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Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

ABSTRACT: Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC.

SUBMITTER: Patel SB

PROVIDER: S-EPMC4706127 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

Patel Shiven B SB Gill David D Garrido-Laguna Ignacio I

OncoTargets and therapy 20151230

Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumu ...[more]

PMID: 26770060

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Project description:ImportanceCombining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.ObjectiveTo determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.Design, setting, and participantsPatients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.InterventionsCetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.Main outcomes and measuresThe primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.ResultsAmong 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).Conclusions and relevanceAmong patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.Trial registrationclinicaltrials.gov identifier: NCT00265850.

Project description:BackgroundAdvanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.MethodsCOIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.FindingsWe registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12.2 months (95% CI 8.8-15.6) and 14.3 months (10.7-20.4), respectively. The most common grade 3-4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).InterpretationCetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Dataset Information

Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

Publications

Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer.

Similar Datasets

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