Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer: A Randomized Phase 2 Clinical Trial

Abstract

Importance: The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established.

Objectives: To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC.

Design, setting, and participants: In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population.

Interventions: mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression.

Main outcomes and measures: The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events.

Results: Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]).

Conclusions and relevance: Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate.

Trial registration: clinicaltrials.gov Identifier: NCT02295930.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Cremolini reported receiving personal fees from F. Hoffman–La Roche, Bayer, Sirtex, and Amgen. Dr Masi reported receiving personal fees from Amgen, F. Hoffman–La Roche, Bayer, Merk Serono, and Sirtex. Dr Tonini reported receiving personal fees from Novartis, F. Hoffman–La Roche, and Molteni. Dr Salvatore reported receiving personal fees from Servier, Bayer, and Sanofi. Dr Falcone reported receiving grants and personal fees from F. Hoffman–La Roche, Amgen, and Merck Serono as well as personal fees from Celgene, Bayer, and Sanofi Aventis. No other disclosures were reported.

Figures

Figure 1.. MACBETH Study CONSORT Diagram

Arm A comprises patients receiving a modified schedule of fluorouracil, oxaliplatin, and irinotecan hydrochloride (mFOLFOXIRI) plus cetuximab, followed by maintenance with cetuximab. Arm B comprises patients receiving mFOLFOXIRI plus cetuximab, followed by maintenance with bevacizumab. ITT indicates intention to treat. aPatients who received at least 1 cycle of maintenance therapy.

Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival, According to Treatment Arm

Arm A comprises 59 patients receiving a modified schedule of fluorouracil, oxaliplatin, and irinotecan hydrochloride (mFOLFOXIRI) plus cetuximab followed by maintenance with cetuximab. Arm B comprises 57 patients receiving mFOLFOXIRI plus cetuximab followed by maintenance with bevacizumab. HR indicates hazard ratio; NE, not estimable.