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

Lessons LearnedThis regimen is a viable option for patients with liver-only metastatic colorectal cancer.Enrollment criteria for future studies should include testing for the newly identified KRAS mutations.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/m2, 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m2 i.v.; irinotecan, 125 mg/m2; oxaliplatin, 85 mg/m2 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 had 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.

Toxicity Syndromes, Patient-Related Clinical Indicator of Toxicity Burden Induced by Intensive Triplet Chemotherapy-Based Regimens in Gastrointestinal Cancers With Metastatic Disease

“…Addition of more drugs in a chemotherapy combination requires the design of proper schedule and doses, to provide the balance between projected/received (>80%) dose intensity (DI) and treatment-related toxicity (1). This clinical balance is even more challenging to realize for intensive triplet chemotherapybased regimens that demonstrated to increase clinical outcome in fit metastatic gastro-intestinal (mGI) cancer patients (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Clinical status of the individual patient, also depending from metastatic tumor extension, is the most important variable justifying differential toxicity in individual patients.…”

Intensive first line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: Preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.

“…[14][15][16][17] A phase II trial in 37 KRAS/ NRAS/HRAS/BRAF wild-type patients evaluated PAN addiction to modified FOLFOXIRI, with an ORR of 60-89%, R0 resection rate of 35%, median PFS of 11.3 and 13.3 months, respectively. 18,19 The high discontinuation rate of started treatment (48%) due to LT, mainly characterized by diarrhea associated with asthenia, confirmed that individual patient toxicity was the main limitation to the use of intensive schedules associating triplet chemotherapy and anti-EGFR-targeted agents in clinical practice. BEV addiction to FOLFOXIRI in a randomized phase III TRIBE trial reported increased clinical outcomes also in wild-type KRAS/NRAS/ BRAF patients.…”

“…Thus, the present study confirmed the need of proper selection of fit patients and evaluation of toxicity. [14][15][16][17][18][19] Different schedules of CET addition to triplet chemotherapy, chrono-IFLO, ERBIRINOX, FOLFOXIRI have been proposed, and reported a high activity (ORR 70-83%), and liver resection rate >60%. [14][15][16][17] A phase II trial in 37 KRAS/ NRAS/HRAS/BRAF wild-type patients evaluated PAN addiction to modified FOLFOXIRI, with an ORR of 60-89%, R0 resection rate of 35%, median PFS of 11.3 and 13.3 months, respectively.…”

“…Among RAS wild-type, the median PFS was 12 months (4 to 20+), and the median OS was 23 months (4-51). Among the 23 patients who received at least two cycles of treatment, the median PFS was 11 months (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and the median OS was 23 months (5+ to 48+). Among the 13 patients treated at the recommended doses, the ORR was 80% (α 0.05, CI ± 26).…”

“…[8][9][10][11][12][13] Anti-EGFR addition to triplet chemotherapy was evaluated in phase I and II trials reaching an ORR of 79-80.9%, a PFS of 9.5-14 months, and an OS of 24.7-37 months, in molecularly unselected patients; in the KRAS exon 2 wild-type, 60-83.3%, 9.9-16 months, 30.3 to not reached; in RAS wild-type, 67.8-89%, 11.2-11.3 months, not reached, respectively. [14][15][16][17][18][19] The range of reported individual grade 3-4 toxicities of diarrhea (25-53%), asthenia (9.5-31.7%), mucositis (6-14%), neutropenia (23.3-48%), and febrile neutropenia (3-6%), represented the main concern for intensive regimens when adding anti-EGFR to triplet chemotherapy. Pharmacogenomic biomarkers, specifically 5-FU degradation rate (5-FUDR) and single nucleotide polymorphisms (SNPs) of different genes, such as ABCB1, CYP3A4, DYPD, UGT1A1 encoding for enzymes involved in 5-FU and CPT11 metabolism have been evaluated to predict gastrointestinal toxicity in individual patients.…”