Reference Detail

Ref Type Journal Article
PMID (29450468)
Authors Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A
Title 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.
Journal JAMA oncology
Vol
Issue
Date 2018 Feb 15
URL
Abstract Text 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.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.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.mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression.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.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%]).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.clinicaltrials.gov Identifier: NCT02295930.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF wild-type KRAS wild-type NRAS wild-type colorectal cancer predicted - sensitive Bevacizumab + Cetuximab + Fluorouracil + Irinotecan + Leucovorin Phase II Actionable In a Phase II trial (MACBETH), first-line treatment with the combination of Erbitux (cetuximab) and FOLFIRI, followed by Avastin (bevacizumab) maintenance, demonstrated activity in BRAF/KRAS/NRAS wild-type metastatic colorectal cancer patients, resulting in a median overall survival in the intent-to-treat population of 32.2 mo and response rate of 75% (43/57), however, resulted in a 10-mo PFS rate of 40.4% (23/57), which did not meet the primary endpoint of 70% (PMID: 29450468; NCT02295930). 29450468
BRAF wild-type KRAS wild-type NRAS wild-type colorectal cancer predicted - sensitive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Phase II Actionable In a Phase II trial (MACBETH), first-line treatment with the combination of Erbitux (cetuximab) and FOLFIRI, followed by Erbitux (cetuximab) maintenance, demonstrated activity in BRAF/KRAS/NRAS wild-type metastatic colorectal cancer patients, resulting in a median overall survival in the intent-to-treat population of 33.2 mo and response rate of 68% (40/59), however, resulted in a 10-mo PFS rate of 50.8% (30/59), which did not meet the primary endpoint of 70% (PMID: 29450468; NCT02295930). 29450468