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A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

ABSTRACT: BACKGROUND:Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis. METHODS:Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate. RESULTS:Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found. CONCLUSION:KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

SUBMITTER: Bendell JC

PROVIDER: S-EPMC4786359 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

Bendell Johanna C JC Zakari Ahmed A Peyton James D JD Boccia Ralph R Moskowitz Mark M Gian Victor V Lipman Andrew A Waterhouse David D LoCicero Richard R Earwood Chris C Lane Cassie M CM Meluch Anthony A

The oncologist 20160224 3

<h4>Background</h4>Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis.<h4>Methods</h4>Patients received FOLF ...[more]

PMID: 26911408

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Project description:BackgroundDoublets plus anti-epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI-bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI-bevacizumab versus doublets plus anti-EGFRs is available in left-sided RAS/BRAF wild-type mCRC.Materials and methodsWe selected patients with left-sided RAS and BRAF wild-type mCRC treated with first-line FOLFOX-panitumumab or FOLFOXIRI-bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score-based analysis was performed to compare FOLFOXIRI-bevacizumab with FOLFOX-panitumumab.ResultsA total of 185 patients received FOLFOX-panitumumab and 132 received FOLFOXIRI-bevacizumab. Median progression-free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI-bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX-panitumumab group (propensity score-adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64-1.04; p = .11; propensity score-adjusted HR for OS, 0.80; 95% CI, 0.59-1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI-bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI-bevacizumab and FOLFOX-panitumumab are valuable treatment options in left-sided RAS/BRAF wild-type mCRC.Implications for practiceA propensity score-based analysis of five trials was performed to compare FOLFOX-panitumumab versus FOLFOXIRI-bevacizumab in left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI-bevacizumab achieved numerically superior survival outcomes versus FOLFOX-panitumumab. Chemotherapy-related adverse events were more frequent in the FOLFOXIRI-bevacizumab group. These observations suggest that although doublet chemotherapy plus anti-EGFRs remains the preferred treatment in patients with left-sided RAS/BRAF wild-type mCRC, FOLFOXIRI-bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients' preference and potential impact on quality of life.

Project description:BackgroundFew data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard first-line option for RAS wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities.MethodsThe PANDA study is a prospective, open-label, multicenter, randomized phase II trial of first-line therapy with panitumumab in combination with dose-adjusted FOLFOX or with 5-fluorouracil monotherapy, in previously untreated elderly patients (≥70 years) with RAS and BRAF wild-type unresectable metastatic colorectal cancer. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 and CRASH score is planned at baseline and G8 will be re-evaluated at disease progression. The primary endpoint is duration of progression-free survival in both arms. Secondary endpoints include prospective evaluation of the prognostic role of G8 score and the correlation of CRASH risk categories with toxicity.DiscussionThe PANDA study aims at exploring safety and efficacy of panitumumab in combination with FOLFOX or with 5FU/LV in elderly patients affected by RAS and BRAF wild-type metastatic colorectal cancer, to identify the most promising treatment strategy in this setting. Additionally, this is the first trial in which the prognostic role of the G8 score will be prospectively evaluated. Results of this study will drive further experimental developments for one or both combinations.Trial registrationPANDA is registered at Clinicaltrials.gov : NCT02904031 , July 11, 2016. PANDA is registered at EudraCT-No.: 2015-003888-10, September 3, 2015.

Project description: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.

Dataset Information

A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

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A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

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