- Email: [email protected]
Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison
Original Study
Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison Toshiki Masuishi,1 Hiroya Taniguchi,1 Satoshi Hamauchi,2 Azusa Komori,1 Yosuke Kito,2 Yukiya Narita,1 Takahiro Tsushima,2 Makoto Ishihara,3 Akiko Todaka,2 Tsutomu Tanaka,3 Tomoya Yokota,2 Shigenori Kadowaki,1 Nozomu Machida,2 Takashi Ura,1 Akira Fukutomi,2 Masashi Ando,1 Yusuke Onozawa,4 Masahiro Tajika,3 Hirofumi Yasui,2 Kei Muro,1 Keita Mori,5 Kentaro Yamazaki2 Abstract It is unclear which drug should be administered first for refractory metastatic colorectal cancer, regorafenib or trifluridine/tipiracil (TAS-102). We retrospectively evaluated 200 patients who had received regorafenib or TAS102 at 2 institutions to compare these 2 drugs in terms of efficacy and safety. Our results suggest that regorafenib and TAS-102 have similar efficacy but different toxicities, which could guide the agent choice. Background: Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods: We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102. Results: A total of 146 and 54 patients received regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P ¼ .27; overall survival hazard ratio, 1.01, P ¼ .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of handefoot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa. Conclusion: Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Adverse event, Chemotherapy, Clinical practice, Efficacy, Subsequent treatment
1
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan 4 Division of Clinical Oncology 5 Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan 2 3
Address for correspondence: Hiroya Taniguchi, PhD, MD, Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan E-mail contact: [email protected]
Submitted: Mar 6, 2016; Revised: Jul 19, 2016; Accepted: Jul 28, 2016
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.07.019
Clinical Colorectal Cancer Month 2016
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Regorafenib Versus TAS-102 for Colorectal Cancer Introduction Colorectal cancer (CRC) is the second most common malignancy, with an estimated 1,361,000 new cases and an estimated 694,000 deaths worldwide each year.1 The standard treatment for patients with unresectable or metastatic CRC (mCRC) includes chemotherapy based on fluoropyrimidines, oxaliplatin, and irinotecan2 combined with anti-vascular endothelial growth factor (VEGF) antibodies3,4 and anti-epidermal growth factor receptor (EGFR) antibodies5-7 in the case of RAS wild-type tumors. Although these drugs have extended the median overall survival (OS) of patients with mCRC to about 30 months,8-10 these outcomes are not satisfactory, and the development of new active drugs is needed. Regorafenib is an oral multikinase inhibitor that blocks the activity of several protein kinases associated with angiogenesis (VEGF receptors 1-3 and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumor microenvironment (platelet-derived growth factor receptor and fibroblast growth factor receptor).11 In the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) trial, which compared regorafenib and placebo in mCRC patients with disease progression after standard treatment, regorafenib resulted in significantly longer OS (median, 6.4 months vs. 5.0 months; hazard ratio [HR], 0.77; P ¼ .0052) and progression-free survival (PFS) (median, 1.9 months vs. 1.7 months; HR, 0.49; P < .0001) compared with placebo.12 Regorafenib has been already approved in the United States, Europe, and Japan (since March 2013) for patients with refractory mCRC. Trifluridine/tipiracil (TAS-102) is a novel oral nucleoside antitumor agent consisting of trifluridine, which is a thymidine-based nucleic acid analogue, and tipiracil hydrochloride, which is a thymidine phosphorylase inhibitor that allows for the maintenance of adequate plasma levels of trifluridine.13,14 In the RECOURSE (TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies) trial, which compared TAS-102 with placebo in patients with mCRC refractory to standard treatment, TAS-102 significantly prolonged OS (median, 7.1 months vs. 5.3 months; HR, 0.58; P < .001) and PFS (median, 2.0 months vs. 1.7 months; HR, 0.48; P < .001) compared with placebo.15 TAS-102 has been approved for patients with refractory mCRC in Japan and the United States since March 2014 and September 2015, respectively, and is under registration in Europe. From these results, both regorafenib and TAS-102 have been recognized as standard treatments refractory mCRC. However, little is known regarding which drug should be administered first, owing to a lack of head-to-head trials. Therefore, we retrospectively compared regorafenib and TAS-102 in terms of efficacy and safety for patients with refractory mCRC.
oxaliplatin, irinotecan, anti-VEGF antibodies, and anti-EGFR antibodies (if KRAS exon 2 wild-type tumor); (3) no previous treatment with regorafenib or TAS-102; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; and (5) adequate bone marrow, hepatic, and renal function. Patients could be included if they had refused or were considered inappropriate to receive oxaliplatin, irinotecan, anti-VEGF antibodies, or anti-EGFR antibodies. All patients provided written informed consent for the treatment. The institutional review boards of the Aichi Cancer Center Hospital (approval no. 2015-1-049) and Shizuoka Cancer Center (approval no. T26-59-26-1-5) reviewed and approved the protocol.
Treatment Regorafenib (160 mg) was administered once daily on days 1 to 21, with 7 days of rest. TAS-102 (35 mg/m2) was administered twice daily, 5 days/wk, with 2 days of rest, for 2 weeks, followed by a 14-day rest period. Both regimens were repeated every 4 weeks. The treatments were continued until disease progression, death, unacceptable toxicity, or patient refusal. We included patients whose initial dose had been reduced by physician decision in the present study.
Treatment Evaluation All patients underwent computed tomography at the start of chemotherapy and then every 2 to 3 months to evaluate the tumor response according to the Response Evaluation Criteria in Solid Tumors, version. 1.1. For the patients with measurable lesions, the response rate is presented as the proportion of patients with a complete or partial response. The disease control rate represents the proportion of patients with a complete response, partial response, or stable disease. Complete response, partial response, and stable disease were considered present without confirmation of the response. PFS was defined as the time from the first administration of a treatment to the first radiologic or clinical observation of disease progression or death from any cause, whichever came first. The time to treatment failure (TTF) was defined as the interval from the first administration of a treatment to the discontinuation of treatment for any cause. OS was defined as the time from the first treatment administration until death from any cause or censoring at the last follow-up date. The median PFS, TTF, and OS were estimated using the Kaplan-Meier method. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Serious adverse events were defined as adverse events that resulted in death, hospitalization, or the prolongation of hospitalization.
Statistical Analysis
Materials and Methods Patients
2
-
The present study a retrospective cohort study to evaluate the efficacy and safety of regorafenib and TAS-102 in patients with refractory mCRC. We evaluated patients who had been treated at the Aichi Cancer Center Hospital and Shizuoka Cancer Center from May 2013 to May 2015. The eligibility criteria were as follows: (1) histologically confirmed unresectable colorectal adenocarcinoma; (2) refractory disease or intolerant to fluoropyrimidines,
Clinical Colorectal Cancer Month 2016
The patient characteristics, response rate, disease control rate, and adverse events were compared using Fisher’s exact test. The TTF, PFS, and OS were compared using a log-rank test with hazard ratios (HRs) and 95% confidence intervals (95% CIs) computed using the Cox proportional hazards model. Because TAS-102 was not available until May 2014 in Japan, OS was also analyzed for the patients treated with regorafenib or TAS-102 after May 2014. Survival differences were also evaluated by multivariate analyses using the Cox proportional hazards model, adjusted HRs presented. In the
Toshiki Masuishi et al multivariate analyses for PFS and OS, the following variables were included: age (< 65 vs. 65 years), gender, ECOG PS (0-1 vs. 2), histologic type (well or moderate vs. poor or mucinous), primary tumor site (right-sided colon vs. left-sided colon or rectum; rightsided colon included the cecum, ascending colon, and right-sided transverse colon; left-sided colon included the left-sided transverse colon, descending colon, and sigmoid colon), number of metastatic sites (1-2 vs. 3), KRAS exon 2 status (wild-type vs. mutant type), time from initiation of first-line chemotherapy (< 18 vs. 18 months), white blood cell count (< 10,000 vs. 10,000 cells/mL), alkaline phosphatase level (< 300 vs. 300 IU/L), and lactate dehydrogenase (LDH) level (< 400 vs. 400 IU/L). In the multivariate analyses for OS after approval of TAS-102 in Japan, we included all variables with P < .05 from the univariate analysis. All statistical analyses were performed using JMP, version 10 (SAS Institute, Cary, NC), and R, version 3.1.1. All statistical tests were 2-sided, with P < .05 considered statistically significant.
Table 1 Patient Characteristics Regorafenib (n [ 146)
TAS-102 (n [ 54)
<65
81 (55)
30 (56)
65
65 (45)
24 (44)
Male
90 (62)
30 (56)
Female
56 (38)
24 (44)
135 (92)
46 (85)
11 (8)
8 (15)
Well/moderately
131 (90)
47 (87)
Poor/mucinous
11 (7)
6 (11)
4 (3)
1 (2)
31 (21)
7 (13)
111 (76)
46 (85)
4 (3)
1 (2)
Characteristic Age (year)
.52
ECOG performance status 2
.17
Histologic type
Unknown
Results
1.00
Gender
0-1
.41
Primary tumor site
Patient Characteristics
Right-sided colona
From May 2013 to March 2015, 206 patients received regorafenib or TAS-102 for the first time. We excluded 5 patients with cancer of the appendix and 1 with an ECOG PS score of 3. Therefore, 146 patients who had received regorafenib (regorafenib group) and 54 patients who had received TAS-102 (TAS-102 group) were included (Table 1). The number of patients with a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels was greater in the regorafenib group than in the TAS-102 group (99% vs. 87%, 97% vs. 81%, and 73% vs. 54%, respectively); almost all other baseline characteristics were similar between the regorafenib and TAS-102 groups.
Left-sided colonb/rectum Unknown
.22
Previous tumor resection
.45
Yes
114 (78)
39 (72)
No
32 (22)
15 (28)
Liver
87 (60)
28 (52)
.34
Lung
100 (68)
34 (63)
.50
Lymph node
85 (58)
28 (52)
.43
Peritoneum
37 (25)
15 (28)
.72
Metastatic sites
Metastatic sites (n)
.27
Treatment Exposure and Subsequent Treatment
1-2
86 (59)
27 (50)
The frequencies and reasons for dose reduction or interruption are listed in Table 2. The initial dose of regorafenib was reduced in 22 patients (15%), and the initial dose of TAS-102 was reduced in 3 patients (6%). The incidence of dose modification and the number of interruptions because of adverse events during the 56 days after the initiation of chemotherapy were significantly greater in the regorafenib group than in the TAS-102 group. The median followup duration was 6.5 and 5.9 months, respectively. The median TTF was 1.8 months (95% CI, 1.6-2.1) and 2.0 months (95% CI, 1.72.8), respectively (HR, 1.22; 95% CI, 0.89-1.70; P ¼ .21). The frequencies and reasons for treatment discontinuation and subsequent treatment are listed in Table 3. At analysis, 146 patients (100%) in the regorafenib group had discontinued treatment and 50 patients (93%) in the TAS-102 group had discontinued treatment. The main reasons for treatment discontinuation in the regorafenib and TAS-102 groups were disease progression (86% and 94%, respectively) and adverse events (9% and 6%, respectively). Subsequent chemotherapy agents were administered to 79 patients (54%) in the regorafenib group and 22 patients (44%) in the TAS102 group (P ¼ .25).
3
60 (41)
27 (50)
Wild
78 (53)
21 (39)
Mutant
67 (45)
32 (59)
1 (1)
1 (2)
Efficacy Of the 134 patients with measurable lesions in the regorafenib group, 1 had a partial response and 43 had stable disease. Of the 48
P Value
KRAS exon 2 status
Unknown
.42
Time from initiation of first-line chemotherapy (mo)
.59
<18
37 (25)
16 (30)
18
109 (75)
38 (70)
Fluoropyrimidine
146 (100)
54 (100)
NA
Oxaliplatin
146 (100)
52 (96)
.07
History of systemic anticancer agents
Irinotecan
144 (99)
47 (87)
Anti-VEGF antibody
138 (95)
52 (96)
Anti-EGFR antibody (KRAS wt)
76 (97)
25 (81)
<10,000
132 (90)
49 (91)
10,000
14 (10)
5 (9)
WBC count (cells/mL)
.002 1.00 .006 1.00
ALP (IU/L)
.017
<300
40 (27)
25 (46)
300
106 (73)
29 (54)
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Regorafenib Versus TAS-102 for Colorectal Cancer Table 1 Continued Characteristic
Table 3 Treatment Discontinuation and Subsequent Treatment Regorafenib (n [ 146)
TAS-102 (n [ 54)
LDH (IU/L)
P Value .23
<400
96 (66)
41 (76)
400
50 (34)
13 (24)
Disease progression
patients with measurable lesions in the TAS-102 group, no patient had a partial response and 18 patients had stable disease. Therefore, the response rate was 0.8% in the regorafenib group and 0% in the TAS-102 group. The disease control rate was 33% in the regorafenib group and 38% in the TAS-102 group (P ¼ .60). At analysis, all the patients (100%) in the regorafenib group and 50 patients (93%) in the TAS-102 group had experienced disease progression. The median PFS was 2.1 months (95% CI, 1.8-2.5 months) in the regorafenib group and 2.1 months (95% CI, 1.8-3.1 months) in the TAS-102 group. No statistically significant difference was found on univariate analysis (HR, 1.20; 95% CI, 0.871.67; P ¼ .27; Figure 1) or multivariate analysis (adjusted HR, 1.27; 95% CI, 0.90-1.83; P ¼ .18). The results of the subgroup analysis suggested that older patients with a poor ECOG PS and
Table 2 Dose Reductions and Interruptions Regorafenib (n [ 146)
TAS-102 (n [ 54)
P Value
Dose reduction Timing Initial
22 (15)
3 (6)
.09
By day 56
79 (54)
11 (20)
<.0001
43 (29)
0 (0)
Reasons (by day 56) Hand-foot syndrome
NA
Proteinuria
8 (6)
0 (0)
Liver dysfunction
7 (5)
0 (0)
Anorexia
0 (0)
5 (9)
Neutropenia
0 (0)
3 (6)
Febrile neutropenia
.14 126 (86)
47 (94)
13 (9)
3 (6)
Refusal with adverse events
5 (3)
0 (0)
Refusal without adverse events
2 (1)
0 (0)
Best supportive care
67 (46)
28 (56)
Chemotherapy
79 (54)
22 (44)
NA
14 (28)
Adverse events
P Value
Subsequent treatment
.25
Chemotherapy regimen Regorafenib TAS-102
44 (30)
NA
Other
35 (24)
8 (16)
Data presented as n (%). Abbreviation: NA ¼ not applicable.
higher LDH levels in the regorafenib group had a tendency toward a shorter PFS than similar patients in the TAS-102 group. At the analysis, 125 patients (86%) in the regorafenib group and 36 (67%) in the TAS-102 group had died. The median OS was 6.7 months (95% CI, 5.8-7.6 months) in the regorafenib group and 6.5 months (95% CI, 5.3-8.3 months) in the TAS-102 group. No statistically significant difference was found on univariate analysis (HR, 1.01; 95% CI, 0.70-1.49; P ¼ .97) or multivariate analysis (adjusted HR, 0.98; 95% CI, 0.65-1.51; P ¼ .92).
Adverse Events The adverse events in the 200 eligible patients are listed in Table 4. The frequency of grade 3 or 4 hand-foot syndrome, increased aspartate transaminase, increased alanine transaminase, and increased bilirubin in the regorafenib group was significantly greater than the frequency in the TAS-102 group (21% vs. 0%, 13% vs. 0%, 10% vs. 0%, and 8% vs. 0%, respectively). However, the frequency of grade 3 or 4 leukopenia, neutropenia, anemia, nausea, and febrile neutropenia in the regorafenib group was significantly lower than the frequency in the TAS-102 group (2% vs. 18%, 3% vs. 37%, 9% vs. 24%, 0% vs. 6%, and 0% vs. 6%, respectively). Serious adverse events associated with treatment occurred in 20 patients (14%) in the regorafenib group (anorexia in 6 patients, liver dysfunction in 5 patients, erythema multiforme in 4 patients, fever in 2 patients, and drug-induced pneumonia, rupture of gastric varices, and bacterial pneumonia in 1 patient each) and in 4 patients (7%) in the TAS-102 group (diskitis, febrile neutropenia, anorexia, and anemia in 1 patient each; P ¼ .33). Of these patients, 1 patient in the regorafenib group died of treatment-related liver dysfunction.
0 (0)
2 (4) 1 (2)
125 (86)
16 (30)
Hand-foot syndrome
48 (33)
0 (0)
Fatigue
15 (10)
3 (6)
Proteinuria
12 (8)
0 (0)
0 (0)
5 (9)
After Approval of TAS-102 in Japan
50 (40)
8 (15)
Of the 200 patients, 38 had received regorafenib and 54 had received TAS-102 after the approval of TAS-102 in Japan. The baseline characteristics were generally similar between the
Dose interruption Timing (by day 56) Reason
Anorexia Other
-
TAS-102 (n [ 50)
21 (14)
Other
4
Regorafenib (n [ 146)
Reason for treatment discontinuation
Data presented as n (%). Abbreviations: ALP ¼ alkaline phosphatase; ECOG ¼ Eastern Cooperative Oncology Group; LDH ¼ lactate dehydrogenase; NA ¼ not applicable; WBC ¼ white blood cell; wt ¼ wild type. a Cecum, ascending colon, and right-sided transverse colon. b Left-sided transverse colon, descending colon, and sigmoid colon.
Variable
Variable
<.0001 NA
Data presented as n (%). Abbreviation: NA ¼ not applicable.
Clinical Colorectal Cancer Month 2016
Toshiki Masuishi et al Figure 1 Kaplan-Meier Curves for Progression-Free Survival (PFS) and Overall Survival (OS). (A) Median PFS Was 2.1 Months in the Regorafenib Group and 2.1 Months in the TAS-102 Group. (B) Median OS Was 6.7 Months in the Regorafenib Group and 6.5 Months in the TAS-102 Group. (C) OS After Approval of TAS-102 in Japan Showing a Median OS of 6.8 Months in the Regorafenib Group and 6.5 Months in the TAS-102 Group
A
B
1.0 HR 1.20 (95% CI 0.87-1.67) P = 0.27
0.8
Regorafenib 0.6
TAS-102
0.4
Regorafenib 0.6
0.2
0.0
0.0 3
6
9
12
TAS-102
0.4
0.2
0
HR 1.01 (95% CI 0.70-1.49) P = 0.97
0.8 OS Probability
PFS Probability
1.0
0
15
3
6
9
Time (months)
C
12
15
18
21
24
Time (months)
1.0 HR 1.14 (95% CI 0.68-1.87) P = 0.62
OS Probability
0.8
0.6
0.4 Regorafenib TAS-102
0.2
0.0 0
3
6
9
12
15
Time (months)
regorafenib and TAS-102 groups. At the analysis, 27 patients (71%) in the regorafenib group and 36 (67%) in the TAS-102 group had died. The median follow-up duration for these patients was 6.4 months in the regorafenib group and 5.9 months in TAS-102 group. The median OS was 6.8 months (95% CI, 5.3-7.7 months) in the regorafenib group and 6.5 months (95% CI, 5.3-8.3 months) in the TAS-102 group. Univariate analysis (HR, 1.14; 95% CI, 0.68-1.87; P ¼ .62) and multivariate analysis (adjusted HR, 1.32; 95% CI, 0.79-2.21; P ¼ .28) revealed no statistically significant differences. The variables included were the number of metastatic sites, white blood cell count, lactate dehydrogenase, and the time from the initiation of first-line chemotherapy. Of the 92 patients treated after the approval of TAS-102 in Japan, some were able to receive treatment with both regorafenib and TAS-102. The
median OS was 7.7 months (95% CI, 6.4-12.6 months) for the 19 patients in the regorafenib group and 7.4 months (95% CI, 4.9 months to not reached) for the 14 patients in the TAS-102 group. Univariate analysis revealed no statistically significant difference (HR, 0.99; 95% CI, 0.41-2.48; P ¼ .99).
Influence of Previous Regorafenib or TAS-102 Treatment on Subsequent Treatment With Opposite Agent The disease control rate for the patients who received regorafenib with and without previous TAS-102 treatment was 29% and 33%, respectively (P ¼ 1.00). The median PFS for patients who received regorafenib with and without previous TAS-102 treatment was 1.9 months (95% CI, 0.9-4.0 months) and 2.1 months (95% CI, 1.82.5 months), respectively (HR, 1.12; 95% CI, 0.60-1.90, P ¼ .70).
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6
Regorafenib (n [ 146) Adverse Events
Grade 1
Grade 2
TAS-102 (n [ 54)
Grade 3
Grade 4
Grade 1
Grade 2
Grade 3
Grade 4
P Value (Grade 3-4) <.0001
Hematologic Neutropenia
11 (8)
10 (7)
3 (2)
1 (1)
5 (9)
9 (17)
14 (26)
6 (11)
Leukopenia
16 (11)
9 (6)
3 (2)
0
6 (11)
16 (30)
9 (17)
1 (2)
.0001
Anemia
64 (44)
32 (22)
12 (8)
1 (1)
15 (28)
16 (30)
13 (24)
0
.008
Thrombocytopenia
55 (38)
23 (16)
8 (5)
3 (2)
15 (28)
3 (6)
2 (4)
0
.52
Nausea
14 (10)
11 (8)
0
0
23 (43)
13 (24)
3 (6)
0
.02
Vomiting
12 (8)
2 (1)
0
0
14 (26)
5 (9)
1 (2)
0
.27
Diarrhea
17 (12)
16 (11)
3 (2)
0
11 (20)
4 (7)
2 (4)
0
.61
Fatigue
48 (33)
50 (34)
1 (1)
0
25 (46)
17 (31)
0
0
1.00
Anorexia
38 (26)
43 (29)
8 (5)
0
16 (30)
21 (39)
6 (11)
0
.21
Mucositis oral
24 (16)
15 (10)
2 (1)
0
13 (24)
4 (7)
0
0
1.00 <.0001
Nonhematologic
Hand-foot syndrome
28 (19)
45 (31)
30 (21)
0
2 (4)
1 (2)
0
0
Rash
14 (10)
11 (8)
6 (4)
0
5 (9)
1 (2)
0
0
.19
AST increased
66 (45)
22 (15)
17 (12)
2 (1)
21 (39)
0
0
0
.002
ALT increased
49 (34)
14 (10)
13 (9)
1 (1)
9 (17)
0
0
0
.01
Bilirubin increased
40 (27)
19 (13)
11 (8)
0
9 (17)
3 (6)
0
0
.04
Creatinine increased
29 (20)
7 (5)
5 (3)
0
6 (11)
0
0
0
.33
Febrile neutropenia
NA
NA
0
0
NA
NA
3 (6)
0
.02
41 (28)
5 (3)
0
0
6 (11)
4 (7)
0
0
NA
Fever
Data presented as n (%). Abbreviations: ALT ¼ alanine transaminase; AST ¼ aspartate transaminase; NA ¼ not applicable.
Regorafenib Versus TAS-102 for Colorectal Cancer
Clinical Colorectal Cancer Month 2016
Table 4 Adverse Events
Toshiki Masuishi et al The frequency of grade 3 or 4 anemia was not significantly greater in patients with previous TAS-102 treatment (21% vs. 9%). The frequency for the other adverse events was similar between the 2 groups. The disease control rate for patients who received TAS-102 with and without previous regorafenib treatment was 34% and 39%, respectively (P ¼ .68). The median PFS for patients who received TAS-102 with and without previous regorafenib treatment was 2.2 months (95% CI, 1.8-3.1 months) and 2.1 months (95% CI, 1.83.1 months), respectively (HR, 1.13; 95% CI, 0.76-1.67; P ¼ .53). The frequency of grade 3 or 4 leukopenia and neutropenia were not significantly greater in patients with previous regorafenib treatment (28% vs. 19% and 51% vs. 37%, respectively). The frequency of the other adverse events was similar.
Discussion In the present retrospective cohort study, regorafenib and TAS102 showed similar efficacy and different toxicity profiles for regorafenib- and TAS-102enaive patients. To our knowledge, the present study is the first to compare regorafenib and TAS-102. The median OS in the TAS-102 group was shorter than that from the RECOURSE trial.15 That might have been because many patients in the TAS-102 group had an ECOG PS of 2 in the present study. However, the response rate, disease control rate, and median PFS in the regorafenib and TAS-102 groups in the present study were similar to those in previous pivotal trials.12,15 Moreover, because of the lead-time bias from the later approval of TAS-102 in the analyses of OS, we also examined these endpoints in patients after the approval of TAS-102 in Japan. Therefore, the results of the present study indicate that regorafenib and TAS-102 have similar efficacy in real clinical practice. The safety profiles in the regorafenib and TAS-102 groups in the present study were almost similar to those in previous pivotal trials,12,15 although the frequency of fatigue, and increased aspartate transaminase, alanine transaminase, and bilirubin levels in the regorafenib group was greater than that in the CORRECT trial and the frequency of fatigue and anorexia in the TAS-102 group was greater than that in the RECOURSE trial. In addition, the frequency of fatigue of any grade was greater in the TAS-102 group than in the regorafenib group. These differences seemed to be attributed to the differences in patient characteristics, especially ECOG PS. Because dose modification and interruption for adverse events in the regorafenib group were required for almost all patients, the initial dose of regorafenib might need to be reduced. Currently, some clinical trials are underway to clarify the efficacy and safety of an initial dose reduction of regorafenib (NCT02368886, UMIN000014661). Our results suggest that patients with previous TAS-102 treatment experienced efficacy and toxicity mostly similar to those for patients without previous TAS-102 with regorafenib treatment. To our knowledge, these results are the first report of the influence of previous TAS-102 on subsequent regorafenib treatment. Likewise, with TAS-102 treatment, patients with previous regorafenib treatment mostly experienced similar efficacy and toxicity to those without previous regorafenib treatment, consistent with a subgroup analysis of the RECOURSE trial. However, patients who received regorafenib after previous TAS-102 tended to have a greater rate of grade 3 or 4 anemia and those who received TAS-102 after previous
regorafenib tended to have a greater rate of grade 3 or 4 leukopenia and neutropenia; thus, these adverse events need to be better managed for these patients. No remarkable differences were found in efficacy between the regorafenib group and TAS-102 group in the entire population included in the present study or the patients treated after the approval of TAS-102 in Japan or the patients who had received both regorafenib and TAS-102. In addition, no remarkable influence was found for previous regorafenib treatment on the efficacy and safety of TAS-102 or vice versa. Therefore, our results suggest that both regorafenib followed by TAS-102 and TAS-102 followed by regorafenib achieve similar efficacy. We should consider which drug is more preferred in individual patients before the administration of these drugs. To our disappointment, predictive biomarkers for the efficacy and safety of regorafenib and TAS-102 have been not established, although von Willebrand factor and TIE-1 have been reported as candidates for regorafenib efficacy.16 The present study demonstrated a low frequency of subsequent chemotherapy in the regorafenib and TAS-102 groups. Because it has been reported that making all active agents available to patients with mCRC improved OS,17 we should consider how patients could be able to receive both drugs to further extend the OS of patients with mCRC. We suggest 2 strategies. First, because the main reason for not receiving subsequent chemotherapy was intolerance, patients should be switched to subsequent chemotherapy treatments earlier. Second, because it is difficult for patients with refractory disease or who are intolerant to standard treatment to receive both drugs, we should use 1 drug in combination with other drugs as an earlier line treatment. Several combination therapies such as regorafenib plus mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin)18 and TAS-102 plus irinotecan19 have been developed. The present study had several limitations. First, it was a retrospective nonrandomized analysis; thus, rigid conclusions should not be drawn from our findings. Second, our study population, especially after approval of TAS-102, was small. However, because the results of our study seem to reflect real clinical practice without the strict eligibility of the CORRECT and RECOURSE trials, our results provide valuable information to the clinical field.
Conclusion Regorafenib and TAS-102 had similar efficacy and different toxicity profiles and, as a result, our results suggest that different toxicity profiles should be considered when selecting these active agents for patients with refractory mCRC.
Clinical Practice Points Regorafenib and TAS-102 both prolong survival for patients
with refractory mCRC. Regorafenib and TAS-102 showed similar efficacy and different
toxicity profiles for regorafenib- and TAS-102enaive patients in real clinical practice without the strict eligibility of previous pivotal trials. Different toxicity profiles should be considered when selecting these active agents for patients with refractory mCRC in clinical practice.
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Regorafenib Versus TAS-102 for Colorectal Cancer Disclosure T. Masuishi, H. Taniguchi, S. Hamauchi, and Y. Narita have received honoraria from Taiho; T. Tsushima has received honoraria from Bayer; Aichi Cancer Center Hospital has received research funding for a clinical study performed by S. Kadowaki from Taiho; and K. Muro and K. Yamazaki have received honoraria from Taiho and Bayer. The remaining authors declare that they have no competing interests.
References 1. Globocan. Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed: February 28, 2015. 2. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229-37. 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-42. 4. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013-9. 5. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369:1023-34. 6. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28:4697-705. 7. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011-9.
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8. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15:1065-75. 9. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371:1609-18. 10. Yamada Y, Takahari D, Matsumoto H, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 2013; 14:1278-86. 11. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011; 129:245-55. 12. Grothey A, Cutsem EV, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303-12. 13. Fukushima M, Suzuki N, Emura T, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2’deoxyribonucleosides. Biochem Pharmacol 2000; 59:1227-36. 14. Tanaka N, Sakamoto K, Okabe H, et al. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep 2014; 32:2319-26. 15. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909-19. 16. Tabernero J, Lenz H-J, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol 2015; 16:937-48. 17. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005; 23: 9441-2. 18. Argiles G, Saunders MP, Rivera F, et al. Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: a phase II trial. Eur J Cancer 2015; 51:942-9. 19. Doi T, Yoshino T, Fuse N, et al. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs 2015; 33:1068-77.
Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison Toshiki Masuishi,1 Hiroya Taniguchi,1 Satoshi Hamauchi,2 Azusa Komori,1 Yosuke Kito,2 Yukiya Narita,1 Takahiro Tsushima,2 Makoto Ishihara,3 Akiko Todaka,2 Tsutomu Tanaka,3 Tomoya Yokota,2 Shigenori Kadowaki,1 Nozomu Machida,2 Takashi Ura,1 Akira Fukutomi,2 Masashi Ando,1 Yusuke Onozawa,4 Masahiro Tajika,3 Hirofumi Yasui,2 Kei Muro,1 Keita Mori,5 Kentaro Yamazaki2 Abstract It is unclear which drug should be administered first for refractory metastatic colorectal cancer, regorafenib or trifluridine/tipiracil (TAS-102). We retrospectively evaluated 200 patients who had received regorafenib or TAS102 at 2 institutions to compare these 2 drugs in terms of efficacy and safety. Our results suggest that regorafenib and TAS-102 have similar efficacy but different toxicities, which could guide the agent choice. Background: Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods: We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102. Results: A total of 146 and 54 patients received regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P ¼ .27; overall survival hazard ratio, 1.01, P ¼ .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of handefoot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa. Conclusion: Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Adverse event, Chemotherapy, Clinical practice, Efficacy, Subsequent treatment
1
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan 4 Division of Clinical Oncology 5 Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan 2 3
Address for correspondence: Hiroya Taniguchi, PhD, MD, Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan E-mail contact: [email protected]
Submitted: Mar 6, 2016; Revised: Jul 19, 2016; Accepted: Jul 28, 2016
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.07.019
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Regorafenib Versus TAS-102 for Colorectal Cancer Introduction Colorectal cancer (CRC) is the second most common malignancy, with an estimated 1,361,000 new cases and an estimated 694,000 deaths worldwide each year.1 The standard treatment for patients with unresectable or metastatic CRC (mCRC) includes chemotherapy based on fluoropyrimidines, oxaliplatin, and irinotecan2 combined with anti-vascular endothelial growth factor (VEGF) antibodies3,4 and anti-epidermal growth factor receptor (EGFR) antibodies5-7 in the case of RAS wild-type tumors. Although these drugs have extended the median overall survival (OS) of patients with mCRC to about 30 months,8-10 these outcomes are not satisfactory, and the development of new active drugs is needed. Regorafenib is an oral multikinase inhibitor that blocks the activity of several protein kinases associated with angiogenesis (VEGF receptors 1-3 and TIE2), oncogenesis (KIT, RET, RAF1, and BRAF), and the tumor microenvironment (platelet-derived growth factor receptor and fibroblast growth factor receptor).11 In the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) trial, which compared regorafenib and placebo in mCRC patients with disease progression after standard treatment, regorafenib resulted in significantly longer OS (median, 6.4 months vs. 5.0 months; hazard ratio [HR], 0.77; P ¼ .0052) and progression-free survival (PFS) (median, 1.9 months vs. 1.7 months; HR, 0.49; P < .0001) compared with placebo.12 Regorafenib has been already approved in the United States, Europe, and Japan (since March 2013) for patients with refractory mCRC. Trifluridine/tipiracil (TAS-102) is a novel oral nucleoside antitumor agent consisting of trifluridine, which is a thymidine-based nucleic acid analogue, and tipiracil hydrochloride, which is a thymidine phosphorylase inhibitor that allows for the maintenance of adequate plasma levels of trifluridine.13,14 In the RECOURSE (TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies) trial, which compared TAS-102 with placebo in patients with mCRC refractory to standard treatment, TAS-102 significantly prolonged OS (median, 7.1 months vs. 5.3 months; HR, 0.58; P < .001) and PFS (median, 2.0 months vs. 1.7 months; HR, 0.48; P < .001) compared with placebo.15 TAS-102 has been approved for patients with refractory mCRC in Japan and the United States since March 2014 and September 2015, respectively, and is under registration in Europe. From these results, both regorafenib and TAS-102 have been recognized as standard treatments refractory mCRC. However, little is known regarding which drug should be administered first, owing to a lack of head-to-head trials. Therefore, we retrospectively compared regorafenib and TAS-102 in terms of efficacy and safety for patients with refractory mCRC.
oxaliplatin, irinotecan, anti-VEGF antibodies, and anti-EGFR antibodies (if KRAS exon 2 wild-type tumor); (3) no previous treatment with regorafenib or TAS-102; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; and (5) adequate bone marrow, hepatic, and renal function. Patients could be included if they had refused or were considered inappropriate to receive oxaliplatin, irinotecan, anti-VEGF antibodies, or anti-EGFR antibodies. All patients provided written informed consent for the treatment. The institutional review boards of the Aichi Cancer Center Hospital (approval no. 2015-1-049) and Shizuoka Cancer Center (approval no. T26-59-26-1-5) reviewed and approved the protocol.
Treatment Regorafenib (160 mg) was administered once daily on days 1 to 21, with 7 days of rest. TAS-102 (35 mg/m2) was administered twice daily, 5 days/wk, with 2 days of rest, for 2 weeks, followed by a 14-day rest period. Both regimens were repeated every 4 weeks. The treatments were continued until disease progression, death, unacceptable toxicity, or patient refusal. We included patients whose initial dose had been reduced by physician decision in the present study.
Treatment Evaluation All patients underwent computed tomography at the start of chemotherapy and then every 2 to 3 months to evaluate the tumor response according to the Response Evaluation Criteria in Solid Tumors, version. 1.1. For the patients with measurable lesions, the response rate is presented as the proportion of patients with a complete or partial response. The disease control rate represents the proportion of patients with a complete response, partial response, or stable disease. Complete response, partial response, and stable disease were considered present without confirmation of the response. PFS was defined as the time from the first administration of a treatment to the first radiologic or clinical observation of disease progression or death from any cause, whichever came first. The time to treatment failure (TTF) was defined as the interval from the first administration of a treatment to the discontinuation of treatment for any cause. OS was defined as the time from the first treatment administration until death from any cause or censoring at the last follow-up date. The median PFS, TTF, and OS were estimated using the Kaplan-Meier method. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Serious adverse events were defined as adverse events that resulted in death, hospitalization, or the prolongation of hospitalization.
Statistical Analysis
Materials and Methods Patients
2
-
The present study a retrospective cohort study to evaluate the efficacy and safety of regorafenib and TAS-102 in patients with refractory mCRC. We evaluated patients who had been treated at the Aichi Cancer Center Hospital and Shizuoka Cancer Center from May 2013 to May 2015. The eligibility criteria were as follows: (1) histologically confirmed unresectable colorectal adenocarcinoma; (2) refractory disease or intolerant to fluoropyrimidines,
Clinical Colorectal Cancer Month 2016
The patient characteristics, response rate, disease control rate, and adverse events were compared using Fisher’s exact test. The TTF, PFS, and OS were compared using a log-rank test with hazard ratios (HRs) and 95% confidence intervals (95% CIs) computed using the Cox proportional hazards model. Because TAS-102 was not available until May 2014 in Japan, OS was also analyzed for the patients treated with regorafenib or TAS-102 after May 2014. Survival differences were also evaluated by multivariate analyses using the Cox proportional hazards model, adjusted HRs presented. In the
Toshiki Masuishi et al multivariate analyses for PFS and OS, the following variables were included: age (< 65 vs. 65 years), gender, ECOG PS (0-1 vs. 2), histologic type (well or moderate vs. poor or mucinous), primary tumor site (right-sided colon vs. left-sided colon or rectum; rightsided colon included the cecum, ascending colon, and right-sided transverse colon; left-sided colon included the left-sided transverse colon, descending colon, and sigmoid colon), number of metastatic sites (1-2 vs. 3), KRAS exon 2 status (wild-type vs. mutant type), time from initiation of first-line chemotherapy (< 18 vs. 18 months), white blood cell count (< 10,000 vs. 10,000 cells/mL), alkaline phosphatase level (< 300 vs. 300 IU/L), and lactate dehydrogenase (LDH) level (< 400 vs. 400 IU/L). In the multivariate analyses for OS after approval of TAS-102 in Japan, we included all variables with P < .05 from the univariate analysis. All statistical analyses were performed using JMP, version 10 (SAS Institute, Cary, NC), and R, version 3.1.1. All statistical tests were 2-sided, with P < .05 considered statistically significant.
Table 1 Patient Characteristics Regorafenib (n [ 146)
TAS-102 (n [ 54)
<65
81 (55)
30 (56)
65
65 (45)
24 (44)
Male
90 (62)
30 (56)
Female
56 (38)
24 (44)
135 (92)
46 (85)
11 (8)
8 (15)
Well/moderately
131 (90)
47 (87)
Poor/mucinous
11 (7)
6 (11)
4 (3)
1 (2)
31 (21)
7 (13)
111 (76)
46 (85)
4 (3)
1 (2)
Characteristic Age (year)
.52
ECOG performance status 2
.17
Histologic type
Unknown
Results
1.00
Gender
0-1
.41
Primary tumor site
Patient Characteristics
Right-sided colona
From May 2013 to March 2015, 206 patients received regorafenib or TAS-102 for the first time. We excluded 5 patients with cancer of the appendix and 1 with an ECOG PS score of 3. Therefore, 146 patients who had received regorafenib (regorafenib group) and 54 patients who had received TAS-102 (TAS-102 group) were included (Table 1). The number of patients with a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels was greater in the regorafenib group than in the TAS-102 group (99% vs. 87%, 97% vs. 81%, and 73% vs. 54%, respectively); almost all other baseline characteristics were similar between the regorafenib and TAS-102 groups.
Left-sided colonb/rectum Unknown
.22
Previous tumor resection
.45
Yes
114 (78)
39 (72)
No
32 (22)
15 (28)
Liver
87 (60)
28 (52)
.34
Lung
100 (68)
34 (63)
.50
Lymph node
85 (58)
28 (52)
.43
Peritoneum
37 (25)
15 (28)
.72
Metastatic sites
Metastatic sites (n)
.27
Treatment Exposure and Subsequent Treatment
1-2
86 (59)
27 (50)
The frequencies and reasons for dose reduction or interruption are listed in Table 2. The initial dose of regorafenib was reduced in 22 patients (15%), and the initial dose of TAS-102 was reduced in 3 patients (6%). The incidence of dose modification and the number of interruptions because of adverse events during the 56 days after the initiation of chemotherapy were significantly greater in the regorafenib group than in the TAS-102 group. The median followup duration was 6.5 and 5.9 months, respectively. The median TTF was 1.8 months (95% CI, 1.6-2.1) and 2.0 months (95% CI, 1.72.8), respectively (HR, 1.22; 95% CI, 0.89-1.70; P ¼ .21). The frequencies and reasons for treatment discontinuation and subsequent treatment are listed in Table 3. At analysis, 146 patients (100%) in the regorafenib group had discontinued treatment and 50 patients (93%) in the TAS-102 group had discontinued treatment. The main reasons for treatment discontinuation in the regorafenib and TAS-102 groups were disease progression (86% and 94%, respectively) and adverse events (9% and 6%, respectively). Subsequent chemotherapy agents were administered to 79 patients (54%) in the regorafenib group and 22 patients (44%) in the TAS102 group (P ¼ .25).
3
60 (41)
27 (50)
Wild
78 (53)
21 (39)
Mutant
67 (45)
32 (59)
1 (1)
1 (2)
Efficacy Of the 134 patients with measurable lesions in the regorafenib group, 1 had a partial response and 43 had stable disease. Of the 48
P Value
KRAS exon 2 status
Unknown
.42
Time from initiation of first-line chemotherapy (mo)
.59
<18
37 (25)
16 (30)
18
109 (75)
38 (70)
Fluoropyrimidine
146 (100)
54 (100)
NA
Oxaliplatin
146 (100)
52 (96)
.07
History of systemic anticancer agents
Irinotecan
144 (99)
47 (87)
Anti-VEGF antibody
138 (95)
52 (96)
Anti-EGFR antibody (KRAS wt)
76 (97)
25 (81)
<10,000
132 (90)
49 (91)
10,000
14 (10)
5 (9)
WBC count (cells/mL)
.002 1.00 .006 1.00
ALP (IU/L)
.017
<300
40 (27)
25 (46)
300
106 (73)
29 (54)
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Regorafenib Versus TAS-102 for Colorectal Cancer Table 1 Continued Characteristic
Table 3 Treatment Discontinuation and Subsequent Treatment Regorafenib (n [ 146)
TAS-102 (n [ 54)
LDH (IU/L)
P Value .23
<400
96 (66)
41 (76)
400
50 (34)
13 (24)
Disease progression
patients with measurable lesions in the TAS-102 group, no patient had a partial response and 18 patients had stable disease. Therefore, the response rate was 0.8% in the regorafenib group and 0% in the TAS-102 group. The disease control rate was 33% in the regorafenib group and 38% in the TAS-102 group (P ¼ .60). At analysis, all the patients (100%) in the regorafenib group and 50 patients (93%) in the TAS-102 group had experienced disease progression. The median PFS was 2.1 months (95% CI, 1.8-2.5 months) in the regorafenib group and 2.1 months (95% CI, 1.8-3.1 months) in the TAS-102 group. No statistically significant difference was found on univariate analysis (HR, 1.20; 95% CI, 0.871.67; P ¼ .27; Figure 1) or multivariate analysis (adjusted HR, 1.27; 95% CI, 0.90-1.83; P ¼ .18). The results of the subgroup analysis suggested that older patients with a poor ECOG PS and
Table 2 Dose Reductions and Interruptions Regorafenib (n [ 146)
TAS-102 (n [ 54)
P Value
Dose reduction Timing Initial
22 (15)
3 (6)
.09
By day 56
79 (54)
11 (20)
<.0001
43 (29)
0 (0)
Reasons (by day 56) Hand-foot syndrome
NA
Proteinuria
8 (6)
0 (0)
Liver dysfunction
7 (5)
0 (0)
Anorexia
0 (0)
5 (9)
Neutropenia
0 (0)
3 (6)
Febrile neutropenia
.14 126 (86)
47 (94)
13 (9)
3 (6)
Refusal with adverse events
5 (3)
0 (0)
Refusal without adverse events
2 (1)
0 (0)
Best supportive care
67 (46)
28 (56)
Chemotherapy
79 (54)
22 (44)
NA
14 (28)
Adverse events
P Value
Subsequent treatment
.25
Chemotherapy regimen Regorafenib TAS-102
44 (30)
NA
Other
35 (24)
8 (16)
Data presented as n (%). Abbreviation: NA ¼ not applicable.
higher LDH levels in the regorafenib group had a tendency toward a shorter PFS than similar patients in the TAS-102 group. At the analysis, 125 patients (86%) in the regorafenib group and 36 (67%) in the TAS-102 group had died. The median OS was 6.7 months (95% CI, 5.8-7.6 months) in the regorafenib group and 6.5 months (95% CI, 5.3-8.3 months) in the TAS-102 group. No statistically significant difference was found on univariate analysis (HR, 1.01; 95% CI, 0.70-1.49; P ¼ .97) or multivariate analysis (adjusted HR, 0.98; 95% CI, 0.65-1.51; P ¼ .92).
Adverse Events The adverse events in the 200 eligible patients are listed in Table 4. The frequency of grade 3 or 4 hand-foot syndrome, increased aspartate transaminase, increased alanine transaminase, and increased bilirubin in the regorafenib group was significantly greater than the frequency in the TAS-102 group (21% vs. 0%, 13% vs. 0%, 10% vs. 0%, and 8% vs. 0%, respectively). However, the frequency of grade 3 or 4 leukopenia, neutropenia, anemia, nausea, and febrile neutropenia in the regorafenib group was significantly lower than the frequency in the TAS-102 group (2% vs. 18%, 3% vs. 37%, 9% vs. 24%, 0% vs. 6%, and 0% vs. 6%, respectively). Serious adverse events associated with treatment occurred in 20 patients (14%) in the regorafenib group (anorexia in 6 patients, liver dysfunction in 5 patients, erythema multiforme in 4 patients, fever in 2 patients, and drug-induced pneumonia, rupture of gastric varices, and bacterial pneumonia in 1 patient each) and in 4 patients (7%) in the TAS-102 group (diskitis, febrile neutropenia, anorexia, and anemia in 1 patient each; P ¼ .33). Of these patients, 1 patient in the regorafenib group died of treatment-related liver dysfunction.
0 (0)
2 (4) 1 (2)
125 (86)
16 (30)
Hand-foot syndrome
48 (33)
0 (0)
Fatigue
15 (10)
3 (6)
Proteinuria
12 (8)
0 (0)
0 (0)
5 (9)
After Approval of TAS-102 in Japan
50 (40)
8 (15)
Of the 200 patients, 38 had received regorafenib and 54 had received TAS-102 after the approval of TAS-102 in Japan. The baseline characteristics were generally similar between the
Dose interruption Timing (by day 56) Reason
Anorexia Other
-
TAS-102 (n [ 50)
21 (14)
Other
4
Regorafenib (n [ 146)
Reason for treatment discontinuation
Data presented as n (%). Abbreviations: ALP ¼ alkaline phosphatase; ECOG ¼ Eastern Cooperative Oncology Group; LDH ¼ lactate dehydrogenase; NA ¼ not applicable; WBC ¼ white blood cell; wt ¼ wild type. a Cecum, ascending colon, and right-sided transverse colon. b Left-sided transverse colon, descending colon, and sigmoid colon.
Variable
Variable
<.0001 NA
Data presented as n (%). Abbreviation: NA ¼ not applicable.
Clinical Colorectal Cancer Month 2016
Toshiki Masuishi et al Figure 1 Kaplan-Meier Curves for Progression-Free Survival (PFS) and Overall Survival (OS). (A) Median PFS Was 2.1 Months in the Regorafenib Group and 2.1 Months in the TAS-102 Group. (B) Median OS Was 6.7 Months in the Regorafenib Group and 6.5 Months in the TAS-102 Group. (C) OS After Approval of TAS-102 in Japan Showing a Median OS of 6.8 Months in the Regorafenib Group and 6.5 Months in the TAS-102 Group
A
B
1.0 HR 1.20 (95% CI 0.87-1.67) P = 0.27
0.8
Regorafenib 0.6
TAS-102
0.4
Regorafenib 0.6
0.2
0.0
0.0 3
6
9
12
TAS-102
0.4
0.2
0
HR 1.01 (95% CI 0.70-1.49) P = 0.97
0.8 OS Probability
PFS Probability
1.0
0
15
3
6
9
Time (months)
C
12
15
18
21
24
Time (months)
1.0 HR 1.14 (95% CI 0.68-1.87) P = 0.62
OS Probability
0.8
0.6
0.4 Regorafenib TAS-102
0.2
0.0 0
3
6
9
12
15
Time (months)
regorafenib and TAS-102 groups. At the analysis, 27 patients (71%) in the regorafenib group and 36 (67%) in the TAS-102 group had died. The median follow-up duration for these patients was 6.4 months in the regorafenib group and 5.9 months in TAS-102 group. The median OS was 6.8 months (95% CI, 5.3-7.7 months) in the regorafenib group and 6.5 months (95% CI, 5.3-8.3 months) in the TAS-102 group. Univariate analysis (HR, 1.14; 95% CI, 0.68-1.87; P ¼ .62) and multivariate analysis (adjusted HR, 1.32; 95% CI, 0.79-2.21; P ¼ .28) revealed no statistically significant differences. The variables included were the number of metastatic sites, white blood cell count, lactate dehydrogenase, and the time from the initiation of first-line chemotherapy. Of the 92 patients treated after the approval of TAS-102 in Japan, some were able to receive treatment with both regorafenib and TAS-102. The
median OS was 7.7 months (95% CI, 6.4-12.6 months) for the 19 patients in the regorafenib group and 7.4 months (95% CI, 4.9 months to not reached) for the 14 patients in the TAS-102 group. Univariate analysis revealed no statistically significant difference (HR, 0.99; 95% CI, 0.41-2.48; P ¼ .99).
Influence of Previous Regorafenib or TAS-102 Treatment on Subsequent Treatment With Opposite Agent The disease control rate for the patients who received regorafenib with and without previous TAS-102 treatment was 29% and 33%, respectively (P ¼ 1.00). The median PFS for patients who received regorafenib with and without previous TAS-102 treatment was 1.9 months (95% CI, 0.9-4.0 months) and 2.1 months (95% CI, 1.82.5 months), respectively (HR, 1.12; 95% CI, 0.60-1.90, P ¼ .70).
Clinical Colorectal Cancer Month 2016
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6
Regorafenib (n [ 146) Adverse Events
Grade 1
Grade 2
TAS-102 (n [ 54)
Grade 3
Grade 4
Grade 1
Grade 2
Grade 3
Grade 4
P Value (Grade 3-4) <.0001
Hematologic Neutropenia
11 (8)
10 (7)
3 (2)
1 (1)
5 (9)
9 (17)
14 (26)
6 (11)
Leukopenia
16 (11)
9 (6)
3 (2)
0
6 (11)
16 (30)
9 (17)
1 (2)
.0001
Anemia
64 (44)
32 (22)
12 (8)
1 (1)
15 (28)
16 (30)
13 (24)
0
.008
Thrombocytopenia
55 (38)
23 (16)
8 (5)
3 (2)
15 (28)
3 (6)
2 (4)
0
.52
Nausea
14 (10)
11 (8)
0
0
23 (43)
13 (24)
3 (6)
0
.02
Vomiting
12 (8)
2 (1)
0
0
14 (26)
5 (9)
1 (2)
0
.27
Diarrhea
17 (12)
16 (11)
3 (2)
0
11 (20)
4 (7)
2 (4)
0
.61
Fatigue
48 (33)
50 (34)
1 (1)
0
25 (46)
17 (31)
0
0
1.00
Anorexia
38 (26)
43 (29)
8 (5)
0
16 (30)
21 (39)
6 (11)
0
.21
Mucositis oral
24 (16)
15 (10)
2 (1)
0
13 (24)
4 (7)
0
0
1.00 <.0001
Nonhematologic
Hand-foot syndrome
28 (19)
45 (31)
30 (21)
0
2 (4)
1 (2)
0
0
Rash
14 (10)
11 (8)
6 (4)
0
5 (9)
1 (2)
0
0
.19
AST increased
66 (45)
22 (15)
17 (12)
2 (1)
21 (39)
0
0
0
.002
ALT increased
49 (34)
14 (10)
13 (9)
1 (1)
9 (17)
0
0
0
.01
Bilirubin increased
40 (27)
19 (13)
11 (8)
0
9 (17)
3 (6)
0
0
.04
Creatinine increased
29 (20)
7 (5)
5 (3)
0
6 (11)
0
0
0
.33
Febrile neutropenia
NA
NA
0
0
NA
NA
3 (6)
0
.02
41 (28)
5 (3)
0
0
6 (11)
4 (7)
0
0
NA
Fever
Data presented as n (%). Abbreviations: ALT ¼ alanine transaminase; AST ¼ aspartate transaminase; NA ¼ not applicable.
Regorafenib Versus TAS-102 for Colorectal Cancer
Clinical Colorectal Cancer Month 2016
Table 4 Adverse Events
Toshiki Masuishi et al The frequency of grade 3 or 4 anemia was not significantly greater in patients with previous TAS-102 treatment (21% vs. 9%). The frequency for the other adverse events was similar between the 2 groups. The disease control rate for patients who received TAS-102 with and without previous regorafenib treatment was 34% and 39%, respectively (P ¼ .68). The median PFS for patients who received TAS-102 with and without previous regorafenib treatment was 2.2 months (95% CI, 1.8-3.1 months) and 2.1 months (95% CI, 1.83.1 months), respectively (HR, 1.13; 95% CI, 0.76-1.67; P ¼ .53). The frequency of grade 3 or 4 leukopenia and neutropenia were not significantly greater in patients with previous regorafenib treatment (28% vs. 19% and 51% vs. 37%, respectively). The frequency of the other adverse events was similar.
Discussion In the present retrospective cohort study, regorafenib and TAS102 showed similar efficacy and different toxicity profiles for regorafenib- and TAS-102enaive patients. To our knowledge, the present study is the first to compare regorafenib and TAS-102. The median OS in the TAS-102 group was shorter than that from the RECOURSE trial.15 That might have been because many patients in the TAS-102 group had an ECOG PS of 2 in the present study. However, the response rate, disease control rate, and median PFS in the regorafenib and TAS-102 groups in the present study were similar to those in previous pivotal trials.12,15 Moreover, because of the lead-time bias from the later approval of TAS-102 in the analyses of OS, we also examined these endpoints in patients after the approval of TAS-102 in Japan. Therefore, the results of the present study indicate that regorafenib and TAS-102 have similar efficacy in real clinical practice. The safety profiles in the regorafenib and TAS-102 groups in the present study were almost similar to those in previous pivotal trials,12,15 although the frequency of fatigue, and increased aspartate transaminase, alanine transaminase, and bilirubin levels in the regorafenib group was greater than that in the CORRECT trial and the frequency of fatigue and anorexia in the TAS-102 group was greater than that in the RECOURSE trial. In addition, the frequency of fatigue of any grade was greater in the TAS-102 group than in the regorafenib group. These differences seemed to be attributed to the differences in patient characteristics, especially ECOG PS. Because dose modification and interruption for adverse events in the regorafenib group were required for almost all patients, the initial dose of regorafenib might need to be reduced. Currently, some clinical trials are underway to clarify the efficacy and safety of an initial dose reduction of regorafenib (NCT02368886, UMIN000014661). Our results suggest that patients with previous TAS-102 treatment experienced efficacy and toxicity mostly similar to those for patients without previous TAS-102 with regorafenib treatment. To our knowledge, these results are the first report of the influence of previous TAS-102 on subsequent regorafenib treatment. Likewise, with TAS-102 treatment, patients with previous regorafenib treatment mostly experienced similar efficacy and toxicity to those without previous regorafenib treatment, consistent with a subgroup analysis of the RECOURSE trial. However, patients who received regorafenib after previous TAS-102 tended to have a greater rate of grade 3 or 4 anemia and those who received TAS-102 after previous
regorafenib tended to have a greater rate of grade 3 or 4 leukopenia and neutropenia; thus, these adverse events need to be better managed for these patients. No remarkable differences were found in efficacy between the regorafenib group and TAS-102 group in the entire population included in the present study or the patients treated after the approval of TAS-102 in Japan or the patients who had received both regorafenib and TAS-102. In addition, no remarkable influence was found for previous regorafenib treatment on the efficacy and safety of TAS-102 or vice versa. Therefore, our results suggest that both regorafenib followed by TAS-102 and TAS-102 followed by regorafenib achieve similar efficacy. We should consider which drug is more preferred in individual patients before the administration of these drugs. To our disappointment, predictive biomarkers for the efficacy and safety of regorafenib and TAS-102 have been not established, although von Willebrand factor and TIE-1 have been reported as candidates for regorafenib efficacy.16 The present study demonstrated a low frequency of subsequent chemotherapy in the regorafenib and TAS-102 groups. Because it has been reported that making all active agents available to patients with mCRC improved OS,17 we should consider how patients could be able to receive both drugs to further extend the OS of patients with mCRC. We suggest 2 strategies. First, because the main reason for not receiving subsequent chemotherapy was intolerance, patients should be switched to subsequent chemotherapy treatments earlier. Second, because it is difficult for patients with refractory disease or who are intolerant to standard treatment to receive both drugs, we should use 1 drug in combination with other drugs as an earlier line treatment. Several combination therapies such as regorafenib plus mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin)18 and TAS-102 plus irinotecan19 have been developed. The present study had several limitations. First, it was a retrospective nonrandomized analysis; thus, rigid conclusions should not be drawn from our findings. Second, our study population, especially after approval of TAS-102, was small. However, because the results of our study seem to reflect real clinical practice without the strict eligibility of the CORRECT and RECOURSE trials, our results provide valuable information to the clinical field.
Conclusion Regorafenib and TAS-102 had similar efficacy and different toxicity profiles and, as a result, our results suggest that different toxicity profiles should be considered when selecting these active agents for patients with refractory mCRC.
Clinical Practice Points Regorafenib and TAS-102 both prolong survival for patients
with refractory mCRC. Regorafenib and TAS-102 showed similar efficacy and different
toxicity profiles for regorafenib- and TAS-102enaive patients in real clinical practice without the strict eligibility of previous pivotal trials. Different toxicity profiles should be considered when selecting these active agents for patients with refractory mCRC in clinical practice.
Clinical Colorectal Cancer Month 2016
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Regorafenib Versus TAS-102 for Colorectal Cancer Disclosure T. Masuishi, H. Taniguchi, S. Hamauchi, and Y. Narita have received honoraria from Taiho; T. Tsushima has received honoraria from Bayer; Aichi Cancer Center Hospital has received research funding for a clinical study performed by S. Kadowaki from Taiho; and K. Muro and K. Yamazaki have received honoraria from Taiho and Bayer. The remaining authors declare that they have no competing interests.
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