Yoshinori Munemoto

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

EAGLE was a randomized, multicenter phase III study which evaluated the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC previously treated with first-line bevacizumab plus an oxaliplatin-based regimen. The results suggest that the higher 10 mg/kg dose offers no clear clinical benefit compared with bevacizumab 5 mg/kg in this setting.

Capecitabine and oxaliplatin combined with bevacizumab are feasible for treating selected Japanese patients at least 75 years of age with metastatic colorectal cancer

BackgroundAlthough number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥75xa0years with mCRC.MethodsThis prospective, open-label phase II trial recruited patients aged ≥75xa0years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5xa0mg/kg of intravenous bevacizumab and 130xa0mg/m2 of oxaliplatin on day 1 of each cycle combined with 2000xa0mg/m2 of oral capecitabine per day on days 1–14 of each cycle. Treatment was repeated every 3xa0weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival.ResultsThirty-six patients (male 58xa0%; median age 78xa0years; colon cancer 67xa0%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0xa0months. Twelve patients (33.3xa0%) experienced adverse effects (AEs)u2009≥u2009grade 3 and frequent AEsu2009≥u2009grade 3, including neutropenia (22.2xa0%) and neuropathy (13.9xa0%). Hypertension was the most frequent AEu2009≥u2009grade 3 associated with bevacizumab (11.1xa0%). Low baseline creatinine clearance associated significantly with the incidence of AEsu2009≥u2009grade 3. Response and disease control rates were 55.6 and 91.7xa0%, respectively. Median progression-free and overall survival times were 11.7xa0months (95xa0% confidence interval, 8.0–13.4xa0months) and 22.9xa0months, respectively.ConclusionXELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥75xa0years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit.

Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study).

AbstractBackgroundThe aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen.MethodsThe patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000xa0mg/m2) twice daily on days 1–14 and oxaliplatin (130xa0mg/m2) on day 1 every 21xa0days (Q3W group) or capecitabine (2,000xa0mg/m2) twice daily on days 1–7 and oxaliplatin (85xa0mg/m2) on day 1 every 14xa0days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs).ResultsA total of 46 patients were enrolled in the trial—22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4xa0months in both groups (hazard ratio [HR] 1.053; pxa0=xa00.880). The median PFS and OS were 3.3 and 9.2xa0months in the Q2W group and 4.3 and 12.1xa0months in the Q3W group, respectively (HRxa01.15; pxa0=xa00.153 and 0.672; pxa0=xa00.836). The most common ngrade 3−4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0xa0%) and diarrhea (9.1 vs 0xa0%), respectively.ConclusionThere was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)

This phase III study is the first study to demonstrate the superiority of new oral fluoropyrimidine S-1 over tegafur–uracil as adjuvant chemotherapy for stage II/III rectal cancer patients with no preoperative treatment in terms of relapse-free survival. S-1 can be considered an important option, especially for patients who have not received preoperative treatment.

Multicenter phase II study of infusional 5‑fluorouracil (5‑FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first‑line treatment in patients with metastatic colorectal cancer (CELINE trial)

The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38–82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1–3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial

PurposeFluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted.MethodsThis single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6xa0mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data.ResultsForty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2xa0months. 23 (57.5%) patients experienced at least one adverse effectu2009≥u2009grade 3. The response rate was 10.0% (95% confidence interval 2.8–23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression.ConclusionsFluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

525PA PHASE III STUDY OF EAGLE COMPARING TWO DOSES OF BEVACIZUMAB COMBINED WITH FOLFIRI IN THE SECOND-LINE SETTING AFTER FIRST-LINE TREATMENT WITH BEVACIZUMAB PLUS OXALIPLATIN-BASED THERAPY : KRAS SUBGROUP FINDINGS

ABSTRACT Aim: ML18147 showed continued bevcizumab(BEV) with second-line chmotherapy for patients with metastatic colorectal cancer (mCRC) treated with bev plus standard first-line chemotherapy, represents an option for patients with mCRC independent of KRS status. EAGLE study evaluted two doses of bev (10u2003mg/kg or 5u2003mg/kg) combined with FOLFIRI in the second-line setting after first-line treatmet with bev plus oxaliplatin-based therapy. Bev 10u2003mg/kg plus FOLFIRI as second-line treatment did not prolong pogression-free survival (PFS) compared with bev 5mg/kg plus FOLFIRI in patients with mCRC. Methods: Outcomes according to tumor KRAS status were evaluated as an exploratory analysis. KRAS data were collected from each institution. Survival analyses using Cox regression and Log-rank test were conducted by subgroups of the KRAS status. Results: Of 387 patients, 326 (84%) had KRAS data; 164 (50%) had KRAS wild-type tumors and 162 (50%) had mutant KRAS tumors. The median PFS was 7.1 months for bev 10u2003mg/kg and 5.9 months for bev 5u2003mg/kg (P = 0.568; HR = 1.04; 95% confidence interval (CI) : 0.76-1.43) for wild-type KRAS and 5.6 months fo bev 10u2003mg/kg and 6.5 months for bev 5mg/kg, respectively ( P = 0.89; HR = 1.10; 95% CI: 0.80-1.51) for mutant KRAS. The P value of test for treatment-subgroup inteaction was 0.956. The median overall survival (OS) was 17.9 months for bev 10mg/kg and 15.5 months for bev 5u2003mg/kg, respectvely (P = 0.244; HR = 0.80; 95% CI : 0.55-1.17) for wild-tpe KRAS and 15.9 months for bev 10u2003mg/kg versus 17.7 months for bev 5u2003mg/kg, respectivly (P = 0.312; HR = 1.21; 95% CI 0.84-1.74) for mutant KRAS. Conclusions: Although possible differences of treatment effect between bev 5u2003mg/kg and 10u2003mg/kg groups were observed for patients with wild-type KRAS, these results revealed bev 10mg/kg plus FOLFIRI as second-line treatment did not prolong PFS compared with bev 5u2003mg/kg plus FOLFIRI in patients with mCRC depending on KRAS status. Disclosure: S. Iwamoto: I have honoraria to disclose from Chugai, MerckSerono; T. Takahashi: I have honoraria to disclose from Chugai, Takeda, Taiho, MerckSerono. Bristol-Meyers Squibb; T. Kato: I have honoraria to disclose from Chugai, Yakult; T. Denda: I have honoraria to disclose from Taiho, Lilly, Sanofi; H. Baba: I have honoraria to disclose from Chugai, Takeda, Taiho; H. Mishima: I have honoraria to disclose from Chugai, Takeda, Taiho, Yakult. Ono, Tsumura, MerckSerono. Bristol-Meyers Squibb, Medicon. All other authors have declared no conflicts of interest.