European Studies Explore Maintenance Strategies for Metastatic Colorectal Cancer

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Susanna ­Hegewisch-Becker, MD, PhD

Benoist Chibaudel, MD

Pilar Garcia Alfonso, MD

Bevacizumab and a short period of erlotinib therapy is a new treatment option in first-line therapy following induction chemotherapy with bevacizumab.

—Benoist Chibaudel, MD

Studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid added insight regarding maintenance therapy in metastatic colorectal cancer, an area lacking a clear recommended strategy following first-line regimens.

Two phase III trials found benefit for bevacizumab (Avastin)-based maintenance regimens but differed with regard to the value of a second maintenance drug. A third exploratory trial examined the benefit of cetuximab (Erbitux) monotherapy.

Maintenance therapy with a fluoropyrimidine plus bevacizumab is a widely accepted strategy, having been shown to prolong progression-free survival and delay second-line therapy, over a complete discontinuation of treatment. However, previous maintenance trials have failed to define a clear standard and have not prospectively compared different approaches. These studies sought to
do that.

Bevacizumab/Erlotinib Combination

The GERCOR DREAM trial in 452 colorectal cancer patients investigated bevacizumab at 7.5 mg/kg every 3 weeks vs bevacizumab plus erlotinib at 150 mg/d, until disease progression, following a standard induction regimen plus bevacizumab.1 The median duration of erlotinib therapy was short, at 3.6 months.

In the final analysis, after a median 50-month follow-up, bevacizumab/erlotinib was superior to bevacizumab monotherapy in terms of progression-free survival and overall survival, according to Benoist Chibaudel, MD, of the Hôpital Saint Antoine in Paris.

In the GERCOR DREAM final analysis, median progression-free survival was 4.9 months with bevacizumab alone and 5.9 months with bevacizumab/erlotinib (hazard ratio [HR] = 0.77, P = .012). Median overall survival after starting maintenance was 22.1 months and 24.9 months, respectively (HR = 0.79, P = .035), with benefit evident among all subgroups.

Dr. Chibaudel noted that postprogression therapy was similar in type and frequency between the arms. “The [epidermal growth factor receptor (EGFR)] antibody remained active in patients who received erlotinib before,” he noted. “The effect is observed whatever the KRAS status. Furthermore, a significant difference in response rate was observed during the chemotherapy-free maintenance therapy in KRAS-mutated tumors (19.7% vs 8.3%),” he added.

He said that safety was acceptable, despite an increased incidence of skin rash (all grades, 89% vs 9%) and diarrhea (59% vs 14%).

The results of GERCOR DREAM suggest that “bevacizumab and a short period of erlotinib therapy is a new treatment option in first-line therapy following induction chemotherapy with bevacizumab,” Dr. Chibaudel maintained.

Bevacizumab Monotherapy

In the AIO KRK 0207 trial, however, bevacizumab monotherapy was not inferior to the standard of care (a fluoropyrimidine plus bevacizumab) as maintenance, after first-line induction with fluoropyrimidine/oxaliplatin/bevacizumab.2 Either strategy was better than no maintenance at all in prolonging remission, though neither improved overall survival, reported ­Susanna ­Hegewisch-Becker, MD, PhD, of Hämatologisch-Onkologische Praxis Eppendorf (HOPE) in Hamburg, Germany.

“Active maintenance treatment is confirmed as standard for most patients, to improve [time to first progression].” she said. “However, the lack of a clear overall survival benefit allows for individualized approaches.”

The population included 852 metastatic patients who received 24 weeks of standard induction therapy. Among the 472 responders, the AIO KRK 0207 study investigated whether treatment discontinuation (ie, no maintenance) or continuation with bevacizumab alone was noninferior to maintenance with fluoropyrimidine/bevacizumab. Maintenance was followed by a planned reinduction of components of the induction regimen: any fluoropyrimidine with or without oxaliplatin or bevacizumab.

Time to failure of strategy, the primary endpoint, was the time from randomization (ie, at the start of maintenance) to either the second progression after maintenance and reinduction, or for patients with progression but not receiving reinduction, time to the use of a new drug (ie, second-line therapy) or no further treatment. Progression-free survival (time to first progression) was a secondary endpoint, as was overall survival.

Median time to failure of strategy was 6.5 months for the whole population, with no statistically significant differences among the arms. A trend favored fluoropyrimidine/bevacizumab vs no therapy (HR = 1.27, P = .054). There were no significant differences in overall survival among the arms, with a median overall survival of 23 months (P = .87).

“Subgroup analyses failed to identify a group of patients with a greater or lesser benefit with active maintenance with [fluoropyrimidine]/bevacizu­mab,” she said.

Time to first progression, from the start of maintenance, was significantly better for either active treatment vs no treatment (HR = 2.05, P < .0001 for fluoropyrimidine/bevacizumab), but was not significantly different between the two active arms. A trend favored fluoropyrimidine/bevacizumab vs bevacizumab alone (6.2 vs 4.6 months, HR = 1.26, P = .061).

“[Time to first progression] was significantly better with active treatment, whereas overall survival was not different,” Dr. Hegewisch-Becker said. “The benefit with active maintenance on [time to first progression] remained significant in all subgroups analyzed.”

The study confirmed the prognostic impact of mutation status, showing that bevacizumab monotherapy was superior to no treatment (P < .001), and was as effective as combination treatment, among patients lacking mutations in RAS and BRAF. In patients with these mutations, the doublet was favored; single-agent bevacizumab was no better than no maintenance at all.

The low rates of reinduction after first progression indicated “a very limited acceptance of this strategy,” she added. The study also showed that outcomes were not impacted by reducing the dose or shortening the course of induction oxaliplatin, which can avoid cumulative neuropathy.

Cetuximab as Maintenance

The phase II MACRO-2 trial found that cetuximab monotherapy was non-inferior to the combination of modified fluorouracil/leucovorin/oxaliplatin (mFOLFOX) plus cetuximab after induction with mFOLFOX/cetuximab, according to Pilar Garcia Alfonso, MD, of the Gregorio Marañón Hospital in Madrid.3

In the noninferiority study, 193 patients were randomly assigned to receive mFOLFOX-6 plus cetuximab for eight cycles, followed by the same regimen as maintenance, or to mFOLFOX-6 plus cetuximab for eight cycles, continuing only with single-agent cetuximab (250 mg/m2 weekly) as maintenance.

The proportion of patients who were progression-free at 9 months—the primary endpoint—was 63.4% with single-agent cetuximab and 71.9% with mFOLFOX/cetuximab, which produced an odds ratio (OR) of 0.6827 that was not significantly different (P = .25), she reported.

Median progression-free survival was 8.9 and 9.8 months (HR = 0.690, P = .09), median overall survival was 23.6 and 22.2 months (HR = 1.151, P = .54), and response rates were 46.5% and 39.1%, respectively (OR = 1.36, P = .33). Treatment-related adverse events were similar, except more neuropathy occurred with the combination.

“The results of the present hypothesis-generating phase II exploratory trial suggest that maintenance therapy with single-agent cetuximab following mFOLFOX plus cetuximab induction is not inferior to continuing treatment with mFOLFOX plus cetuximab,” Dr. Garcia Alfonso concluded.

The study investigators do not recommend this approach at this time. “MACRO-2 is the first study to evaluate this and it suggests maintenance cetuximab is not inferior, but this must be confirmed in a phase III trial,” she said. ■

Disclosure: Drs. Chibaudel, Hegewisch-Becker, and Garcia Alfonso reported no potential conflicts of interest.


1. Chibaudel B, Tournigand C, Samson B, et al: Bevacizumab-erlotinib as maintenance therapy in metastatic colorectal cancer. Final results of the GERCOR DREAM study. ESMO 2014 Congress. Abstract 497O. Presented September 27, 2014.

2. Hegewisch-Becker S, Graeven U, Lerchenmueller C, et al: Maintenance strategy with fluoropyrimidines plus bevacizumab, bev alone or no treatment, following a 24-week first-line induction with FP, oxaliplatin and bev for patients with metastatic colorectal cancer: Mature data and subgroup analysis of the AIO KRK 0207 phase III study. ESMO 2014 Congress. Abstract 498O. Presented September 27, 2014.

3. Garcia Alfonso P, Benavides M, Sanchez Ruiz A, et al: Phase II study of first-line mFOLFOX plus cetuximab (C) for 8 cycles followed by mFOLFOX plus C or single agent C as maintenance therapy in patients with KRAS wild type metastatic colorectal cancer: The MACRO-2 trial (Spanish Cooperative Group for the Treatment of Digestive Tumors). ESMO 2014 Congress. Abstract 499O. Presented September 27, 2014.

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