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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

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.[1] FOLFIRI is now a standard first-line treatment for metastatic CRC.[1] 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.[8] It is also now approved for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors.[9]

Sunitinib has shown antitumor activity in non-clinical CRC models, both as a single agent[4] 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.[10]

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.[11] 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).[12] Results of the single-arm phase II study are presented here.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patients

Patients aged ≥20 years with histologically- or cytologically-confirmed adenocarcinoma of the colon or rectum, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function were included in the study. All patients had unresectable or metastatic disease by diagnostic imaging and were candidates for FOLFIRI therapy. No prior systemic chemotherapy for unresectable or metastatic CRC was permitted (prior adjuvant therapy was allowed providing there was longer than 6 months between the end of therapy and documentation of recurrent disease). Patients had measurable disease based on RECIST version 1.0.[13]

Patients were excluded if they had had full-field radiotherapy ≤4 weeks prior to study treatment or limited-field radiotherapy ≤2 weeks prior to study treatment, or previous radiation treatment to >30% of bone marrow. Additional exclusion criteria comprised: recent surgery or major bleeding; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess ≤6 months prior to study treatment (unless the affected tissue had been removed surgically); unresolved bowel obstruction or chronic diarrhea; arrhythmia grade 2 or higher (CTCAE version 3.0); clinically significant cardiovascular disease, cardiac dysrhythmias, or prolonged QTc interval; or central nervous system involvement.

Study design and treatment plan

This open-label, single-arm, phase II study was carried out in multiple centers and investigated the efficacy and safety/tolerability of sunitinib combined with FOLFIRI in a Japanese population. The study protocol was approved by the institutional review board or independent ethics committee of each participating center, and conformed to the provisions of the Declaration of Helsinki (1996). All patients provided written informed consent.

Patients received sunitinib plus FOLFIRI as first-line therapy for unresectable or metastatic CRC. Oral sunitinib 37.5 mg/day was given on Schedule 4/2. Intravenous FOLFIRI was given using standard procedures every 2 weeks: levo-leucovorin 200 mg/m2; irinotecan 180 mg/m2; immediately followed by 5-FU 400 mg/m2 bolus then 5-FU 2400 mg/m2 as a 46-h infusion. Treatment cycles were 6 weeks in duration (each 6-week sunitinib cycle included three cycles of FOLFIRI).

Treatment was continued until disease progression or withdrawal of treatment for another reason. Dose delays or reductions were permitted to manage treatment-related AEs. For sunitinib and FOLFIRI, dose delays >4 weeks were generally not permitted. Sunitinib doses could be reduced to 12.5 mg/day; FOLFIRI doses could be reduced according to institutional practices or guidelines provided in the study protocol. The use of hematopoietic growth factors was permitted.

Study assessments

The primary study endpoint was PFS, defined as time from the date of enrolment to first documentation of objective tumor progression or death due to any cause, whichever occurred first. Secondary endpoints included OS, RECIST-defined ORR and CBR,[13] and safety.

Tumors were imaged at baseline, every 6 weeks, when disease progression was suspected, to confirm an objective response (partial response or complete response) ≥4 weeks after initial documentation of response, and at the end of treatment/study withdrawal (if not carried out in the previous 6 weeks). Tumor assessments were subjected to review by study investigators and members of an Independent Radiological Committee.

Safety was evaluated based on AEs, laboratory results, physical examinations, vital signs, performance status, and electrocardiograms. Severity of AEs was graded using the National Cancer Institute CTCAE (version 3.0).

A Steering Committee reviewed efficacy and safety data periodically throughout the study and made recommendations regarding study amendment, continuation, and discontinuation.

Statistical methods

As this was a single-arm, exploratory, phase II study, there were no formal hypotheses for statistical testing. The planned sample size of 70 patients was determined based on assumptions that median PFS would be 8.0 months for patients receiving FOLFIRI alone (historical data)[14] and 10.8 months for patients receiving sunitinib plus FOLFIRI (a 35% improvement). Seventy patients would permit construction of a two-sided 95% CI with a width of approximately 7.2 months, if patient accrual was accomplished in 2 years and follow-up continued for 2 years.

The efficacy and safety analysis population included all enrolled patients with adenocarcinoma of the colon or rectum and unresectable or metastatic disease who had received at least one dose of study medication. Time-to-event endpoints were analyzed using Kaplan–Meier methods. Other efficacy and safety data were summarized using descriptive statistics.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Study conduct, patients, and treatments

Enrolment began in April 2008, with 71 patients enrolled by May 2009. In June 2009, the study was closed early when the concurrent phase III study of the same treatment regimen in non-Japanese patients with metastatic CRC (www.ClinicalTrials.gov identifier: NCT00457691) was halted due to futility.[12] Sunitinib discontinuation was recommended, or left to investigator discretion in patients with clinical benefit. The efficacy and safety analysis population comprised all 71 patients.

Patient baseline characteristics are summarized in Table 1. Patients started a median of three treatment cycles (range, 1–11; Table 2). Overall, the sunitinib dose was delayed in 66% of patients, was interrupted in 99% of patients, and was reduced in 59% of patients (Table 2). The resulting median sunitinib RDI was <53%. The median RDI for irinotecan, leucovorin, and 5-FU was <58% (Table 2). Most patients withdrew from study treatment/the study due to disease progression (59%, n = 42) or AEs (18%, n = 13).

Table 1. Baseline characteristics of Japanese patients with unresectable/metastatic colorectal cancer treated with sunitinib and FOLFIRI (n = 71)
 Sunitinib 37.5 mg/day (Schedule 4/2) plus FOLFIRI
  1. a

    n = 3 unknown.

  2. b

    Patients received prior adjuvant therapy which was allowed providing there was >6 months between the end of therapy and documentation of recurrent disease. ECOG, Eastern Cooperative Oncology Group; FOLFORI, leucovorin, 5-fluorouracil, and irinotecan; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off.

Gender, n (%)
Male42 (59.2)
Female29 (40.8)
Median age, years (range)60 (26–78)
ECOG performance status, n (%)
055 (77.5)
116 (22.5)
No. of organ sites with disease, n (%)
147 (66.2)
>124 (33.8)
Primary tumor site, n (%)
Colon37 (52.1)
Rectum34 (47.9)
Prior adjuvant treatment, n (%)8 (11.3)
Prior surgery, n (%)53 (74.6)
Prior radiation therapy, n (%)3 (4.2)
Prior systemic therapy, n (%)a
1 regimenb6 (8.5)
2 regimensb2 (2.8)
None60 (84.5)
Table 2. Study treatment exposure in Japanese patients with unresectable/metastatic colorectal cancer treated with sunitinib and FOLFIRI (n = 71)
 Sunitinib 37.5 mg/day (Schedule 4/2) plus FOLFIRI
SunitinibIrinotecanLeucovorin5-FU bolus5-FU infusion
  1. a

    n = 70. –, not available; FOLFORI, leucovorin, 5-fluorouracil (5-FU), and irinotecan; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off.

Median no. of cycles started (range)3 (1–11)3 (1–11)3 (1–11)3 (1–11)3 (1–11)
Patients with ≥1 dose delay, n (%)47 (66.2)61 (85.9)61 (85.9)58 (81.7)61 (85.9)
Patients with ≥1 dose interruption, n (%)70 (98.6)6 (8.5)4 (5.6)4 (5.6)
Patients with dose reductions, n (%)
1 reduction36 (50.7)40 (56.3)14 (19.7)38 (53.5)35 (49.3)
≥2 reductions6 (8.5)10 (14.1)2 (2.8)4 (5.6)6 (8.5)
Median relative dose intensity, % (range)53 (11–92)49 (27–80)a58 (27–80)a52 (27–77)a

Efficacy

At the time of data analysis, 44 patients (62.0%) had progressed (by independent review); median PFS was 6.7 months (95% CI, 4.7–9.2; Fig. 1). By investigator assessment, 45 patients (63.4%) had progressed; median PFS was 7.2 months (95% CI, 5.4–9.5). Post-hoc analyses of PFS by baseline characteristics are shown in Table 3.

image

Figure 1. Kaplan–Meier curve of progression-free survival (independent assessment) in Japanese patients with unresectable/metastatic colorectal cancer who were treated with sunitinib and FOLFIRI.

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Table 3. Post-hoc analysis of progression-free survival according to baseline variables in Japanese patients with unresectable/metastatic colorectal cancer were treated with sunitinib and FOLFIRI (n = 71)
Variable n Median PFS (months)HR (95% CI)
  1. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS, progression-free survival.

Age
<65506.71.2 (0.6–2.3)
≥65216.3
Gender
Male427.61.4 (0.8–2.5)
Female295.3
Primary disease site
Colon376.31.2 (0.7–2.2)
Rectum347.5
Time since diagnosis
<7 weeks475.61.0 (1.0–1.0)
≥7 weeks247.5
ECOG PS
0547.50.5 (0.3–1.1)
1174.7
Disease stage
<IV1815.50.5 (0.2–1.2)
IV536.7
No. of disease sites
1477.50.61 (0.3–1.1)
>1244.7

At the time of data analysis, eight patients (11.3%) had died (7 [9.9%] due to the disease under study and 1 [1.4%] due to other causes) and median OS had not yet been reached (due to early study closure).

The ORR by independent assessment was 36.6% (one complete and 25 partial responses; Fig. 2, Table 4), and the CBR was 83.1% (Table 4). The investigator-assessed ORR was 42.3% (30 partial responses), and the CBR was 88.7%. Median duration of response was 28.3 weeks (95% CI, 25.1–44.3 weeks; independent review).

image

Figure 2. Change from baseline in target lesion size per evaluable patient (independent assessment). Seventy-one Japanese patients with unresectable/metastatic colorectal cancer were treated with sunitinib and FOLFIRI. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

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Table 4. Best overall objective response (independent assessment) in Japanese patients with unresectable/metastatic colorectal cancer treated with sunitinib and FOLFIRI (n = 71)
 Sunitinib 37.5 mg/day (Schedule 4/2) plus FOLFIRI
  1. a

    Patient died prior to having sufficient evaluations for overall response.

  2. b

    Calculated using exact method based on binomial distribution. FOLFORI, leucovorin, 5-fluorouracil, and irinotecan; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off.

Best overall objective response, n (%)
Complete response1 (1.4)
Partial response25 (35.2)
Stable disease/no response33 (46.5)
Objective progression6 (8.5)
Early deatha1 (1.4)
Indeterminate5 (7.0)
Objective response rate, % (95% exact confidence intervalb)36.6 (25.5–48.9)

Safety

Non-hematological, all-causality, any-grade, AEs are summarized in Table 5. Decreased appetite (16.9%), vomiting (11.3%), and hypertension (9.9%) were the most common grade 3 or 4 AEs judged related to treatment. One patient, a 65-year-old woman who had smoked for 45 years, died due to a grade 5 AE, myocardial infarction, which was considered to be related to all study medications.

Table 5. Adverse events, regardless of causality, reported in ≥20% of patients with unresectable/metastatic colorectal cancer treated with sunitinib and FOLFIRI (n = 71)
Adverse event, n (%)Sunitinib 37.5 mg/day (Schedule 4/2) plus FOLFIRI
Grade 1Grade 2Grade 3Grade 4All grades
  1. a

    Based on adverse event reports. There was one grade 5 adverse event of myocardial infarction. ALT, alanine transaminase; AST, aspartate transaminase; FOLFORI, leucovorin, 5-fluorouracil, and irinotecan; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off.

Neutropeniaa0 (0.0)1 (1.4)29 (40.8)39 (54.9)69 (97.2)
Leukopeniaa0 (0.0)21 (29.6)41 (57.7)7 (9.9)69 (97.2)
Thrombocytopeniaa23 (32.4)16 (22.5)16 (22.5)5 (7.0)60 (84.5)
Diarrhea31 (43.7)18 (25.4)7 (9.9)0 (0.0)56 (78.9)
Nausea37 (52.1)13 (18.3)6 (8.5)0 (0.0)56 (78.9)
Decreased appetite30 (42.3)11 (15.5)12 (16.9)0 (0.0)53 (74.6)
Fatigue30 (42.3)11 (15.5)6 (8.5)0 (0.0)47 (66.2)
Alopecia40 (56.3)4 (5.6)0 (0.0)0 (0.0)44 (62.0)
Vomiting21 (29.6)11 (15.5)8 (11.3)0 (0.0)40 (56.3)
Stomatitis25 (35.2)9 (12.7)2 (2.8)0 (0.0)36 (50.7)
Dysgeusia33 (46.5)2 (2.8)0 (0.0)0 (0.0)35 (49.3)
Hand–foot syndrome23 (32.4)5 (7.0)5 (7.0)0 (0.0)33 (46.5)
Anemiaa11 (15.5)14 (19.7)5 (7.0)2 (2.8)32 (45.1)
Constipation24 (33.8)5 (7.0)0 (0.0)0 (0.0)29 (40.8)
Pyrexia20 (28.2)7 (9.9)0 (0.0)0 (0.0)27 (38.0)
Hypertension9 (12.7)9 (12.7)7 (9.9)0 (0.0)25 (35.2)
Lymphocyte count decreaseda0 (0.0)11 (15.5)12 (16.9)1 (1.4)24 (33.8)
Blood albumin decreaseda13 (18.3)6 (8.5)3 (4.2)0 (0.0)22 (31.0)
Skin discoloration22 (31.0)0 (0.0)0 (0.0)0 (0.0)22 (31.0)
ALT increaseda11 (15.5)4 (5.6)3 (4.2)0 (0.0)18 (25.4)
Febrile neutropeniaa0 (0.0)0 (0.0)17 (23.9)0 (0.0)17 (23.9)
AST increaseda12 (16.9)2 (2.8)2 (2.8)0 (0.0)16 (22.5)
Blood phosphorous decreaseda3 (4.2)4 (5.6)8 (11.3)0 (0.0)15 (21.1)

Thirty-two patients (45.1%) experienced serious AEs, considered by the investigator to be related to study treatment in 29 patients (40.8%). The most common treatment-related serious AEs were febrile neutropenia and decreased appetite (8.5% each; Table 6).

Table 6. Treatment-related serious adverse events in Japanese patients with unresectable/metastatic colorectal cancer treated with sunitinib and FOLFIRI (n = 71)
System organ classSunitinib 37.5 mg/day (Schedule 4/2) plus FOLFIRI
Preferred termn (%)
  1. FOLFORI, leucovorin, 5-fluorouracil, and irinotecan; Schedule 4/2, 4 weeks on treatment followed by 2 weeks off.

Blood and lymphatic

system disorders

Febrile neutropenia6 (8.5)
Leukopenia2 (2.8)
Thrombocytopenia2 (2.8)
Lymphadenitis1 (1.4)
Neutropenia1 (1.4)
Cardiac disordersMyocardial infarction1 (1.4)
Gastrointestinal disordersVomiting5 (7.0)
Nausea4 (5.6)
Intestinal obstruction2 (2.8)
Diarrhea1 (1.4)
Gastric dilation1 (1.4)
Gastrointestinal perforation1 (1.4)
Hemorrhoids1 (1.4)
Ileus1 (1.4)
Pneumonitis intestinalis1 (1.4)

General disorders and

administration site

conditions

Fatigue2 (2.8)
Pyrexia1 (1.4)

Infections and

infestations

Abdominal abscess1 (1.4)
Infection1 (1.4)
Influenza1 (1.4)
Localized infection1 (1.4)
Pneumonia1 (1.4)
Septic shock1 (1.4)

Injury, poisoning, and

procedural complications

Wound complication1 (1.4)
Wound dehiscence1 (1.4)
InvestigationsNeutrophil count decreased3 (4.2)

White blood cell count

decreased

1 (1.4)

Metabolism and nutrition

disorders

Decreased appetite6 (8.5)
Dehydration1 (1.4)
Nervous system disordersCerebral infarction1 (1.4)
Renal and urinary disordersHydronephrosis1 (1.4)
Vascular disordersHypertension1 (1.4)
Thrombosis1 (1.4)

Sixty-seven patients (94.4%) required sunitinib dose interruptions and 69 patients (97.2%) required FOLFIRI dose interruption due to AEs. Seven patients (9.9%) required sunitinib dose reduction and 10 patients (14.1%) required FOLFIRI dose reduction due to AEs. Study treatment (sunitinib and FOLFIRI) was discontinued permanently due to AEs in 13 patients (18.3%).

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

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.[12] 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%.[15] 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%.[17] 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.[22] 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.[23] 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%).[12] 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.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

This study was funded by Pfizer. Medical writing support was provided by Nicola Crofts at ACUMED (Tytherington, UK) and was funded by Pfizer. The authors would like to thank all of the participating patients and their families, as well as the investigators, research nurses, study coordinators, and operations staff.

Disclosure Statement

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Naoko Mizutani and Maria Jose Lechuga are Pfizer employees and hold Pfizer stock. Satoshi Hashigaki is a Pfizer employee. Yasushi Tsuji, Taroh Satoh, Akihito Tsuji, Kei Muro, Motoki Yoshida, Tomohiro Nishina, Michitaka Nagase, Yoshito Komatsu, Takeshi Kato, Yoshinori Miyata, and Tadamichi Denda have no conflicts of interest to disclose.

Abbreviations
5-FU

5-fluorouracil

AE

adverse event

CBR

clinical benefit rate

CI

confidence interval

CRC

colorectal cancer

CTCAE

Common Terminology Criteria for Adverse Events

FOLFIRI

leucovorin, 5-fluorouracil, and irinotecan

FOLFOX

5-fluorouracil, leucovorin, and oxaliplatin

mFOLFOX

modified FOLFOX regimen

ORR

objective response rate

OS

overall survival

PFS

progression-free survival

RDI

relative dose intensity

RECIST

Response Evaluation Criteria in Solid Tumors

Schedule 2/2

2 weeks on treatment followed by 2 weeks off

Schedule 4/2

4 weeks on treatment followed by 2 weeks off

VEGFR

vascular endothelial growth factor receptor

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
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