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- Materials and Methods
- Disclosure Statement
This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naïve unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m2 + irinotecan 180 mg/m2, followed by 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression-free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 1–11) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.7–9.2) by independent review, 7.2 months (95% confidence interval, 5.4–9.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with www.ClinicalTrials.gov (NCT00668863). (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02320.x, 2012)
The median survival of patients with metastatic CRC has improved over the past decade, from approximately 1 year with 5-FU-based monotherapy to approximately 2 years with combination systemic therapy. FOLFIRI is now a standard first-line treatment for metastatic CRC. The addition of other agents (typically the anti-VEGF mAb, bevacizumab) to FOLFIRI has improved patient outcomes.
Sunitinib malate (SUTENT; Pfizer, New York, NY, USA) is an oral, multitargeted tyrosine kinase inhibitor of VEGFR-1, -2, and -3, platelet-derived growth factor receptors (-α and -β), stem cell factor receptor, FMS-like tyrosine kinase 3, colony-stimulating factor 1 receptor, and glial cell line-derived neurotrophic receptor.[2-7] Sunitinib is currently approved multinationally for the treatment of advanced renal cell carcinoma and imatinib-resistant/-intolerant gastrointestinal stromal tumor. It is also now approved for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors.
Sunitinib has shown antitumor activity in non-clinical CRC models, both as a single agent and in combination with chemotherapy (Pfizer, unpublished data, 2002). In a phase II study of patients with previously treated metastatic CRC, single-agent sunitinib showed some evidence of efficacy (median OS, 10.2 months in patients with bevacizumab-naïve tumors; 7.1 months in patients with bevacizumab-pretreated tumors) and the study investigators concluded that sunitinib warranted further evaluation in combination with standard regimens used to treat metastatic CRC.
Subsequently, a phase I study investigated sunitinib combined with FOLFIRI in patients with chemotherapy-naïve metastatic CRC, and identified the maximum tolerated dose of sunitinib as 37.5 mg/day given on Schedule 4/2. This regimen was evaluated further in two concurrent first-line metastatic CRC studies: a phase II, open-label, single-arm study in Japanese patients (www.ClinicalTrials.gov identifier: NCT00668863); and a phase III, double-blind, randomized study in non-Japanese patients (www.ClinicalTrials.gov identifier: NCT00457691). Results of the single-arm phase II study are presented here.
- Top of page
- Materials and Methods
- Disclosure Statement
This phase II study investigated sunitinib combined with FOLFIRI for the first-line treatment of Japanese patients with unresectable or metastatic CRC. The study was closed early when the concurrent phase III study of first-line sunitinib plus FOLFIRI in non-Japanese patients with metastatic CRC was stopped due to futility; median PFS was 7.8 months in the sunitinib plus FOLFIRI arm, and 8.4 months in the placebo plus FOLFIRI arm. In the present study, median PFS (6.7 months by independent review; 7.2 months by investigator assessment), as well as ORR (36.6% by independent review; 42.3% by investigator assessment) and CBR (83.1% by independent review; 88.7% by investigator assessment), were similar to previous studies of 5-FU and irinotecan-containing chemotherapy regimens in Japanese patients.[15-21] Median PFS in our trial was less than the target of 10.8 months (35% improvement compared with FOLFIRI alone), indicating that the addition of sunitinib did not result in enhanced efficacy. The survival data were not mature at the time of analysis, due to early study termination.
In a retrospective analysis of 48 Japanese patients with unresectable, metastatic CRC who received FOLFIRI (n = 38 first-line), median PFS was 8.4 months and the ORR was 37%. In 42 Japanese patients with advanced CRC (UGT1A1*1/*1, and *1/*6 or *1/*28 genotypes) who received first-line FOLFIRI, median PFS was 8.5–8.6 months (approximately 36.9–37.4 weeks) and ORR was 48–56%. In other studies of Japanese patients with advanced or recurrent CRC, ORR ranged between 38% and 50%.[16, 18, 19]
Regrettably, the design of the present study did not include molecular profiling or biomarker investigations, therefore precluding the identification of specific patient populations who may benefit from the sunitinib plus FOLFIRI regimen. It is possible that the low RDIs of 53% for sunitinib and <58% for FOLFIRI in the present study might have led to suboptimal treatment benefit. It is known, for example, that increased exposure to sunitinib is associated with improved clinical outcome. The low RDIs in the present study likely resulted from the increased toxicity (e.g. the high incidence of severe hematologic AEs) associated with combination treatment that resulted in dose interruption and/or dose reduction. The RDI on Schedule 4/2 was lower than on Schedule 2/2 in a study of sunitinib combined with mFOLFOX6 in Japanese patients, although the small patient population limited the availability of dose-intensity data. Maintaining the dose of sunitinib, particularly when combined with intensive chemotherapy, may be important in order to prolong median PFS. Therefore, Schedule 2/2 may be the optimal schedule to use when combining sunitinib with FOLFIRI or FOLFOX. Early study termination might also have contributed to the observed efficacy outcomes, and/or metastatic CRC cells may not be particularly dependent upon the signaling pathways inhibited by sunitinib. Further analyses would be necessary to confirm these hypotheses.
As mentioned above, there was a high incidence of severe (CTCAE grade 3/4) hematologic AEs when these Japanese patients with treatment-naïve unresectable or metastatic CRC received combination sunitinib plus FOLFIRI (neutropenia, 95.8%; leukopenia, 67.6%; thrombocytopenia, 29.6%; and febrile neutropenia, 23.9%). Additionally, almost 20% of patients discontinued study treatment permanently due to AEs, and over 90% required temporary interruptions of study treatment in order to manage treatment-related toxicities. The combination of sunitinib and FOLFIRI was associated with a higher incidence of grade ≥ 3 hematologic laboratory abnormalities compared with placebo plus FOLFIRI in the concurrent phase III study in non-Japanese patients (neutropenia, 68% vs 30%, respectively; thrombocytopenia, 11% vs <1%; and febrile neutropenia, 7% vs 3%). Moreover, recent studies in Japanese metastatic CRC patients have reported that patients with certain UGT1A1*28 or UGT1A1*6 polymorphisms are more susceptible to irinotecan-related neutropenia when treated with FOLFIRI.[16, 24]UGT1A1 genotype was not evaluated in the present study and all patients received the full irinotecan starting dose (180 mg/m2). This might, in part, have contributed to the high incidence of severe hematologic AEs reported here. Further, findings from the present study suggest that prophylactic use of oral antibacterial agents may be useful in patients receiving this regimen.
In conclusion, sunitinib 37.5 mg/day on Schedule 4/2 combined with FOLFIRI in Japanese patients with unresectable or metastatic CRC showed similar clinical activity (median PFS, ORR) compared with historical findings for 5-FU and irinotecan-containing regimens. The median PFS achieved in this trial did not meet the target of a 35% improvement compared with FOLFIRI alone, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. Additionally, combination treatment was associated with a high incidence of grade 3/4 hematologic AEs that may have impacted the RDIs. We anticipate that further investigation of sunitinib in combination with chemotherapy on Schedule 2/2, together with the identification of biomarkers of response, may be required.