investigators observed no major differences between arms. As expected, more patients in arm 1 had grade 3 or 4 adverse events (53.8% vs 47.9% in arm 2), Dr. Tabernero said. Four patients in arm 1 and eight patients in arm 2 had adverse events leading to death. Of note, only one patient in the bevacizumab-only arm had a gastrointestinal perforation, compared with two patients in the control arm.

Conclusions Questioned

Discussant Alan Venook, MD, Professor of Clinical Medicine at the University of California, San Francisco, questioned the authors' conclusion that they can reliably exclude a detriment of larger than 3 weeks of PFS. Instead, based on a statistician's review of the authors' data (HR = 1.11; 95% CI = 0.89-1.37; median PFS = 10 months), he believes the excess hazard in the experimental arm is approximately 3.7 months. He said this does not indicate noninferiority.

In response, Dr. Tabernero told The ASCO Post, "We can rule out a difference of more than 3 weeks on the median [PFS], but the 95% CI could include a maximum of 3 months."

However, Dr. Venook told the presentation attendees, "Based on overall survival, PFS is not terribly relevant in this analysis, because patients live the same length of time."

He did agree with Dr. Tabernero's comment that further studies of single-agent bevacizumab after standard chemotherapy for metastatic colorectal cancer are warranted.

A member of the audience commented that bevacizumab is an expensive maintenance treatment, and the study should have included a no-treatment arm after induction chemotherapy concluded. ■

Reference

1. Tabernero J, Aranda E, Gomez A, et al: Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). 2010 ASCO Annual Meeting. Abstract 3501. Presented June 6, 2010.