As reported recently in Lancet Oncology by Jaafar Bennouna, MD, of Institut de Cancérologie de l’Ouest, Nantes, France, and colleagues, the phase III ML18147 trial showed a survival benefit with continued bevacizumab (Avastin) treatment after first progression in metastatic colorectal cancer.1 The trial formed the basis of bevacizumab’s recent approval for use in combination with fluoropyrimidine/irinotecan– or fluoropyrimidine/oxaliplatin–based chemotherapy in the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.
This open-label trial, performed in 220 centers in 15 countries, enrolled patients aged 18 years or older with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy. Patients were randomly assigned to receive second-line therapy with (n = 409) or without (n = 411) bevacizumab at 2.5 mg/kg per week (either 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). For second-line chemotherapy, patients were switched to irinotecan-based treatment if their first-line regimen was oxaliplatin-based and vice versa. Treatment continued until progressive disease, unacceptable toxicity, or patient refusal. The primary endpoint was overall survival.
Patients in the bevacizumab and chemotherapy-alone groups were well matched for sex (65% vs 63% male), age (median 63 years in both), ECOG performance status (0 and 1 in 44% and 55% vs 43% and 52%), and proportions of patients who had progression within 9 months on first-line treatment (54% vs 56%), liver metastasis only (27% vs 29%), metastasis to more than one organ (64% vs 61%), received their last bevacizumab dose greater than 42 days prior to the study (23% in both), and received irinotecan-based (59% vs 58%) or oxaliplatin-based (41% vs 42%) first-line therapy.
Patients were well matched for type of chemotherapy in second-line treatment. For irinotecan-based regimens, 16% of the bevacizumab group vs 14% of the chemotherapy-alone group received sFOLFIRI (simplified leucovorin, fluorouracil [5-FU], irinotecan); 7% vs 7% received the hybrid regimen LV5FU2 CPT11 (irinotecan plus bolus and infusion 5-FU with high-dose leucovorin); and 12% vs 12% received XELIRI (capecitabine [Xeloda] plus irinotecan).
For oxaliplatin-based therapy, 9% of the bevacizumab group vs 9% of the chemotherapy-alone group received FOLFOX4 (leucovorin, 5-FU, oxaliplatin); 9% vs 9% received sFOLFOX4 (simplified FOLFOX); 16% vs 13% received FOLFOX6; 6% vs 9% received FUFOX (another combination of 5-FU, leucovorin, oxaliplatin); and 14% vs 11% received XELOX (capecitabine plus oxaliplatin).
Other regimens were received by 12% of the bevacizumab group vs 16% of the chemotherapy-alone group.
Improved Overall Survival
Median follow-up was 11.1 months in the bevacizumab group and 9.6 months in the chemotherapy-alone group; median treatment exposure was 4.2 months and 3.2 months, respectively. Median overall survival was 11.2 months in the bevacizumab group vs 9.8 months in the chemotherapy-alone group, representing a significant 19% reduction in risk of death with bevacizumab treatment (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.69-0.94, P = .0062).
From the start of first-line treatment, median overall survival was 23.9 months in the bevacizumab group and 22.5 months in the chemotherapy-alone group (HR = 0.90, P = .17). After completion of study treatment, 69% of the bevacizumab group and 68% of the chemotherapy-alone group received additional treatment, including bevacizumab in 11% and 12% and anti-EGFR treatment in 39% and 41%.
Of patients with known KRAS status (n = 616), EGFR inhibitors were given to 70% and 69% of those with KRAS wild-type tumors and to 7% and 9% of those with KRAS mutant tumors; further bevacizumab was given to 17% and 22% of those with KRAS mutant tumors and to 8% and 8% of those with wild-type tumors.
A prespecified subgroup analysis showed fairly consistent overall survival benefits with bevacizumab treatment according to age, ECOG performance status, duration of progression-free survival on first-line treatment, oxaliplatin- or irinotecan-based first-line treatment, time since last bevacizumab dose prior to the study, presence of liver metastasis only, and number of organs with metastasis. The hazard ratio for male patients was 0.73, whereas that for female patients was 0.99; however, there was no significant treatment by sex interaction on regression analysis.
Median progression-free survival was 5.7 months in the bevacizumab group vs 4.1 months in the chemotherapy-alone group, representing a 32% reduction in risk of progression with bevacizumab treatment (HR = 0.68, P < .0001). Confirmed response occurred in 5% of the bevacizumab group (including complete response in one patient) and 4% of the chemotherapy-alone group (complete response in two patients). A post hoc analysis showed an improved disease control rate with bevacizumab treatment (68% vs 54%, P < .0001).
Outcome by KRAS status
Subgroup analysis according to KRAS status showed progression-free survival benefits of bevacizumab in both patients with wild-type KRAS (HR = 0.61, P < .0001) and those with mutant KRAS (HR = 0.70, P = .003). Bevacizumab treatment was associated with a significant Overall survival benefit in patients with wild-type KRAS (HR = 0.69, P = .005) but not in those with mutant KRAS (HR = 0.92, P = .50). However, there was no significant treatment by KRAS interaction for either progression-free survival or overall survival on regression analysis.
Grade 3 to 5 adverse events occurred in 64% of the bevacizumab group and 57% of the chemotherapy-alone group, with the most common being neutropenia (16% and 13%), diarrhea (10% and 8%), and asthenia (6% and 4%). Notable grade 3 to 5 adverse events that occurred more frequently in the bevacizumab group were bleeding or hemorrhage (2% vs < 1%), gastrointestinal (GI) perforation (2% vs < 1%), and venous thromboembolic events (5% vs 3%).
Eleven adverse events resulted in death in each group. Those considered related to study treatment consisted of upper GI hemorrhage, cerebrovascular accident, sudden death, and neutropenia in one patient each in the bevacizumab group, and intestinal perforation, general physical health deterioration, and acute prerenal failure in one patient each in the chemotherapy-alone group. Overall, death not related to progressive disease occurred in 6% of patients in the bevacizumab group and 5% of patients in the chemotherapy-alone group.
Serious adverse events occurred in 32% of the bevacizumab group and in 33% of the chemotherapy-alone group; the most common were diarrhea (3% and 4%), pyrexia (2% and 3%), and neutropenia (2% and 2%). Treatment was discontinued due to adverse events in 16% of the bevacizumab group, including discontinuation of bevacizumab alone in 2%, and in 9% of the chemotherapy-alone group.
The authors concluded, “The findings in our study challenge the conventional definition of treatment resistance and lend support to the hypothesis that continued VEGF inhibition throughout the growth and metastasis of tumors is beneficial for patients with metastatic [colorectal cancer]….The results…could serve as proof of principle that maintaining angiogenesis inhibition while switching chemotherapy from the first and second lines in [colorectal cancer] has clinical benefits in patients. This approach is also being investigated in studies of other tumor types, including metastatic breast and non–small-cell lung cancers.”
The study was sponsored by Hoffmann-La Roche. ■
Disclosures: Dr. Bennouna has received consulting fees or honoraria and travel grants from Roche, is an advisory board member for Roche and Boehringer Ingelheim, and has received payment for lectures including service on speakers’ bureaus from Roche, Sanofi-Aventis, and Merck.
Dr. Sastre has received consulting fees or honoraria and research funding from Roche. D Arnold has received consulting fees or honoraria from Roche, Merck, and Amgen and research funding from Roche.
Dr. Österlund has received consulting fees, honoraria, travel grants, or lecturing fees from Roche, Amgen, and Merck, research funding from Roche, and is an advisory board member for Roche, Amgen, Bayer, Sanofi-Aventis, and Merck.
Dr. Van Cutsem has received research funding from Roche.
Dr. von Moos has received consulting fees or honoraria from Roche and Novartis, research funding from Roche and Amgen, is an advisory board member for Roche, Amgen, Merck, and Novartis, and has provided expert testimony for Amgen.
Dr. Viéitez has received research funding, payment for lectures including service on speakers’ bureaus, and travel, accommodations, or meeting expenses from Roche.
Dr. Bouché has received research funding and travel grants from Roche, payment for the development of educational presentations from Roche and Amgen, and is an advisory board member for Roche and Merck.
Dr. Borg has received travel grants from Roche.
Dr. Steffens has received travel grants from Roche and is an advisory board member for Roche, Merck, and Amgen.
Dr. Reyes-Rivera is employed by and owns stock or stock options in Genentech.
Dr. Bendahmane is employed by and owns stock or stock options in Roche.
Dr. André has received consulting fees or honoraria and travel grants from Roche, payment for lectures or speakers’ bureaus from Roche, Amgen, Merck, and Sanofi-Aventis, and is an advisory board member for Roche.
Dr. Kubicka has received consulting fees or honoraria, travel grants, and payment for lectures including service on speakers’ bureaus from Roche.
Drs. Greil, Alonso-Orduña, and Schlichting have no conflicts of interest.
1. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomized phase III trial. Lancet Oncol 14:29-37, 2013.
The so-called TML (Treatment across Multiple Lines) study reported by Bennouna and colleagues investigated the efficacy of bevacizumab (Avastin) beyond progression from first- to second-line therapy in advanced colorectal cancer, a strategy that was supported by data from observational cohort...