(capecitabine plus irinotecan) versus FOLFIRI ... - The Lancet

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Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial Rui-Hua Xu*†, Kei Muro*†, Satoshi Morita, Satoru Iwasa, Sae Won Han, Wei Wang, Masahito Kotaka, Masato Nakamura, Joong Bae Ahn, Yan-Hong Deng, Takeshi Kato, Sang-Hee Cho, Yi Ba, Hiroshi Matsuoka, Keun-Wook Lee, Tao Zhang, Yasuhide Yamada, Junichi Sakamoto, Young Suk Park†, Tae Won Kim†

Summary

Background Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer.

Lancet Oncol 2018

Methods We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m² intravenously on day 1 plus oral capecitabine 800 mg/m² twice daily on days 1−14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m² intravenously on day 1, leucovorin 200 mg/m² intravenously on day 1, fluorouracil 400 mg/m² intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m²], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants.

See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(18)30194-3

Findings Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7–24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3−19·1) in the mXELIRI group and 15·4 months (13·0−17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71–1·02; pnon-inferiority1), previous use of oxaliplatin treatment (yes vs no), and concurrent bevacizumab treatment (with vs without). Owing to differences in the administration schedules, patients and clinicians were not masked to the allocated treatment.

Procedures Patients in the FOLFIRI group received intravenous infusion of irinotecan (180 mg/m²) over 90 min, levogyre (l)-leucovorin (200 mg/m²; or dextro-levogyre [d, l]leucovorin [400 mg/m²] if l-leucovorin was unavailable) over 120 min, and fluorouracil (400 mg/m²) bolus on day 1 followed by a 46-h continuous infusion of fluorouracil (2400 mg/m²), repeated every 14 days with or without intravenous bevacizumab (5 mg/kg) administered over 30–90 min on day 1. Patients in the mXELIRI group received a 90-min intravenous infusion of irinotecan (200 mg/m²) on day 1 and oral administration of capecitabine (800 mg/m²) tablet twice daily on days 1–14, repeated every 21 days with or without intravenous bevacizumab (7·5 mg/kg) given over 30–90 min on day 1. The decision making regarding concomitant bevacizumab therapy for both groups was at the discretion of investigators and patients, in the context of regional health-care policies and medical environment. Patients were tested for homozygosity or double heterozygosity for UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms (UGT1A1*28 and UGT1A1*6) at baseline. In both treatment groups, the dose for irinotecan was started at 150 mg/m² in patients who were identified to be homozygous for UGT1A1*6 or UGT1A1*28 or double heterozygous for UGT1A1*6 and UGT1A1*28 to minimise the risk of serious adverse events.17

We did not define a minimum or maximum number of treatment cycles. Treatment continued until disease progression, intolerable toxicity, or withdrawal at the patient’s own discretion. We did CT or MRI scans at baseline, week 6, week 12, and every 8 weeks thereafter. Qualified onsite investigators, who were masked to patient treatment information, assessed tumour response or progression using the Response Evaluation Criteria in Solid Tumors (version 1.1). Additionally, onsite investigators graded adverse events using the National Cancer Institute Common Terminology Criteria (version 4.0), and also recorded laboratory parameters of peripheral blood counts, blood biochemistry, and urinalysis (only for patients receiving concomitant bevacizumab) on the first day of each cycle (or the day before) in both groups during the protocol treatment period. Toxicities could be managed by dose reduction or discontinuation of irinotecan, capecitabine, or bevacizumab in the mXELIRI group and of irinotecan, fluorouracil, or bevacizumab in the FOLFIRI group. Detailed treatment modification criteria are available in the appendix (pp 7–8).

See Online for appendix

Outcomes The primary endpoint was overall survival, defined as the time from the date of randomisation to the date of death from any cause. Secondary endpoints were progression-free survival (from the date of randomisation to the date of confirmed progression or death from any cause, whichever occurred first), time to treatment failure (from the date of randomisation to the date of confirmed progression, death from any cause, or dis continuation of protocol treatment, whichever occurred first), overall response (the proportion of eligible patients with measurable lesions at baseline with a best overall response of complete response or partial response), disease control (proportion of eligible patients with measurable lesions with a best overall response of complete response, partial response, or stable disease), relative dose intensity (the ratio of delivered dose intensity of chemotherapy to dose intensity planned per protocol), incidence of adverse events, and the association between UGT1A1 poly morphisms (UGT1A1*28 or UGT1A1*6, or both) and the incidence of adverse events. The association between UGT1A1 polymorphisms and safety will be reported elsewhere.

Statistical analysis On the basis of data from two previous phase 3 trials that included FOLFIRI with or without bevacizumab or mXELIRI with or without bevacizumab as the second-line treatment for patients with refractory metastatic colorectal cancer,15,18 the median overall survival was assumed to be 11 months for patients treated with FOLFIRI alone and 13 months for patients treated with FOLFIRI plus bevacizumab. The

www.thelancet.com/oncology Published online March 16, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30140-2

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650 patients enrolled

326 randomly assigned to mXELIRI with or without bevacizumab

324 randomly assigned to FOLFIRI with or without bevacizumab

5 patients ineligible 2 recurrence more than 6 months after last dose of adjuvant chemotherapy 1 use of aspirin for more than 325 mg/day 1 baseline haemoglobin less than 9·0 g/dL 1 baseline total bilirubin more than 1·5 mg/dL

321 met eligibility criteria

4 patients ineligible 3 recurrence more than 6 months after last dose of adjuvant chemotherapy 1 gastrointestinal bleeding

320 met eligibility criteria

11 did not start assigned treatment 4 withdrew consent 5 disease progression 1 lost to follow-up 1 intercurrent death from disease

326 patients in intention-to-treat population 310 patients in per-protocol and safety population

10 did not start assigned treatment 6 withdrew consent 3 disease progression 1 lost to follow-up

324 patients in intention-to-treat population 310 patients in per-protocol and safety population

Figure 1: Trial profile mXELIRI=modified capecitabine plus irinotecan. FOLFIRI=leucovorin, fluorouracil, and irinotecan.

administration of concomitant bevacizumab varied by country because of diﬀerences in regional health-care policies and the medical environment. Generally, concomitant bevacizumab was given to a greater proportion of Japanese and South Korean patients than Chinese patients. On the basis of the estimated proportion of patients receiving treatment with or without bevacizumab (70% vs 30%) and the estimated median overall survival for these subgroups, the median overall survival of patients in our study for the FOLFIRI with or without bevacizumab group was assumed to be 12·6 months. The use of an upper margin of 1·30 for the hazard ratio (HR; estimated median overall survival of 12·6 months for the FOLFIRI group vs 9·7 months for the mXELIRI group) and a one-sided significance level of 0·025 ensured a power of 80% to show the noninferiority of mXELIRI versus FOLFIRI. Accordingly, an estimated 464 death events were needed to show noninferiority; therefore, an enrolment of at least 600 patients, accounting for a 5% annual dropout rate, was set for the study. If this non-inferiority hypothesis was proven, a second hypothesis was prospectively planned to be tested with a more stringent non-inferiority upper margin HR of 1·25 in the protocol. Additionally, if both of these analyses yielded positive results, a test for superiority of mXELIRI over FOLFIRI would be done. This superiority test was exploratory and post hoc, and the upper margin for the HR was set as 1·0. We did the efficacy analyses of overall survival and progression free-survival in the intention-to-treat 4

population, which included all patients who were enrolled and randomly allocated to the treatment groups. We did additional efficacy analyses of overall response and disease control and the safety analysis in the perprotocol population, which excluded patients in whom a major violation of the inclusion or exclusion criteria was discovered after study enrolment and also excluded patients who did not receive any of the planned protocol treatments. We generated survival curves using the Kaplan-Meier method. Additionally, we did log-rank tests stratified by the randomisation factors to assess overall survival, progression-free survival, and time to treatment failure. The HRs and 95% CIs were estimated with use of the stratified Cox proportional hazards models. We assessed between-group differences in overall response and disease control using χ² tests. Additionally, we used the Cox proportional hazards models to calculate HRs with 95% CIs and pinteraction values for predefined subgroup analyses. The predefined subgroups were age, sex, country, ECOG performance status, disease stage at diagnosis, primary tumour location, number of metastatic sites, liver metastases, liver-limited metastases, previous use of oxaliplatin, postoperative adjuvant chemotherapy, previous use of anti-EGFR therapy, previous use of bevacizumab, concomitant bevacizumab, alkaline phosphatase, KRAS status, and UGT1A1 polymorphism. For sensitivity analysis, we did a predefined stratified Cox proportional hazards analysis for overall survival only, adding the KRAS gene


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mXELIRI with or without bevacizumab (n=326)

FOLFIRI with or without bevacizumab (n=324)

1

206 (63%)

209 (65%)

Double heterozygotes or homozygotes

24 (7%)

26 (8%)

Yes

209 (64%)

190 (59%)

No

117 (36%)

134 (41%)

Liver metastases

Liver-limited metastases Yes

65 (20%)

60 (19%)

No

261 (80%)

264 (81%)

Yes

317 (97%)

317 (98%)

No

9 (3%)

7 (2%)

Previous use of oxaliplatin

Previous use of oxaliplatin in adjuvant therapy Yes

59 (18%)

71 (22%)

No

267 (82%)

253 (78%)

KRAS status Wild type

134 (41%)

129 (40%)

Mutant

93 (29%)

101 (31%)

Unknown

99 (30%)

94 (29%)

Data are n (%) or median (IQR). mXELIRI=modified capecitabine plus irinotecan. FOLFIRI=leucovorin, fluorouracil, and irinotecan. ECOG=Eastern Cooperative Oncology Group. UGT1A1=UDP-glucuronosyltransferase 1A1. *Defined as distant metastasis detected at diagnosis. †Patients with overlapping or multiple lesions were counted in both the right-sided and left-sided subgroups. ‡The interval between the last administration of the first-line therapy and randomisation.

Table 1: Baseline characteristics

Postoperative adjuvant chemotherapy Yes

70 (21%)

89 (27%)

No

256 (79%)

235 (73%)

(Table 1 continues in next column)

status as a covariate because interaction with the prognostic factors such as difference in the distribution of KRAS status or anti-EGFR antibody drugs cannot be ruled out. No statistical method such as data imputation was used to deal with missing data. All p values were two-sided. We did all statistical analyses with SAS (version 9.3). This study is registered with ClinicalTrials.gov, number NCT01996306, and UMIN Clinical Trials Registry, number UMIN000012263.

Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive either mXELIRI (n=326) or FOLFIRI (n=324), either with or without bevacizumab in both groups, as a second-line therapy for metastatic colorectal cancer. 16 patients in the mXELIRI group and 14 in the FOLFIRI group were identified as ineligible after enrolment or did not receive any study


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100

FOLFIRI with or without bevacizumab mXELIRI with or without bevacizumab

Overall survival (%)

75

50

25

0

HR 0·85 (95% CI 0·71–1·02) 0

Number at risk (number censored) FOLFIRI with or 324 (0) without bevacizumab mXELIRI with or 326 (0) without bevacizumab

6

12 18 24 Time since randomisation (months)

30

36

277 (7)

187 (8)

136 (8)

88 (18)

43 (44)

12 (66)

287 (6)

223 (7)

154 (8)

99 (21)

42 (49)

11 (73)

Figure 2: Overall survival mXELIRI=modified capecitabine plus irinotecan; FOLFIRI=leucovorin, fluorouracil, and irinotecan. HR=hazard ratio.

treatment (figure 1). Baseline characteristics were well balanced between the treatment groups (table 1). Concomitant bevacizumab was given to 269 (83%) of 326 patients in the mXELIRI group and 272 (84%) of 324 in the FOLFIRI group. 57 (17%) patients in the mXELIRI group and 67 (21%) in the FOLFIRI group had recurrence within 6 months after the last administration of adjuvant therapy. 317 (97%) in the mXELIRI group and 317 (98%) in the FOLFIRI group received previous oxaliplatin. In the per-protocol population (n=310 in each group), the median treatment duration was eight cycles (24 weeks; IQR 9–39 weeks) for the mXELIRI group and eight cycles (16 weeks; IQR 8–32 weeks) for the FOLFIRI group. Treatment was discontinued in a total of 306 (99%) of 310 patients in the mXELIRI group because of disease progression (208 [67%]), adverse events (24 [8%]), and patient refusal (39 [13%]); and 301 (97%) of 310 in the FOLFIRI group because of disease progression (192 [62%]), adverse events (29 [9%]), and patient refusal (47 [15%]). Reasons for treatment discontinuation other than disease progression, adverse events, and patient refusal were not specified during data collection; therefore, data are not shown for these other reasons of treatment discontinuation. A delay in treatment administration was necessary for 249 (80%) of 310 patients in the mXELIRI group and 281 (91%) of 310 in the FOLFIRI group, and a dose reduction was needed for 171 (55%) patients in the mXELIRI group and 231 (75%) in the FOLFIRI group. The relative dose intensity was 85·2% for irinotecan and 85·6% for capecitabine in the mXELIRI group; and 73·3% for irinotecan, 73·9% for fluorouracil, and 95·2% for leucovorin in the FOLFIRI group. At the cutoff date for the collection of survival data (July 28, 2017), a total of 490 deaths were confirmed (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab 6

group). With a median follow-up of 15·8 months (IQR 8·7–24·9) for the entire study population, the median overall survival was 16·8 months (95% CI 15·3−19·1) in the mXELIRI group and 15·4 months (13·0−17·7) in the FOLFIRI group (figure 2). The corresponding HR was 0·85 (95% CI 0·71−1·02), and the upper margin of the 95% CI was less than the predefined non-inferiority margin of 1·30 (Cox proportional hazards model pnon-inferiority