Japanese mCRC Research Articles

Identification of site-specific genome alterations in metastatic colorectal cancer: Sub-study 003 of the SCRUM-Japan GI-SCREEN.

578 Background: Primary tumor sidedness is known to be an independent prognostic factor and a predictor for the efficacy of anti-EGFR antibody. However, limited information is available regarding the role of primary tumor site for the treatment of metastatic colorectal cancer (mCRC) patients (pts), including gene mutation profiles, prognosis, and prediction for treatment. This study was conducted as a sub-study of the SCRUM-Japan GI-SCREEN, the Nationwide Cancer Genome Screening Project in Japan. Methods: Among participants of the GI-Screen 2013-01-CRC, untreated pts with mCRC which samples were collected from primary site were eligible. DNA and RNA were extracted from FFPE tumor samples and then were analyzed by the Oncomine Cancer Research Panel detecting gene mutations, copy number variants (CNV), and fusions across 143 genes in a CLIA certified CAP accredited laboratory. The detected genomic variant data were classified according to genetic drivers of cancer including gain- and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase. Results: Among 1011 enrolled pts from Feb. 2015 to Mar 2017, a total of 561 samples were analyzed (median age, 66.0 years; 232 [41.4 %] female). Frequency of female, undifferentiated, mucinous or signet ring cell subtype were gradually increased as the primary site became the right side. Median site-specific survival was 22.4 months (m) in the cecum, 25.3 m in the ascending colon, 21.2 m in the transverse colon, 72.5 m in the descending colon, 36.5 m in the sigmoid colon, and 39.6 m in the rectum. Gene alterations differed in each primary site. Among frequently observed gene alterations, FBXW7 mutation in rectum, ATM mutation in transverse colon, BRAF and SMAD4 mutations in ascending colon significantly contributed to poor prognosis. Conclusions: This study revealed the site-specific survival and gene alterations in Japanese mCRC pts. These novel knowledges provide an intriguing background to investigate new targeted approaches in these pts and represent the progress toward precision medicine. We will analyze the site-specific therapeutic effect of molecular targeting agents, including anti-EGFR antibody. Clinical trial information: UMIN000031242.

Retrospective multicenter study for assessment of association between imaging change and outcome after treatment of regorafenib: KSCC1603.

509 Background: Molecular-targeted drugs are known to have angiogenesis-inhibiting properties, and thus can inhibit angiogenesis inside the tumor tissue to cause necrosis, even if the tumor diameter is unchanged. We retrospectively investigated relationship between imaging change associated with regorafenib (REGO) treatment and the treatment outcome in Japanese mCRC. Methods: Eligibility included ECOG-PS 0 or 1, treated with REGO with lung or liver metastasis, started dose with 120 or 160mg/day of regorafenib and duration of treatment (DOT) must be 35 days or more (excluding interruption). Patients (Pts) were performed baseline CT within 28 days before and first CT assessment were between eight and 12 weeks after start of regorafenib. The main objective of this analysis is to investigate the correlation between the imaging change and outcome. As imaging change, onset or increase of Cavitation of lung lesion (CLL), morphologic response of liver lesion (MRL), Change of liver metastasis density (CLD) were evaluated. In all cases, independent two radiologists are evaluating radiological change after regorafenib treatment. Results: We finally screened 671 cases and 231 cases were eligible. The pts background was male/female 147/84, median age 64.0 (range: 32-83), median DOT of REGO 86 days (range: 35-818). The pts with lung metastasis were 153, and with liver metastasis were 166. CLL were positive in 69 (40.0%) pts. The median progression free survival (PFS) of the pts with/without CLL were 3.2/2.4 months (HR 0.794; 95% CI 0.584-1.080). Median overall survival (OS) of the pts with/without CLL were 10.5/9.0 months (HR 1.058; 95% CI 0.751-1.489). Median OS of pts with/without CLL in female were 11.4/7.9 months (HR 0.630; 95% CI 0.352-1.127). The MRL and CLD of liver metastasis were analyzed in 147 / 91 pt. Median OS of pts with/without MRL were 9.9/8.2 months (HR 1.015; 95% CI 0.581-1.774) and Median OS with/ without CLD were 11.6/7.0 months (HR 0.604; 95% CI 0.353-1.031). Conclusions: Cavitation of lung metastasis may predict PFS of the pts but not OS. Change of Liver metastasis density were predictor of favorable outcome to regorafenib. (UMIN000023329).

Safety and efficacy of regorafenib post-marketing surveillance (PMS) in Japanese patients with metastatic colorectal cancer (mCRC).

721 Background: The oral multikinase inhibitor regorafenib (REG) was approved for unresectable mCRC in Japan in 2013 based on the results of the global CORRECT phase 3 trial, which included 100 Japanese patients (pts). A PMS (NCT01843400) was conducted to assess the safety and efficacy of REG for the treatment of Japanese mCRC in clinical practice. Methods: Pre-registration was applied in the PMS. Adverse events (AEs), laboratory tests, drug exposure and anti-tumor effects were prospectively monitored for 6 months after initiating REG. One-year survival data was also collected. Target enrollment was 1,250 pts. Results: 1,303 pts were enrolled from March 2013 to May 2015. At the interim analysis as of August 2015, 787 pts were evaluable for safety and efficacy: male 57%; age ≥ 65 yrs 52%; ECOG Performance Status (PS) 0/1/2 40%/51%/10%; KRAS status wild-type/mutant 50%/47%; treatment line of REG 3rd /4th/ ≥ 5thline 40%/36%/24%; starting dose of REG 160 mg/120mg 66%/22%. Drug related adverse events (AE) were reported in 702 pts (89%). Most common AEs were hand foot skin reaction [(HFSR) 56%], liver dysfunction (32%, including 17% hepatic laboratory abnormalities), hypertension (27%), platelet count decreased (17%) and fatigue (14%). Rates of any grade of the major AEs typically peaked the first 2 months after starting REG and were relatively stable afterwards. Median time to treatment failure (TTF) was 2.1 months [range 1.9– 2.2]; median overall survival (OS) was 7.0 months [range 6.3– 7.8]. In exploratory analyses, rates of any grade and ≥ grade 3 HFSR and liver dysfunction were higher at the starting dose of 160mg (the dose of the first day of the first cycle) than in that of 120mg or less. Pts who had HFSR had a significantly longer OS than pts who did not (hazard ratio 0.573; 95% confidential interval0.470–0.698; p < 0.0001). TTF of pts with PS 0 tended to be longer than that of pts with PS ≥ 1. Conclusions: The safety and efficacy profiles of REG in Japanese pts in clinical practice are consistent with those of Japanese pts in the CORRECT trial. The results from > 1200 pts enrolled in the PMS will be presented at the meeting. Clinical trial information: NCT01843400.

Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05).

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR. We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman's rank correlation coefficient. In 54 participants, the RR, median PFS, and OS were 66.7% (95% CI, 53.4-77.8%), 11.1months, and 33.9months, respectively. There was no unexpected toxicity. Forty (80%) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3vs. 3.7months, HR 0.26, p = 0.0003; 42.8 vs. 9.0months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3%. The DpR correlated with OS (r s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r s = 0.587, r s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities. Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

A multinational, randomized, phase III trial of XELIRI (+bevacizumab) versus FOLFIRI (+bevacizumab) as the second-line chemotherapy for metastatic colorectal cancer: Asian XELIRI project (AXEPT).

TPS780 Background: Life-prolonging systemic therapy such as chemotherapy (FOLFOX, XELOX, FOLFIRI, 5-FU/LV) with / without molecular targeted agents (bevacizumab, afilibercept, cetuximab, panitumumab) are important treatment for metastatic colorectal cancer (mCRC). On the other hand, it is required to establish an evidence of convenient therapy including oral anticancer agent which is expected lower risk of safety. XELIRI was already examined by various doses in this decade, and result of AIO 0604 was regarded as one of the most appropriate regimen. The BIX phase II study showed the tolerability and promising efficacy of the AIO regimen for Japanese mCRC patients (Hamamoto Y, et al. Oncologist 2014). Methods: Asian XELIRI Project (AXEPT) is an East Asian collaborated, open label, randomized phase III clinical trial designed to demonstrate the non-inferiority of XELIRI (+bevacizumab) to the standard of care FOLFIRI (+bevacizumab) as the second-line chemotherapy in patients with mCRC. The primary endpoint is median overall survival. The secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, relative dose intensity, safety, correlation between UGT1A1 polymorphisms (*28, *6) and safety. Eligible patients were 20 years of age and older, had histologically proven CRC, ECOG performance status 0-2, adequate organ function, progression or difficult to continue after first line regimen. Patients were randomized 1:1 to standard FOLFIRI (+bevacizuamb 5mg/kg day1), repeated every 14 days (Group A) or XELIRI, Irinotecan 200mg/m2 day1, and capecitabine 1600mg/m2 day 1-14 (+bevacizumab 7.5mg/kg day1), repeated every 21 days (Group B). A Total of 464 events were needed to show non-inferiority with a two-sided α of 0·05 and a power of 80%, a target sample size of 600 patients was required. (The 95% CI upper limit of the hazard ratio was pre-specified as less than 1.3.). Enrollment has started in December 2013. As of August 2015, 98 centers in the Japan, South Korea and China are participating in this trial. Clinical trial information: NCT01996306. UMIN000012263. Clinical trial information: NCT01996306.

EGFR ligands and ERCC1 mRNA expression to predict clinical outcome in Japanese (JPN) patients (pts) with metastatic colorectal cancer (mCRC) harboring overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) treated with cetuximab (cet) plus oxaliplatin-based chemotherapy (JACCRO CC-05/06 AR).

618 Background: Previous studies have reported that EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), are potential predictive markers for cet and high ERCC1 expression is associated with resistance to platinum-containing chemotherapy. However, there are still few studies to assess predictive values of these expression levels in JPN mCRC pts. The aim of this study was to evaluate the values in JPN mCRC pts treated with cet. Methods: This study enrolled 77 pts with tissue available from 2 prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Total RNA isolated by macro-dissection from tissue was screened by RT-PCR for mRNA expression levels of AREG, EREG, and ERCC1, the cut-off values of which were based on the optimal cut-off value using the maximal chi-square approach on tumor response with adjusted p values. The same cut-off values were used to evaluate associations with progression-free survival (PFS) and overall survival (OS). Results: Median age and follow-up time were 63 (range: 39-79) years old and 24.7 (range: 5.5-39.3) months, respectively. In 73 evaluable pts, response rate (RR) was 77 % (95% CI, 67 to 86), but no significant association was seen in RR. Pts with high AREG expression (>1.59) had significantly longer PFS (11.6 vs. 6.6 months, HR: 0.53, logrank p=0.047) but not OS in 67 assessable pts. Pts with low ERCC1 expression (≤1.35) had significantly longer OS (42.8 vs. 22.0 months, HR: 2.46, logrank p=0.014) but a trend toward longer PFS (11.6 vs. 8.9 months, HR: 1.63, logrank p=0.092) in 68 assessable pts. On the other hand, high EREG expression (>3.21) was not associated with clinical outcome in 64 assessable pts. Conclusions: Our study identified predictive roles for AREG and ERCC1 mRNA expression in JPN mCRC pts treated with cet plus oxaliplatin. However, extended RAS mutations analysis is warranted (UMIN000010635).

Association of EGFR CA simple sequence repeat 1 (CA-SSR1) variant with cetuximab (cet)-induced skin toxicity (ST) in Japanese metastatic colorectal cancer (mCRC) patients (pts) with overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) (JACCRO CC-05/06 AR).

582 Background: Associations of EGFR gene copy number (GCN) and EGFR CA-SSR1 polymorphism with clinical outcome still remain controversial in mCRC pts treated with cet. Interethnic differences in the repeat number of EGFRCA-SSR1 have been reported between Caucasian and Asians, however, there have been few reports about the associations with clinical outcome in Japanese pts. The aim of this study was to evaluate the predictive value of two biomarkers in Japanese mCRC pts treated with cet. Methods: This study enrolled 77 pts with tumor available from two prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in mCRC pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Genomic DNA isolated by macro-dissection from tissue was screened for the EGFR GCN determined by FISH on FFPE tumor specimens with the cut-off value of 2.9, adopted as previously reported (Cappuzzo F, et al., 2008), and the EGFR CA-SSR1 short (S; ≤19) / long (L; ≥20) determined by PCR amplification and fragment length analysis using capillary electrophoresis. Associations of the biomarkers with efficacy, including response, progression-free survival, and overall survival, were evaluated. Additional analysis was addressed at a possible association between the EGFRCA-SSR1 and ST. Results: The frequency of the L alleles of the EGFR CA-SSR1 was 64%. There was no significant association between two biomarkers and efficacy. However, the EGFR CA-SSR1 variant significantly correlated with ST evaluated on 8 weeks after initial administration. The rate of ST with grade 2 or 3 was 33% (10/30), 19% (5/26), and 64% (7/11) in LL, SL, and SS genotype, respectively (fisher's exact test p=0.03). Conclusions: Our study provides first evidence that the EGFR CA-SSR1 variant was associated with cet-induced ST in Japanese mCRC pts. No predictive value for cet treatment could be identified in our screened biomarkers, however, extended RAS mutations analysis is warranted (UMIN000010635).

A prospective study of XELIRI plus bevacizumab as the first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101).

752 Background: XELIRI plus bevacizumab (Bev) might be one of the standard therapies for metastatic colorectal cancer (mCRC). However, there was no clinical practice data in Japan. This study was designed to evaluate the efficacy and safety of XELIRI plus Bev in clinical practice in Japanese mCRC patients (pts.). Methods: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated mCRC; presence of measurable lesions; age ≥20 years; ECOG performance status (PS) of 0–2; and adequate organ function. Pts received Bev 7.5 mg/kg day 1 and XELIRI (irinotecan 200 mg/m2 day 1 plus capecitabine 800 mg/m2 bid d1-14) q3w. This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint was RECIST-confirmed objective response rate (ORR). A sample size of 35 was planned for a threshold ORR of 30% and expected value of 53%, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: A total of 36 pts (male/female, 23/13; median age, 65.0 years (range 44.0-80.0); PS 0/1/2, 31/5/0) were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one withdrew the informed consent before the start of protocol treatment. Thirty-four pts were assessed for response; CR 0, PR 18, SD 9, PD 4, and NE 3. The confirmed ORR was 52.9% (90% CI, 37.7-67.8%). Median PFS was 9.6 months (95% CI, 5.1-11.1 months) and mOS was 23.0 months (95% CI, 11.3-NE months). mTTF was 5.3 months (95% CI, 3.2-8.3 months). The most common grade 3/4 adverse events were neutropenia 31.4%, anemia 20.0%, thrombocytopenia 5.7%, hyponatremia 20.0%, anorexia 20.0%, diarrhea 22.8%, fatigue 0.0%, hypertension 2.9%, hand-foot syndrome 0.0%, and bleeding 0.0%. Conclusions: First-line treatment of XELIRI + Bev showed a promising response rate and an acceptable tolerability profile in the clinical practice in Japanese mCRC pts. Clinical trial information: UMIN000006070.

Phase II Trial of Cetuximab plus Irinotecan for Oxaliplatin- and Irinotecan-Based Chemotherapy-Refractory Patients with Advanced and/or Metastatic Colorectal Cancer: Evaluation of Efficacy and Safety Based on KRAS Mutation Status (T-CORE0801)

Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. Methods: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. Results:KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. Conclusion: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.

A phase (Ph) Ib study of irinotecan (IRI), levofolinate (LV), and 5-fluorouracil (5-FU) (FOLFIRI) plus ramucirumab (RAM; IMC-1121B) drug product in Japanese (JP) patients (pts) with metastatic colorectal carcinoma (mCRC) progressive during or following first-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and a fluoropyrimidine (FP) (CP12-1029/NCT01286818).

591 Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We assessed the safety of RAM + FOLFIRI among JP mCRC pts. Methods: Eligible pts had measurable or nonmeasurable disease, ECOG PS 0-1 with disease progression during or within 6 mos following 1st-line therapy with BEV, OXALI, and a FP. Pts received 8 mg/kg RAM IV every 2 wks + FOLFIRI (IRI: 180 mg/m2, LV: 200 mg/m2, 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hrs). Dose-limiting toxicities (DLTs) were assessed Cycle 1 Day 1 to Cycle 3 Day 1. We assessed the safety of RAM + FOLFIRI among JP mCRC pts to support the participation of Japan in a global Ph 3 mCRC study. Results: 6 pts were treated; all pts completed study as of 3/19/2012. Median age was 62 yrs (range 48-71). 4 pts had colon cancer and 2 pts had rectal cancer . 1 of 6 pts experienced a DLT (Grade [G] 2 proteinuria and G4 neutropenia resulting in dose delay >2 wks). All 6 pts (100%) experienced at least one G3 adverse event (AE): neutropenia (5 pts; 83%), proteinuria (2 pts; 33%), anemia, thrombocytopenia, hypertension (1 pt each, 17%). 3 pts (50%) experienced G4 neutropenia. 2 pts discontinued (D/C) RAM due to G2 and G3 proteinuria, respectively; 1 pt D/C FOLFIRI due to G3 neutropenia. There were no serious AEs or deaths. Best overall response: 1 PR (17%), 4 SD (67%), 1 PD (17%). Median PFS: 7.3m (range: 1.25-10.91m; 95% CI: 1.2 – 10.9). As of 9/24/2012, 57 JP pts have been enrolled into ongoing P3 study I4T-MC-JVBB. Conclusions: RAM + FOLFIRI were reasonably tolerated and demonstrated anti-tumor activity in JP mCRC pts previously treated with BEV, OXALI, and a FP. The incidence of proteinuria in this small cohort of JP pts appears higher than that observed in other studies evaluating RAM to date. These safety data supported the enrollment of JP pts into an ongoing global P3 mCRC study. Clinical trial information: NCT01286818.

A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC0902).

583 Background: XELOX plus bevacizumab (Bev) is one of the standard therapies for metastatic colorectal cancer (mCRC). However there was no clinical practice date in Japan. This study was designed to evaluate the efficacy and safety of XELOX plus Bev in the clinical practice in Japanese mCRC patients (pts) including the elderly. Methods: The study design was multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated mCRC; presence of measurable lesions; age 20 years; ECOG performance status (PS) 0–2; and adequate organ function. Pts received Bev 7.5 mg/kg d1 and XELOX (oxaliplatin 130 mg/m2 d1 plus capecitabine 1,000 mg/m2 bid d1-14) q3w. This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint was RECIST-confirmed objective response rate (ORR). A sample size of 41 was planned for a threshold ORR of 30% and expected value of 50%, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: Of the 47 pts (male/female, 29/18; median age, 66 years (range 38-81); PS 0/1/2, 40/5/2) enrolled from May 2010 to Mar 2011. One patient did not fulfill the eligibility criteria. 46 pts were assessed for response; CR 1 pts, PR 23 pts, SD 15 pts, PD 2 pts, and NE 5 pts. The confirmed ORR was 52.2% (90% CI, 39.2-65.0%). The response rate across all time points without confirmation was 67.4% (95% CI, 52.0-80.5%). Median PFS and OS have not yet been reached. The most common grade 3/4 adverse events were anorexia 12.8%, neutropenia 10.6%, fatigue 8.5%, hypertension 4.3%, thrombocytopenia 4.3%, hand-foot syndrome 2.1% and bleeding 2.1%. Grade 3/4 peripheral neuropathy did not occur. Conclusions: First-line treatment of XELOX + Bev showed a promising response rate and an acceptable tolerability profile in the clinical practice in Japanese mCRC pts including the elderly. Clinical trial information: UMIN000003915.

O2-039 - Prospective Trial of Cetuximab Plus Irinotecan for Oxaliplatin and Irinotecan-Based Chemotherapy-Refractory Patients Advanced and/or Metastatic Colorectal Cancer, Evaluation of the Efficacy and Safety Based on Mutation Status of the EGFR Related Genes

ABSTRACT Background Activating mutation of the KRAS gene is a predictive biomarker for the loss of efficacy to Anti-EGFR antibody therapy. However, this was mainly established by the evidences of Caucasian studies. Then, this prospective study investigated the role of KRAS and other EGFR-related gene mutations on efficacy and safety to cetuximab plus irinotecan in Japanese patients with metastatic colorectal cancer (mCRC). Method We conducted a prospective study to analyze objective response to cetuximab plus irinotecan in molecularly defined KRAS wild-type (WT) or mutant subgroups of chemotherapy–refractory mCRC. KRAS mutations were detected by direct sequence on DNA from formalin-fixed, paraffin-embedded tissue of patients treated in 11 centers in Japan. Additional EGFR-related genes such as BRAF, PIK3CA, NRAS and AKT1 were examined. Results Forty-three patients were enrolled. KRAS mutations were found in 31.7% of 41 eligible patients. Response rate (RR) to cetuximab plus irinotecan, the primary end point of the study, was 17.9% and 0% for the WT KRAS patients and mutant KRAS patients, respectively. Progression-free survivals were 3.7 months versus 1.6 months (P = 0.0039); overall survivals were 7.7 months versus 4.4 months (P = 0.0005) for the WT KRAS patients and mutant KRAS patients, respectively. No significant differences in toxicity were observed between the WT and mutant KRAS groups. The combination of five genes analysis made the difference of clinical outcomes wider between all WT group and any mutant group. Conclusion We confirmed that the KRAS status is a useful predictive maker for the efficacy to cetuximab plus irinotecan therapy in Japanese mCRC patients, even though the response rate in the KRAS WT group was lower than expected. The combination of analysis in EGFR-related genes possibly contributes to the better prediction of the response.

655 - The Efficacy and Safety of Bevacizumab Beyond First Progression in Japanese Patients Treated with First-Line Mfolfox6 Followed By Second-Line Folfiri in Advanced Colorectal Cancer: a Multicenter, Single-Arm Phase Ii Trial (CCOG-0801); Final Report

ABSTRACT Purpose The aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression in Japanese patients with metastatic colorectal cancer (mCRC). Methods Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression free survival (PFS), response rate (RR), disease control rate (DCR) and safety. Results In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to 17.5 months). Thirty one patients went on to receive second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5 months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, the primary endpoint, was 18.0 months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7 to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after median follow up period of 35.9 months. No critical events associated with bevacizumab were observed during the second-line therapy. Concluson The planned continuation of bevacizumab during second-line treatment is feasible for Japanese mCRC patients. A prospective randomized control study to confirm efficacy is warranted. Disclosure All authors have declared no conflicts of interest.

The efficacy and safety of bevacizumab beyond first progression in patients treated with first-line mFOLFOX6 followed by second-line FOLFIRI in advanced colorectal cancer: a multicenter, single-arm, phase II trial (CCOG-0801)

PurposeThe aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression (BBP) in Japanese patients with metastatic colorectal cancer (mCRC).MethodsPreviously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after the second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety.ResultsIn the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7 %, DCR of 89.4 %, and median PFS of 13.1 months (95 % CI, 8.7–17.5 months). Thirty-one patients went on to receive a second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6 %, DCR of 62.1 %, and median PFS of 7.3 months (95 % CI, 5.0–9.6 months). Median 2nd PFS was 18.0 months (95 % CI, 13.7–22.3 months). The median OS and SBP were 30.8 months (95 % CI, 27.6–34.0 months) and 19.6 months (95 % CI, 13.5–25.7 months), respectively. No critical events associated with bevacizumab were observed during the second-line therapy.ConclusionThe planned continuation of bevacizumab during a second-line treatment, BBP strategy, is feasible for the Japanese mCRC patients.

Modified FOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab beyond first progression in advanced colorectal cancer: CCOG-0801 study.

641 Background: Bevacizumab provides survival benefit as the first-line and second-line therapies in metastatic colorectal cancer (mCRC). A large observational study suggested use of bevacizumab beyond first progression (BBP) improved survival. This prompted us to conduct a multicenter phase II study of mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizimab in mCRC to further explore the strategy of BBP in Japanese patients. Methods: Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after the second-line therapy. If the patient failed to receive the second-line treatment due to medical reasons or refusal, the PFS during the first-line therapy was used for analysis. Secondary endpoints were PFS, overall survival (OS), response rate (RR), disease control rate (DCR) and safety. Results: In the first-line therapy, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7%, DCR of 89.4% and median PFS of 11.7 months. Thirty patients went on to receive the second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6%, DCR of 62.1%, and median PFS of 6.0 months. Median 2nd PFS was 16.2 months. Median survival time did not reach the median follow-up time of 27.4 months. Severe adverse events associated with bevacizumab during the first-line therapy were a venous thromboembolic event in one case (2%), a grade 2 bleeding event in one case (2%) and GI perforation in one case (2%). However, no critical events associated with bevacizumab were reported during the second-line therapy. Conclusions: The planned continuation of bevacizumab during the second line treatment is feasible in Japanese mCRC patients. A prospective randomized control study to confirm the efficacy has to be conducted in the future.

A randomized pilot study comparing safety and efficacy of irinotecan plus S-1 plus bevacizumab (IRIS+BV) and modified FOLFIRI plus BV (mFOLFIRI+BV) in patients (pts) with metastatic colorectal cancer (mCRC): The result of efficacy report of T-CORE0702.

e14001 Background: We conducted a randomized pilot study to compare the safety and efficacy of IRIS+BV and mFOLFIRI+BV against Japanese mCRC (T-CORE0702) and reported that IRIS+BV is a safe regimen...

Modified FOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC. Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC). Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%). The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

MFOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study.

569 Background: In metastatic colorectal cancer (mCRC), a combination of leucovorin and fluorouracil with oxaliplatin (FOLFOX) is one of the standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. The aim of this study was to evaluate modified FOLFOX6 (mFOLFOX6) with the intermittent oxaliplatin treatment and maintenance therapy with S-1, oral fluoropyrimidine derivative, in the first-line treatment of mCRC. Methods: Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 5-fluorouracil continuous 2400 mg/m2, every 2 weeks) followed by maintenance therapy with oral S-1 (S-1 80- 120mg/body days 1-28, every 6 weeks). Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or tumor progression. The primary study end point was duration of disease control (DDC). Results: Twenty of the 30 patients (66.7%) who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in thirteen patients (43.0%). Median DDC was 9.3 months. Median progression-free survival (PFS) was 7.9 months. Overall response rates and disease control rates were 40.0% and 86.6% for the initial mFOLFOX6, 25.0% and 55.0% for S-1 maintenance therapy and 23.1% and 76.9% for mFOLFOX6 reintroduction. Twenty-eight patients (93.3%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.3%). Conclusions: The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible first-line treatment for Japanese mCRC patients. Further prospective randamized control study is warranted. No significant financial relationships to disclose.

Distributions of FcγRIIa-131 and FcγRIIIa-158 polymorphisms and clinical response to cetuximab in Japanese patients with metastatic colorectal cancer (mCRC).

565 Background: Polymorphisms in fragment C receptor (FcγR) are expected as a predictive biomarker of cetuximab (Cmab). Previous studies have convincingly confirmed the distributions (dists) of FcγR polymorphisms in Western population and shown the existence of linkage disequilibrium (LD) between FcγRIIa and FcγRIIIa polymorphisms. Meanwhile, the dists in Asian population have been unknown but a few studies for non-cancer patients have suggested the difference in dists between Asian and Western populations. We investigated the dists of FcγR polymorphisms and their association with clinical response to Cmab in Japanese mCRC patients. Methods: Ninety-three patients with irinotecan/oxaliplatin/5-FU-refractory mCRC and treated by Cmab plus irinotecan or Cmab monotherapy were retrospectively registered from 8 centers in Japan. FcγR polymorphisms were determined from genomic DNA extracted from peripheral blood samples based on the Multiplex allele-specific PCR method. Comparisons according to FcγR polymorphisms were evaluated using Fisher's exact test for response rate (RR) and log-rank test for progression-free survival curves (PFS). Results: The dists of FcγRIIa HH/HR/RR and FcγRIIIa VV/VF/FF were 68/30/2% and 4/40/56%, respectively (Table). The absence of LD between FcγRIIa and FcγRIIIa polymorphisms was confirmed (GENEPOP, p=0.526; Linkdis, p=0.146). Of 74 patients with KRAS wild-type and treated by Cmab plus irinotecan, no difference according to FcγR polymorphisms was observed in either RR (IIa: HH 37% vs. HR/RR 36%, p=1.00; IIIa: VV/VF 39% vs. FF 35%, p= 0.81) or PFS curves (IIa: HH vs. HR/RR, p=0.84; IIIa: VV/VF vs. FF, p=0.09). Similar results were seen in patients treated by cetuximab monotherapy. Conclusions: This study clarified an ethnic difference in the frequencies of FcγR polymorphisms. Associations between the polymorphisms and clinical response to Cmab did not reach a statistical significance. [Table: see text] No significant financial relationships to disclose.

Relationship between methylation status of PTEN and point mutation of the EGFR L2 domain and efficacy of cetuximab in metastatic colorectal cancer.

458 Background: The KRAS mutation has been associated with resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in metastatic colorectal cancer (mCRC). However, the predictive biomarkers of cetuximab resistance in KRAS wild-type mCRC remain unknown. We explored the possible roles of PTEN methylation and mutation of the EGFR L2 domain, which is the site of binding to cetuximab, in cetuximab resistance in KRAS wild-type mCRC. Methods: The subjects were 247 mCRC patients screened for KRAS status at the National Cancer Center Hospital between September 2008 and April 2010. Genomic DNA was extracted from formalin- fixed paraffin-embedded colorectal cancer tissue samples. Mutation analysis of KRAS and the EGFR L2 domain was performed by direct sequencing. Methylation analysis of PTEN was performed by quantitative real-time methylation-specific PCR with a set of primers specific to the methylated and unmethylated sequences, using sodium bisulfate-modified DNA. Results: Of the 247 mCRC patients, 136 patients had wild-type KRAS (55%). In 9 of these patients, the quality of the DNA was sufficient for analysis of PTEN methylation levels. Eight of the 9 patients received a cetuximab-based regimen (with irinotecan: 4, monotherapy: 4). The best response was PR in 4 patients (25%), SD in 2 (12.5%), and PD in 2 (12.5%). The best response of the one patient with methylated PTEN treated with cetuximab and irinotecan was SD. Mutation analysis of the EGFR L2 domain was performed in 65 of the 136 patients with wild-type KRAS. All of them received a cetuximab-based regimen (with irinotecan: 50, monotherapy: 15). The best response was PR in 13 patients (20%), SD in 26 (40%), PD in 20 (31%). The one patient who had a mutation at exon 9 showed a partial response to cetuximab and irinotecan. Conclusions: Methylation of PTEN and mutation of the EGFR L2 domain were analyzed in Japanese mCRC patients. Our findings do not provide sufficient evidence that EGFR L2 domain mutation and methylation of PTEN are correlated with resistance to cetuximab. No significant financial relationships to disclose.