Two trials reported at the 2016 Gastrointestinal Cancers Symposium evaluated bevacizumab (Avastin)-containing regimens in the first-line treatment of metastatic colorectal cancer and supported some, but not all, previous findings.
The STEAM trial found some numerical differences but no statistically significant improvement between sequential or concurrent FOLFOXIRI plus bevacizumab and FOLFOX plus bevacizumab.1 The MAVERICC trial found numerically better outcomes with FOLFIRI/bevacizumab over FOLFOX/bevacizumab, but the differences were not statistically significant; it also failed to show predictive value for the potential biomarker ERCC1 (excision repair cross-complementation group 1 gene).2
FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin), FOLFIRI (5-FU, leucovorin, irinotecan), and FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan) are well established in the treatment of metastatic colorectal cancer. ERCC1 belongs to a family of DNA-repair genes, and its expression is believed to be a marker of resistance to platinum compounds.
STEAM: Trends Favor Triplet Regimen
The STEAM trial was the first study to compare sequential FOLFOXIRI plus bevacizumab, concurrent FOLFOXIRI plus bevacizumab, and FOLFOX plus bevacizumab head to head.
“Compared to FOLFOX/bevacizumab, the triplet regimen of concurrent FOLFOXIRI/bevacizumab demonstrated trends for improved response rates, progression-free survival, and metastatic resection rates,” reported Johanna Bendell, MD, of the Sara Cannon Research Institute, Nashville.
STEAM and MAVERICC Trials in Metastatic Colorectal Cancer
- The STEAM trial compared FOLFOXIRI plus bevacizumab, given sequentially and concurrently, and FOLFOX plus bevacizumab, with nonstatistically significant trends favoring FOLFOXIRI. The results align with the findings from the previous TRIBE study.
- The biomarker-driven MAVERICC trial found no statistically significant difference between FOLFIRI/bevacizumab and FOLFOX/bevacizumab, and it failed to demonstrate predictive value for the potential biomarker ERCC1.
The study randomized 280 patients to one of these arms for a 4-month induction phase, followed by leucovorin/5-FU/bevacizumab or capecitabine/bevacizumab. Upon disease progression, patients received investigator’s choice of fluoropyrimidine-based chemotherapy. Median follow-up was approximately 1 year.
Median progression-free survival was 9.3 months with FOLFOX/bevacizumab, 11.7 months with concurrent FOLFOXIRI/bevacizumab (hazard ratio [HR] = 0.672; 95% confidence interval [CI]: 0.489–0.922), and 10.7 months with sequential FOLFOXIRI/bevacizumab (HR = 0.738; 95% CI: 0.537–1.012).
Liver resection rates were 15.1% with concurrent FOLFOXIRI/bevacizumab, 9.8% with sequential FOLFOXIRI/bevacizumab, and 7.4% with FOLFOX/bevacizumab. Response rates were 60.2%, 62.0% and 47.4%, respectively, she said.
All regimens were well tolerated, but more grade 3 or higher hypertension was observed with concurrent FOLFOXIRI/bevacizumab.
“The interim results of STEAM align with the findings from TRIBE,3 which support the role of FOLFOXIRI/bevacizumab as a treatment option in selected patients with first-line metastatic colorectal cancer,” said Dr. Bendell.
MAVERICC: ERCC1 Does Not Predict Benefit
Heinz-Josef Lenz, MD
The biomarker-driven MAVERICC trial found no difference in progression-free or overall survival between patients with colorectal tumors that expressed, or did not express, ERCC1, a potential marker for chemoresistance, reported Heinz-Josef Lenz, MD, of the Keck School of Medicine at the University of Southern California, Los Angeles. In addition, ERCC1 failed to identify patients who may have better or worse outcomes when treated with bevacizumab added to FOLFOX or FOLFIRI.
The study randomized 376 patients with previously untreated metastatic colorectal cancer to one of the two regimens. The primary endpoint was the association between ERCC1 and progression-free survival. The investigators will later report their evaluation of vascular endothelial growth factor (VEGF) receptor A as a potential marker for response to bevacizumab.
Median progression-free survival was 10.1 months in the FOLFOX/bevacizumab arm and 12.6 months in the FOLFIRI/bevacizumab arm (HR = 0.79; P = .56); median overall survival was 23.9 and 27.5 months
(HR = 0.76; P = .086), respectively. Neither difference was statistically significant, nor did ERCC1 demonstrate a significant association with outcomes, Dr. Lenz reported.
“In the first-line treatment of metastatic colorectal cancer, FOLFIRI/bevacizumab and FOLFOX/ bevacizumab appeared comparable in this exploratory study,” he said.
Although ERCC1 was not associated with outcomes, Dr. Lenz said. “The results should be interpreted with caution due to the lower prevalence of tumor ERCC1.” Approximately 35% of patients had tumors with high expression of ERCC1, whereas some other studies have found more patients to be ERCC1-positive. ■
Disclosure: Dr. Bendell reported no potential conflicts of interest. Dr. Lenz is on the advisory board of and receives clinical trial support from Genentech/Roche.
References
1. Bendell JC, Tan BR, Reeves JA, et al: Overall response rate in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line treatment of patients with metastatic colorectal cancer. 2016 Gastrointestinal Cancers Symposium. Abstract 492. Presented January 21, 2016.
2. Lenz H-J, Lee F-C, Yau L, et al: MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab vs FOLFIRI-bevacizumab with biomarker stratification as first-line chemotherapy in patients with metastatic colorectal cancer. 2016 Gastrointestinal Cancers Symposium. Abstract 493. Presented January 21, 2016.
3. Loupakis F, Cremolini C, Masi G, et al: Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371:1609-1618, 2014.
