Intensive upfront therapy improves progression-free and possibly overall survival in the first-line setting. These findings could potentially change my practice. I have favored sequential therapy because it is less toxic, but this study [TRIBE 3] is persuading me to perhaps use the triplet [FOLFOXIRI/bevacizumab] up front.
—Tony Reid, MD, PhD
At the Best of ASCO Meeting in Los Angeles, Tony Reid, MD, PhD, Director of the Early Phase Clinical Research Program and Professor of Hematology/Oncology at the University of California, San Diego, reviewed important findings in metastatic colorectal cancer presented at the 2013 ASCO Annual Meeting, and offered his thoughts on their clinical application.
Presurgical Treatment Options
The new EPOC study presented evaluated cetuximab (Erbitux) plus chemotherapy, vs chemotherapy alone, for operable metastatic colorectal cancer in patients with KRAS wild-type tumors.1 While response rates were higher with the combination, progression-free survival was significantly worse with cetuximab: 14.1 months vs 20.5 months with chemotherapy alone (HR = 1.49; P = .030). Median overall survival was not reached in the chemotherapy alone arm and was 39.1 months with chemotherapy/cetuximab (HR = 1.40; P = .163).
“EPOC showed a detrimental effect of cetuximab when added to chemotherapy. No specific subset accounted for this finding. We also learned that response rate does not predict progression-free or overall survival,” Dr. Reid said. “The results of the EPOC trial indicate a disconnect between response rate and overall survival but do not support the use of cetuximab presurgically in operable patients with KRAS wild-type tumors.”
First-Line Metastatic Disease
The German FIRE 3 study compared the addition of bevacizumab (Avastin) vs cetuximab, given with FOLFIRI (leucovorin, fluorouracil [5‑FU], irinotecan), in the first-line treatment of KRAS wild-type metastatic disease.1 Among the 592 patients, the intent-to treat analysis showed no significant differences between the two treatment arms in terms of response rates, however, among patients assessable for response, ie, those who received at least three cycles (n = 526), response rates were higher with cetuximab (72% vs 63%; P = .017).
Progression-free survival was approximately 10 months in either arm (P = .547), however, “intriguingly,” overall survival was better with cetuximab: 28.7 vs 25.0 months with bevacizumab (HR = 0.77; P = .017). Despite this, he called the regimens “essentially equivalent.”
“FIRE 3 showed that bevacizumab and cetuximab have similar progression-free survival rates when added to FOLFIRI,” Dr. Reid said. “Regarding overall survival, the duration of exposure to first-line treatment was about 5 months in either arm, but the curves did not separate until about 18 months. While the overall survival was better among patients randomized to the arm that received cetuximab as part of the first-line treatment, the delay in separation of the curves did not occur until 13 months after the first-line therapy was discontinued. This prolonged delay suggests that the difference in survival was due to what happened in the second-line setting, where there was greater use of bevacizumab after cetuximab.”
TRIBE asked which of two regimens—FOLFIRI (the control arm) vs FOLFOXFIRI (leucovorin, 5-FU, irinotecan, oxaliplatin)—might be the best backbone for bevacizumab in unresectable patients. 3 The study concluded that FOLFOXIRI may be superior in terms of progression-free and overall survival. Surgical resections rates (negative margins) were also numerically greater. FOLFOXIRI/bevacizumab carried more side effects but no greater incidence of serious adverse events.
Median progression-free survival was 12.2 months with FOLFOXIRI/bevacizumab vs 9.7 months with FOLFIRI/bevacizumab (HR = 0.73; P = .0012). The progression-free survival rate at 2 years was 20.3% vs 11.4%, respectively. Median overall survival in the intent-to-treat population was 31.0 vs 25.8 months (HR = 0.83; P = .125), with a strong trend favoring -FOLFOXIRI in the stratified analysis (HR = 0.79; P = .054). Response rates were also higher with FOLFOXIRI (65% vs 53%; P = .006).
There was no notable difference in toxicity, suggesting that -“FOLFOXIRI can be given relatively safely, especially with dose reductions,” Dr. Reid suggested.
In subset analyses, the benefit of FOLFOXIRI was especially strong for BRAF-mutated tumors (HR = 0.55) compared to wild-type (HR = 0.83). Benefit was seen in both KRAS-mutated (HR = 0.84) and wild-type tumors (HR = 0.83). “For the patient with poor genetics, FOLFOXIRI/bevacizumab may be a beneficial regimen,” he suggested.
Drawing conclusions from the TRIBE study, Dr. Reid said, “Intensive upfront therapy improves progression-free and possibly overall survival in the first-line setting. These findings could potentially change my practice. I have favored sequential therapy because it is less toxic, but this study is persuading me to use the triplet up front for appropriate patients.”
A recent meta-analysis of 10 studies evaluated the use of various maintenance therapy approaches and, taken together, these studies showed no detrimental effect to maintenance regimens. Two studies presented at ASCO 2013, and reviewed at the Best of ASCO meeting, evaluated maintenance therapy. CAIRO 2 compared capecitabine plus bevacizumab vs observation after induction treatment while the DREAM trial evaluated bevacizumab with or without erlotinib (Tarceva), according to KRAS status.
The phase III CAIRO3 study, by the Dutch Colorectal Cancer Group, randomized 558 metastatic patients with stable disease after six cycles of CAPOX (capecitabine/oxaliplatin) plus bevacizumab to continued capecitabine/bevacizumab as maintenance, vs observation.4 At the time of second progression, patients were reintroduced to CAPOX/bevacizumab (or other treatment) and were evaluated again for time to second progression.
Time to first progression was significantly prolonged by maintenance therapy: 8.5 months vs 4.1 months with observation (unadjusted HR = 0.41; P < .001). Time to second progression was also significantly longer in the maintenance arm: 19.8 months vs 15.0 months, respectively (adjusted HR = 0.63; P < .001). Overall survival was 21.7 months and 18.2 months, respectively, which was not statistically significant in the stratified analysis (HR = 0.87; P = .156) but reached significance in the adjusted analysis (adjusted HR = 0.80; P = .035).
“Maintenance was significantly better. Patients benefited from being kept on treatment. Did this translate into an overall survival advantage? Yes, but with qualifications. In the intent-to-treat analysis the difference was not statistically significant, but in the adjusted analysis it was,” he said “The findings favor treating patients with capecitabine/bevacizumab as maintenance rather than no therapy; however, the difference in overall survival advantage was only significant when adjusted for the time from diagnosis to randomization and for the stage of disease.”
The DREAM Trial (OPTIMOX III), involving 452 metastatic patients, showed that the addition of erlotinib to bevacizumab—a nonchemotherapy doublet—following induction therapy significantly increases progression-free survival over maintenance with bevacizumab alone, and resulted in a median overall survival time of 25 months.5
It also showed that, in contrast to treatment with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), benefit from erlotinib is not governed by KRAS tumor status. Interestingly, the benefit of the combination was mainly observed in patients with KRAS-mutated -tumors.
The study randomized patients with one of the two maintenance arms after induction therapy with a bevacizumab-based regimen. Patients received single-agent bevacizumab 7.5 mg/kg every 3 weeks or bevacizumab plus erlotininb 150 mg/d. Median progression-free survival from the time of maintenance initiation was 5.9 months with the combination vs 4.8 months with the single agent (HR = 0.76; P = .0096).
Interestingly, the treatments conveyed similar benefits regardless of KRAS status, however, patients with KRAS-mutated tumors had longer progression-free survival than wild-type patients (nearly 10 months, vs 6 months), “which is contrary to what we would expect,” he said. The combination was slightly more toxic, especially for skin toxicity (grade 3/4 in 20%) and diarrhea (grade 3/4 in 9%).
Dr. Reid commented that the doublet allows patients to continue treatment “off chemotherapy” and “hopefully to tolerate second-line therapy better,” but the comparator of bevacizumab alone is not typical of clinical practice.” He suggested, “A more appropriate arm might have been bevacizumab plus 5-FU or capecitabine.However, the findings support the notion that maintenance therapy with this nonchemotherapy doublet could be of benefit.” ■
Disclosure: Dr. Reid is a consultant for Genentech, Bristol-Myers Squibb, and Novartis.
1. Primrose JN, Falk S, Finch-Jones M et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. 2013 ASCO Annual Meeting. Abstract 3504. Presented June 1, 2013.
2. Heinemann V, von Weikersthal LF, Decker T et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.
3. Falcone A, Cremolini C, Masi G et al. FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer patients: results of the phase III TRIBE trial by GONO group. 2013 ASCO Annual Meeting. Abstract 3505. Presented June 1, 2013.
4. Koopman M, Simkens LHJ, Tije AJT et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer Group. 2013 ASCO Annual Meeting. Abstract 3502. Presented June 1, 2013.
5. Tournigand C, Chibaudel B, Samson B et al. Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer according to KRAS: Results of the GERCOR DREAM phase III trial. 2013 ASCO Annual Meeting. Abstract 3515. Presented June 4, 2013.