FOLFIRI Arm Research Articles

Comparison of the second-line treatment efficacy in advanced gastric cancer patients previously treated with taxane-based triplet chemotherapy: a Turkish Oncology Group Study

Objective This study aimed to assess the efficacy and safety of FOLFIRI and paclitaxel in patients with advanced gastric cancer (AGC) who were previously treated with first-line modified docetaxel, cisplatin, 5-fluorouracil (mDCF), or 5-fluorouracil, oxaliplatin, docetaxel (FLOT). Methods Patients who received a triplet regimen in the first line setting and were treated with FOLFIRI or paclitaxel in the second-line treatment were included. Results The study included 198 patients, with 115 receiving FOLFIRI and 83 receiving paclitaxel. The median age was 58 (range = 24–69). The median progression-free survival (mPFS) was 5.2 [95% confidence interval (CI) = 4.4–5.5] months in the FOLFIRI arm, and 4.1 (95% CI = 3.3–4.6) months in the paclitaxel arm (p = .007). The median overall survival (mOS) was 9.4 (95% CI = 7.4–10.5) months in the FOLFIRI arm and 7.2 (95% CI = 5.6–8.3) months in the paclitaxel arm (p = .008). Grade 3–4 neuropathy was higher in patients receiving paclitaxel compared to those receiving FOLFIRI (p = .04). Grade 3–4 diarrhea was 8% in the FOLFIRI arm and 2.4% in the paclitaxel arm (p = .02). Conclusion Beyond progression with docetaxel-based triplet chemotherapy, FOLFIRI may be preferred as a second-line treatment over paclitaxel due to its longer mPFS and mOS.

Early identification and treatment of occult metastatic disease in stage III colon cancer (SU2C ACT3 clinical trial).

148 Background: Despite adjuvant chemotherapy, nearly 30% of patients with Stage III colon cancer (CC) will recur. We are performing a randomized clinical trial using a plasma-only circulating tumor DNA (ctDNA) platform after adjuvant therapy for patients with ctDNA-positive Stage III CC. Methods: Patients (pts) with Stage III CC are eligible for prescreening, including tumor tissue profiling by next-generation sequencing. Pts are screened 3-6 weeks after adjuvant chemotherapy. At screening blood is collected for ctDNA analysis with a CLIA-certified sequencing panel (Reveal, Guardant Health). A baseline CT scan is required to confirm lack of metastases. Pts with undetectable ctDNA (-) at screening undergo surveillance with imaging, labs and ctDNA testing every 3 months (Arm 3). ctDNA-detectable (+) pts who are biomarker-negative are randomized to 1:1 to FOLFIRI (Arm 1) or active surveillance (Arm 2). ctDNA+ pts with an actionable biomarker (biomarker-positive) are given 6 months biomarker-directed therapy as follows: V600E/MSS- encorafenib, binimetinib and cetuximab (Arm 5), HER2 amplified trastuzumab/pertuzumab (arm 6), and MSI-H nivolumab (Arm 4). Primary outcome is ctDNA clearance in Arms 1 and 2, 1-month after completion of additional adjuvant therapy or surveillance. Secondary outcomes include RFS and OS in Arms 1 and 2, ctDNA clearance and RFS/OS in the other arms. An interim analysis is planned after 13 patients are enrolled in Arm 1 and primary outcome will be assessed after 50 patients’ complete treatment/surveillance in Arms 1 and 2. Results: From 4/16/2020 through 9/8/2023, 147 patients were screened, 66 screen failed. Pre-screening as well as active ongoing enrollment is underway. To date, 73 patients have enrolled (46 male and 27 female). 53 (72.6%) were white. 10 (13.7%) patients were noted to be ctDNA+ within 6 weeks of completion of adjuvant therapy: 4 in Arm 1; 5 in Arm 2; 1 in Arm 4. 63 pts were ctDNA- and in Arm 3. Conclusions: In this ctDNA guided trial, with single time-point testing, only 13.7% of pts were ctDNA+ after adjuvant chemotherapy. 90% of ctDNA+ patients did not have an actionable biomarker. Strict windows for eligibility and enrollment initially restricted eligibility but these were adjusted to increase eligibility. To mitigate the low positivity rate and allow us to meet our accrual goals in arm 1 and 2, the protocol was amended to allow for entry into the ctDNA+ arms at any time during the first 3 years after completion of adjuvant therapy as opposed to within 6 weeks of completion of adjuvant therapy. The lessons learnt would have implications for other ctDNA-driven clinical trials. Clinical trial information: NCT03803553. Patient distribution in the SU2C ACT3 study. Total Screened Pre-Screening Screen Fail Enrolled Off Study ctDNA Treatment Arm + - Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 147 8 66 73 10 10 63 4 5 63 1 0 0

Regorafenib plus FOLFIRI with irinotecan dose escalated according to UGT1A1 genotyping in patients with metastatic colorectal cancer.

125 Background: This multicenter, phase II, randomized, open-label, 2-arm parallel trial aims to compare the efficacy and safety profiles of regorafenib plus irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping with regorafenib alone in previously treated patients with metastatic colorectal cancer (mCRC). Methods: A total of 153 patients were planned to randomize at a ratio of 2:1 for receiving regorafenib plus FOLFIRI (arm A, 102 patients) or regorafenib alone (arm B, 52 patients), respectively. For both arms, regorafenib were given for 21 consecutive days (Day 1 to 21) of each 28-day cycle at a maintained dose of 120 mg. However, for arm A, patients received regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1 genotypes. FOLFIRI were on the first day of each 28-day cycle only. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and disease control rate (DCR), and adverse events (AEs). Results: Finally, a total of 116 patients were enrolled to be analyzed, including 74 in arm A and 42 in arm B. The significantly better PFS was observed in arm A, 4.8 and 3.0 months, respectively ( p = 0.016). Moreover, in patients with RAS wild type, the significantly better PFS was observed in arm A, 6.3 and 2.1 months, respectively ( p = 0.003). The OS was not significantly different between group A and B, 9.8 and 12.6 months, respectively ( p = 0.970). However, in patients with RAS wild type, the trend of better OS was observed in arm A, 14.3 and 6.9 months, respectively ( p = 0.158). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). Combination treatment of regorafenib plus FOLFIRI was independent favorable prognostic factor for PFS ( P = 0.008; hazard ratio [HR], 1.892; 95% CI, 1.182 – 3.027). Regarding severe AEs, there were no significant differences between the two groups (all P>0.05). Conclusions: Combination treatment of regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1genotyping results in a significant better PFS and comparable AEs. Moreover, patients with RAS wild type of CRC would be more beneficial for this combination treatment.

Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).

Simple SummaryNowadays, the surgery of liver metastases remains the only hope of a cure for patients with colorectal cancer. Pathological responses evaluated after preoperative treatment strongly influences the risk of relapse and patient survival. Previous studies reported that preoperative bevacizumab combined with an oxaliplatin-based chemotherapy provided a higher pathological response rate compared with an irinotecan-based regimen or chemotherapy alone. This prospective trial, having recruited 65 patients with resectable colorectal liver metastases, ambitioned to report a higher major pathological response rate after mFOLFOX6-bevacizumab compared to FOLFIRI-bevacizumab. Among the 57 patients with 159 resected metastases, no difference in major pathological response rate was observed between treatments. Nevertheless, the trial prospectively confirmed the pathological response of resected colorectal liver metastases as a significant biomarker for tumor recurrence, justifying its implementation in clinical practice. Interestingly, we observed that the homogeneity of the pathological response and histological growth pattern of liver metastases was also strongly associated with patient’s survival.Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204–0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104–1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel – results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO

BackgroundRamucirumab and paclitaxel is the standard second-line therapy in patients with metastatic gastroesophageal adenocarcinoma. We report the efficacy and safety analyses of FOLFIRI and ramucirumab versus paclitaxel and ramucirumab after the failure of a platinum- and fluoropyrimidine-containing chemotherapy. MethodsThis multicenter, investigator initiated, phase II trial randomised patients with gastroesophageal adenocarcinoma to either FOLFIRI plus ramucirumab (RAM) (arm A) or paclitaxel plus RAM (arm B). The primary end-point was 6-month overall survival (OS) rate, with a proportion of ≥65% in arm A considered a positive signal for further investigation. Results111 patients (65% of patients had prior docetaxel) were enrolled and 110 patients qualified for ITT population (arm A, 72; arm B, 38). The study did not meet the primary end-point for the comparison with historical control, as 6-month OS rate in the FOLFIRI plus RAM arm was 54% (95% CI 44–67). In between arm comparison, OS was similar (hazard ratio, HR 0.97 [95% CI 0.62–1.52]), while objective response rates (ORRs) and PFS were numerically better in arm A versus arm B (HR for PFS 0.73; ORR, 22% versus 11%). These differences were largely attributed to favourable efficacy results for arm A in docetaxel-pretreated patients (HR, 0.49; ORR, 25% versus 8%). In the safety population (n = 106), grade 3-5 adverse events were similar between arms (arm A, 75%; arm B, 68%). ConclusionThe RAMIRIS trial demonstrated feasibility of FOLFIRI plus RAM. While the study was formally negative, it provided a signal to further investigate this combination for the group of patients with previous docetaxel therapy. Trial registrationclinicaltrials.gov identifier: NCT03081143.

Germline polymorphisms in genes maintaining replication fork to predict the efficacy of oxaliplatin and irinotecan in metastatic colorectal cancer (mCRC) patients enrolled in MAVERICC trial.

3139 Background: Protection of replication forks is critical for the survival of cancer cells. Chemotherapeutic drugs such as oxaliplatin and irinotecan can impede the progression of replication forks by inducing DNA lesions, which cause fork collapse and generate double-strand breaks. We hypothesized that functional genetic variants in genes involved in the maintenance of replication forks may predict the efficacy of cytotoxic drugs in mCRC patients. Methods: We analyzed genomic and clinical data from MAVERICC, a phase II trial which compared mFOLFOX6 and FOLFIRI in combination with bevacizumab in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Candidate six missense single nucleotide polymorphisms (SNPs) ( SLFN11 rs9898983, SLFN11 rs12453150, RPA1 rs5030749, MCM3 rs2230240, TIMELESS rs2291739, and TIMELESS rs774047) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. To confirm the predictive value, the treatment-by-SNP interaction was tested. Results: A total of 324 patients were available for the SNP analyses (mFOLFOX6 plus bevacizumab arm [OHP arm]: n = 161; FOLFIRI plus bevacizumab arm [IRI arm]: n = 163). In the OHP arm, univariable analysis showed a significantly better PFS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. However, neither of these SNP’s associations were confirmed by multivariable analysis: TIMELESS rs2291739 (any A allele vs G/G, hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.31–1.17, p = 0.12) and TIMELESS rs774047 (any C allele vs T/T, HR = 0.74, 95% CI = 0.41–1.36, p = 0.33). In the IRI arm, univariable analysis showed a significantly worse OS in patients with G/G genotype of TIMELESS rs2291739 compared to those with any A allele, and in patients with T/T genotype of TIMELESS rs774047 compared to those with any C allele. Multivariable analysis confirmed the significant associations in these SNPs: TIMELESS rs2291739 (any A allele vs G/G, HR = 3.06, 95% CI = 1.49–6.25, p &lt; 0.01) and TIMELESS rs774047 (any C allele vs T/T, HR = 2.95, 95% CI = 1.43–6.08, p &lt; 0.01). Treatment-by-SNP interaction test confirmed the significant predictive value of both SNPs, both on PFS and OS. Conclusions: Germline polymorphisms in the TIMELESS gene involved in the protection of replication forks may predict efficacy of oxaliplatin and irinotecan in mCRC patients. Our novel findings warrant further validation studies.

Abstract PO-071: Simulation of colorectal cancer clinical trials using real-world data and machine learning

Abstract Objectives To explore the feasibility of using real-world data (RWD) with machine learning methods to simulate colorectal cancer (CRC) trials (i.e., 6 Phase III randomized clinical trials comparing other treatment regimens with FOLFIRI—an FDA-approved standard of care first line chemotherapy treatment in patients with metastatic CRC). Methods We used RWD from the OneFlorida Clinical Research Consortium, a clinical research network contributing to the national PCORnet with longitudinal linked electronic health records of ~15 million Floridians. We used the study protocols in the original trials, including the eligibility criteria, to define the various study populations. We focused on patients’ safety outcomes in terms of the occurrence of severe adverse events (SAEs) after the treatments; calculated SAE prevalence, mean SAEs per patient, and SAE event rates for each category defined in the CTCAE v5.0. We considered two scenarios: (1) only simulating the control arm (CA) (i.e., the FOLFIRI arm), and (2) simulating both the CA and experimental arm (EA) (e.g., Panitumumab + FOLFIRI) and calculating the relative risk of SAE between the 2 arms. Two sampling strategies were used to simulate study population: random sampling and proportional sampling with gender and race. Among the 6 trials, only 2 had sufficient patients in OneFlorida for the two-arm simulations. We used propensity score matching (PSM) on baseline characteristics such as age, gender, race, and comorbidities to simulate the randomization process. In addition to the traditional logistic regression (LR) model, we considered machine learning (ML) models for PSM (such as neural networks) as LR-based PSM assumes linearity of the underlying variables. Each trial was simulated 1,000 times. Results Consistent with the existing literature, the mean SAE and SAE event rates were higher in all CAs simulated through RWD from OneFlorida. The proportional sampling strategy provided estimates of SAE prevalence more comparable to rates reported by the original trials. In the two-arm simulations, no significant differences were observed in the matched case-control samples using LR or ML methods. As expected with patients treated in real-world settings, larger mean SAEs and SAE event rates (but similar SAE prevalence ) were observed in the simulations compared with the original trials. The risk ratios of having SAE obtained from simulations comparing CA vs. EA were very close to the ratios calculated from the original trials. Conclusion Our study showed feasibility of simulating cancer trials using RWD and obtained comparable estimates to the original trial in terms of patient safety outcomes. Despite more SAEs in RWD, ratios between CAs and EAs were similar to the previously published rigorously conducted trials. Future in-depth investigations are warranted and shall consider state-of-the-art AI methods such as deep learning and causal AI methods to help tackle issues with using RWD for cancer trial simulation (e.g., data bias, high-dimensionality). Citation Format: Zhaoyi Chen, Hansi Zhang, Thomas George, Mattia Prosperi, Yi Guo, Dejana Braithwaite, Elizabeth Shenkman, Jonathan Licht, Jiang Bian. Simulation of colorectal cancer clinical trials using real-world data and machine learning [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-071.

Cost-effectiveness of Capecitabine + Irinotecan Versus Leucovorin + Fluorouracil + Irinotecan in the Second-line Treatment of Metastatic Colorectal Cancer in China

PurposeThe AXEPT trial demonstrated that modified XELIRI (mXELIRI; capecitabine + irinotecan) was noninferior to standard treatment with FOLFIRI (fluorouracil + leucovorin + irinotecan), both ± bevacizumab, in the treatment of metastatic colorectal cancer (mCRC). The present study was designed to evaluate the cost-effectiveness of mXELIRI versus FOLFIRI as a second-line treatment of mCRC. MethodsWe developed a Markov model to estimate the costs and health outcomes of mXELIRI and FOLFIRI in patients with mCRC from the Chinese payer perspective. Survival data, transition probabilities, and health utility values were obtained from published studies. The costs of drugs were obtained from the West China Hospital. Life-years (LYs), quality-adjusted life-years (QALYs) gained, incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER) values were regarded as the primary end points. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the impact of uncertainty of parameters in the analysis. FindingsThe effectiveness was found to be 0.48 QALYs (1.14 LYs) in the mXELIRI arm and 0.41 QALYs (1.05 LYs) in the FOLFIRI arm, with total costs of 29,896.41 US dollars (USD) in the mXELIRI arm and 28,894.68 USD in the FOLFIRI arm. The ICER and ICUR with mXELIRI versus FOLFIRI were 11,130.33 USD/LY and 14,310.43 USD/QALY gained, which were less than the willingness-to-pay threshold in China (25,840.88 USD/QALY). ImplicationsBased on the results of this study, mXELIRI was found to be a cost-effective alternative to FOLFIRI as a second-line treatment of mCRC in patients in China.

Phase Ib/IIa study of GC1118 in combination with irinotecan or FOLFIRI in patients with metastatic solid tumors.

3592 Background: GC1118 is a novel anti-EGFR monoclonal antibody which has a unique binding epitope and superior ligand inhibition potential. It showed promising antitumor activity as a single agent in the phase I study. This study aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GC1118 in combination with irinotecan or FOLFIRI in metastatic solid tumors and evaluate the efficacy of GC1118 plus FOLFIRI as a second line therapy for RAS and BRAF wild-type metastatic colorectal cancer. Methods: Phase 1b part was designed to evaluate weekly GC1118 (starting from 3 mg/kg) in combination with biweekly irinotecan (180mg/m2) or FOLFIRI (irinotecan 180mg/m2, leucovorin 400mg/m2, 5-FU 400 mg/m2 bolus, and 5-FU 2400mg/m2 over 46hrs) in a 3+3 design. In the phase 2a part, the RP2D of GC1118 is administered in combination with FOLFIRI in a Simon’s two stage design with objective response rate (ORR) as the primary endpoint. Results: 13 pts were enrolled in phase 1b and received 3mg/kg of GC1118 with irinotecan (N = 6) or FOLFIRI (N = 7). DLT occurred in 2 pts (G4 neutropenia, G2 rash) in irinotecan arm and 1pt (G3 neutropenia) in FOLFIRI arm with 3mg/kg of GC1118 and it was determined as MTD and RP2D. Adverse events (AE) of grade ≥ 3 included neutropenia (61.5 %), skin rash (15.4 %) and diarrhea (15.4%). Dose reductions due to GC1118-related AE were required in 6 (46.2%) patients. Among 10 response-evaluable pts in phase 1b, best overall response was PR in 3 and SD in 6, and median PFS was 12 months. In stage 1 of phase 2a (N = 9), 4 PR and 5 SD were observed (ORR 44.4%, 95% CI 13.7 – 78.8). We moved to stage 2, and are currently enrolling additional 20 pts. AE of grade ≥ 3 included neutropenia (66.7%), skin rash (22.2%) and diarrhea (11.1%). Updated data of the phase 2a part will be presented at the meeting. Conclusions: The MTD and RP2D of weekly GC1118 in combination with irinotecan or FOLFIRI was 3mg/kg. Preliminary results of GC1118 and FOLFIRI as a 2nd line treatment in mCRC suggests promising antitumor activity and acceptable safety profile. Clinical trial information: NCT03454620 .

Prognostic importance of primary tumor resection and synchronous metastasis on overall survival in metastatic colorectal cancer: Data from the FIRE-3 (AIO KRK-0306) study.

4070 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In the present analysis of the FIRE-3 trial we explored the impact of primary tumor resection on outcome in relation to anti-EGFR vs. anti-VEGF treatment. Furthermore, we investigated the prognostic value of synchronous versus metachronous metastases. Results: In patients with synchronous disease no significant difference in OS was detected when comparing resected (n=339) vs. non-resected (n=97) patients (p-value: 0.29, HR: 1.17, 95%-CI: 0.88 – 1.55). In the cetuximab arm, resection (n=167) showed no significant benefit in OS when compared to non-resection (n=52) (p-value: 0.51, HR: 1.15, 95%-CI: 0.77 – 1.71). Treated with bevacizumab, similar results were present, when comparing resection (n=172) vs. non-resection (n=45); (p-value: 0.29, HR: 1.25, 95%-CI: 0.83 – 1.9). A strong trend was seen when comparing OS in treatment arms cet. (n=219) vs. bev. (n=217)) for patients with synchronous disease; (p-value: 0.05, HR: 1,26, 95%-CI: 1.0 - 1.59). 436/592 pts suffered from synchronous, 153/592 from metachronous disease (in 3/592 pts the information was not given). Median OS in pts with synchronous disease was 24.5 months and 29.5 in pts with metachronous disease (p-value: 0.02, HR: 0.76, 95%-CI: 0.6 - 0.96). In pts treated in the cetuximab arm metachronous disease (n=77) was associated with a trend towards longer OS when compared to synchronous disease (n= 219) (p-value: 0.13, HR: 0.76, 95%-CI: 0.54 – 1.1). The same effect was present in the bevacizumab arm (p-value: 0.05, HR: 0.73, 95%-CI 0.53 – 1.0) when comparing pts with synchronous disease (n=217) vs. pts. with metachronous disease (n=76). Conclusions: In the FIRE-3 study, metachronous disease was associated with superior OS compared to synchronous disease. This finding was accentuated in the bevacizumab arm. The role of resection of the primary tumor had no impact on survival. Clinical trial information: NCT00433927 .

The efficacy and safety of FOLFIRI+BEV/mXELIRI+BEV by UGT1A1 polymorphisms in metastatic colorectal cancer AXEPT trial

Abstract Background Irinotecan have been well known to correlate between UGT1A1 polymorphisms (UGT1A1) and adverse events. Modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1 to14 every 3 weeks) has shown non inferiority of overall survival compared with FOLFIRI based on Asian XELIRI ProjecT (AXEPT) as second line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 and the efficacy and safety of irinotecan-based chemotherapy. Methods Patients were randomized FOLFIRI ± bevacizumab (BV) or modified XELIRI ± BV based on UGT1A1 results (wild type, heterozygosity, and homozygosity). With regard to irinotecan dosage in both treatment arms, the reduced dosage (150mg/m2) were administered in case of homozygosity. Assessed endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR), relative dose intensity (RDI) and safety. Result UGT1A1 was available for all 650 randomized patients (wild type, 309 (47.5%) heterozygosity, 291 (44.8%) and homozygosity, 50 (7.7%)). Median OS was of patients with a wild/hetero/homo was 14.3, 18.3 and 9.1 months in FOLFIRI arm and 18.1, 16.3 and 13.0 months in mXELIRI arm, respectively. Median PFS of patients with a wild/hetero/homo was 6.8, 8.8 and 4.8 months in FOLFIRI arm and was 8.3, 8.7 and 6.5 months in mXELIRI arm, respectively. Grade 3, 4 toxicities of special interests (wild/hetero/homo) were neutropenia (35.9%/50.4%/45.8% in FOLFIRI arm and 17.0%/15.7%/21.7% in mXELIRI arm), febrile neutropenia (5.9%/2.3%/4.2% in FOLFIRI arm and 1.4%/4.3%/8.7% in XELIRI arm), and diarrhea (1.3%/6.0%/0% in FOLFIRI arm and 4.8%/10.7%/0% in mXELIRI arm). Conclusions mXELIRI±BV was showed the good efficacy and well tolerated in patients with all UGT1A1 polymorphisms. mXELIRI+BV could be an alternative to FOLFIRI as a standard second line backbone treatment for mCRC.

LBA36 - Randomized phase II study of CAPTEM versus FOLFIRI in RAS mutated, MGMT methylated metastatic colorectal cancer (mCRC): Final analysis, tumour biomarkers and methylated ctDNA

BackgroundIn non-randomized trials, temozolomide (TMZ) has shown activity in about 10% of pts with chemorefractory mCRC bearing MGMT methylation. MethodsThis multicenter, randomized phase II trial investigated PFS superiority of second-line CAPTEM (Arm A) vs FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts had ECOG PS 0-1, measurable disease, and failed prior oxaliplatin-based therapy. Randomization to arm A (capecitabine 750mg/sqm b.i.d. days 1-14 plus TMZ 75mg/sqm b.i.d. days 10-14 q28) or B was stratified according to time elapsed from the start of oxaliplatin-based therapy and PD (</≥9 months); prior bevacizumab. A one-sided log-rank test with an overall sample size of 82 pts (41 per arm) achieved 90% power at 5% significance level to detect PFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory biomarkers: MGMT IHC; methylBEAMing (MB) in tumor and ctDNA. ResultsA total of 86 pts were randomized (43 per arm). After a median follow-up of 30.5 months (IQR 12.2-36.3), 79 disease PFS events occurred. PFS and OS were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) months in arm A vs 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B (HR=1.86 [0.82-1.72] and HR=0.97 [0.58-1.61]), respectively. ORR and DCR were 11.6% and 53.5% in both arms. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. In the subgroup with negative MGMT IHC expression, there were no significant differences between the two arms in terms of activity and efficacy endpoints, whereas in pts with positive MGMT IHC expression CAPTEM regimen was associated with significantly inferior outcomes in terms of PFS (2.0 vs 3.5 mos; HR=2.08 [1.02-4.21]), OS (5.7 vs 10.6 mos; OR=1.07 [0.39-2.93]) and DCR (15.4 vs 56.5%; OR=0.23 [0.04-0.99]), interaction test p=0.125, 0.732, 0.028. Predicting outcomes with MB was more accurate when using ctDNA vs tumor DNA. ConclusionsTMZ-based treatment should be investigated by a phase III trial, ideally conducted in patients with MGMT methylated/MGMT IHC negative tumors. Clinical trial identificationNCT02414009. Legal entity responsible for the studyFondazione IRCCS Istituto Nazionale Tumori di Milano. FundingFondazione IRCCS Istituto Nazionale Tumori di Milano. DisclosureF. Pietrantonio: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. F. Morano: Honoraria (self): Servier Italia SpA . S. Lonardi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Bristol-Mayers-Squibb. L. Rimassa: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Italfarmaco; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Baxter; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: ArQule; Honoraria (self), Advisory / Consultancy: Xelixis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai. A. Sartore-Bianchi: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Honoraria (self), Advisory / Consultancy: TizianaLife Sciences; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Pharm Research Associated; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Octimet Oncology; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Teofarma; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini. All other authors have declared no conflicts of interest.

550P - Updated results of NORDIC 8, a randomised trial of cetuximab every 2 weeks with FOLFIRI or cetuximab with alternating FOLFIRI/FOLFOX in patients with RAS and BRAF wild type metastatic colorectal cancer

BackgroundCetuximab (cet) improves efficacy of first-line FOLFIRI in pts with RAS/RAFwt metastatic colorectal cancer (mCRC). Triplet chemotherapy improves efficacy further but with increased toxicity. Alternating FOLFIRI/FOLFOX is a different way to administer all 3 cytotoxic drugs. We report the updated results from Nordic 8, a multi-centre, randomised trial comparing cet with FOLFIRI (arm A) or with FOLFIRI alternating with FOLFOX (arm B). MethodsIn this investigator initiated randomised trial, 173 chemo-naïve mCRC patients received cet with FOLFIRI or cet with FOLFIRI (2 cycles) alternating with FOLFOX until PD. Main inclusion criteria were PS 0 or 1, RASwt and ESMO group 1-3 (prior to April 2014 only ESMO group 1 when 36 patients had been included)). The primary endpoint was RR (increase from 60% to 75%) and secondary endpoints were PFS, OS and safety. All endpoints were evaluated by the local investigator. ResultsFrom May 2012 to May 2018, 173 patients were randomized. Median age was 64 years (25% were at least 70 years), female 34%, PS 0 61%, ESMO group 1/2/3 64%/23%/13%. Baseline characteristics were well-balanced between the two groups. Median duration of therapy was 6.2 months in both arms and patients received a median of 11 and 12 cycles, respectively, without any difference in dose-intensity. In arm A and B overall RR was 69% and 78% (p=0.17), median PFS was 11.9 (arm A) and 11.8 months (arm B) (HR 1.10; p=0.60), and median OS was 40.7 and 39.2 months (HR 1.05; p=0.82), respectively. Most important grade ≥ 3 adverse events were neutropenia (15% vs 17%), rash (9% vs 15%), diarrhoea (7% vs 11%), fatigue (7% vs 7%), and febrile neutropenia (3% vs 1%); 20% in arm B experienced neuropathy grade 2 (no grade 3). Final and updated PFS and OS with sub-group analysis will be presented. ConclusionsCet every two weeks in combination with FOLFIRI or alternating FOLFIRI/FOLFOX is well tolerated with high RR and long OS. We recommend FOLFIRI + cet every 2 weeks in patients with RAS and BRAFwt mCRC. Clinical trial identification2011-004188-65. Legal entity responsible for the studyNordic Biomodulation Group. FundingMerck. DisclosureC. Kersten: Research grant / Funding (institution), Licensing / Royalties, Relationship is unrelated to this study: Merck KGaA. All other authors have declared no conflicts of interest.

A randomized phase II trial of second-line CAPTEM versus FOLFIRI in MGMT methylated, RAS mutated metastatic colorectal cancer (mCRC) patients.

3509 Background: Overall response rate (ORR) to temozolomide (TMZ) is ∼10% in refractory mCRC pts with MGMT methylation detected by qualitative assays, e.g. methylation-specific PCR (MSP). ORR to irinotecan/FOLFIRI in second-line trials was 4-16%. The efficacy of TMZ may be improved by its combinatorial use in earlier lines and molecular selection beyond MSP. Lack of MGMT expression by immunohistochemistry (IHC) and high MGMT % methylation by MethylBEAMing (MB) are prognostic for higher ORR/PFS in TMZ-treated pts. Methods: This multicenter, randomized phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A: capecitabine 750 mg/sqm bid days1-14/TMZ 75 mg/sqm bid days10-14q28 days) over FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts: ECOG PS 0-1, measurable disease, failure of 1st-line oxaliplatin-based tx (or relapse within 6 mos from oxaliplatin-based adjuvant tx). Randomization was stratified by time from the start of oxaliplatin-based therapy to PD ( &lt; /≥9 months); prior bevacizumab (yes/no). A one-sided log-rank test with a sample size of 82 pts (41 per arm) achieved 90% power at a 5% significance level to detect mPFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory endpoints: predictive value of MGMT IHC/MB. Results: From Nov 2014 to Feb 2019, 82 pts (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44/56%, median age 70/67, ECOG PS 0 54/51%, right-sidedness 37/39%, 1 metastatic site 44/34%, prior bevacizumab 68/66%, 1st-line PFS 9,4/10,2 months. At a median follow up of 26.6 mos, 70 PFS/46 OS events were collected. The mPFS was 3.6 vs 4.1 mos in arm A vs B (HR = 1.26;95%CI 0.78-2.02;p = 0.34) and mOS was 9.1 vs 14.2 mos (HR =1.08;95%CI 0.60-1.94;p = 0.79). ORR and DCR (arm A/B): 12/10% and 51/51%. Grade 3-4 adverse events: 15/44% (diarrhea 0/12%, stomatitis 0/7%, anemia 2/10%, neutropenia 2/22%, thrombocytopenia 7/0%). Neither MGMT IHC nor MB status were prognostic. MGMT IHC positive subgroup, arm A (n = 12) vs arm B (n = 22): mPFS, 2.0 vs 4.1 mos (HR = 2.06;95%CI 0.96-4.45;p = 0.06), mOS, 6.4 vs 10.6 mos (p = 0.78), ORR (0% vs 14%) and DCR (25% vs 55%;OR = 0.28;95%CI 0.06-1.31;p = 0.11). In MGMT IHC negative subgroup, no PFS/OS/ORR/DCR differences were noted between the two arms. P interaction IHCxArm: 0.171 for PFS, 0.917 for OS, 0.06 for DCR. Similar accuracy was achieved by MB. Conclusions: The use of TMZ should be explored by phase 3 trials enrolling MGMT IHC-negative +/- high MGMT % methylated mCRC. Clinical trial information: NCT02414009.

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

BackgroundThe phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo+FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methodsPlasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1:1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1:2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. ResultsBiomarker results were available from>80% (n=894) of patients. Analysis of the ME subset determined a VEGF-D level of 115pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME+MC populations found that the median OS in the ramucirumab+FOLFIRI arm compared with placebo+FOLFIRI showed an improvement of 2.4months in the high VEGF-D subgroup [13.9months (95% CI 12.5–15.6) versus 11.5months (95% CI 10.1–12.4), respectively], and a decrease of 0.5month in the low VEGF-D subgroup [12.6months (95% CI 10.7–14.0) versus 13.1months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. ConclusionsThe RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registrationNCT01183780.

Polymorphisms in beta-defensin pathways and clinical outcomes in metastatic colorectal cancer patients treated with FOLFIRI-bevacizumab in two randomized phase III trials.

662 Background: Beta defensin 1 (DEFB1) and 2 (DEFB4A) are antimicrobial peptides secreted from colonic epithelial cells in response to inflammation. DEFB1 has been shown to serve as a tumor suppressor, whereas high concentrations of DEFB4A are linked with angiogenesis. This study examines the impact of single nucleotide polymorphisms (SNPs) in beta-defensin pathways in two independent phase III trials: FIRE-3 and TRIBE. Methods: The OncoArray database containing 530K SNP markers provided by Illumina was used to find associations between clinical outcomes and 10 functional SNPs from DEFB1, DEFB4A, PPARG, NFKB1, MUC2, and TLR4 genes. Patients treated with first-line FOLFIRI/bevacizumab (bev) in the randomized phase III FIRE-3 trial (n = 107) and TRIBE trial (n = 215) served as discovery and validation cohorts respectively. The FIRE-3 FOLFIRI and cetuximab (cet) arm served as a negative control (n = 129). Results: A total of 451 patients were included. The NFKB1 rs3821958 SNP showed significant association with OS and PFS in overall pts and those with left-sided CRC. Compared to pts carrying the mutant A allele, those with the wild-type G/G genotype had a shorter median OS (19 vs 40 mts) and PFS (9.2 vs 11.7 mts) in both univariate ((OS: HR = 2.32, 95%CI 1.21-4.42, p = 0.006) (PFS: HR = 1.93, 95%CI: 1.11-3.37, p = 0.014)) and multivariable analysis ((OS: HR = 2.90, 95%CI 1.47-5.70, p = 0.002) (PFS: HR = 2.08, 95%CI:1.18-3.67, p = 0.012)). This finding was validated in TRIBE, where carriers of G allele had shorter PFS in univariate analysis (HR = 1.44, p = 0.019). Opposite results were observed in pts receiving cet, where G/G carriers had improved OS in univariate analysis (HR = 0.46, p = 0.048). Pts with left-sided CRC who carried the wild-type allele had poorer OS and PFS in both trials. Conclusions: NFKB1 rs3821958 SNP is known to activate DEFB1 and is downstream of EGFR. Harboring a mutant allele in this SNP confers a mortality benefit in left-sided and overall pts treated with bev, and worsens OS in pts receiving cet. Hence, NFKB1 could serve as an important predictive biomarker. Future studies are warranted to further elucidate its role in colorectal cancer.

A multinational, randomized, phase III trial of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab as second-line therapy for metastatic colorectal cancer: Safety analysis of Asian XELIRI project (AXEPT).

681 Background: Several studies have shown that capecitabine plus irinotecan (XELIRI) has promising efficacy and safety in patients with metastatic colorectal cancer. AXEPT is a non-inferiority, phase III comparison of XELIRI with or without bevacizumab vs 5-fluorouracil/folinic acid plus irinotecan (FOLFIRI) with or without bevacizumab as second-line therapy in patients with metastatic colorectal cancer. Methods: We undertook an open-label, non-inferiority, randomized phase III trial in South Korea, China and Japan. Patients were randomized 1:1 to XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 twice daily for 2 weeks in a 3-week cycle) with or without bevacizumab 7.5 mg/kg or FOLFIRI with or without bevacizumab. The primary endpoint was overall survival. Results: From December 2013 to August 2015, 650 patients were enrolled and 625 (311 in FOLFIRI and 314 in XELIRI) were included to safety analysis at the cutoff dates on August 31, 2016. Patient baseline characteristics including KRAS status and UGT1A1 gene polymorphism were similar between the two treatment arms. Prior chemotherapy with oxaliplatin was given to 97.4% in both arms. The overall incidence of grade 3-4 toxicity was 73% in FOLFIRI arm and 53.2% in XELIRI arm. Whereas FOLFIRI was associated with more grade 3-4 neutropenia (43.7% vs 16.2%), leucopenia (13.5% vs 7.3%) and all grades anemia (80.4% vs 69.4%) than XELIRI, XELIRI was associated with more all grades hand-foot syndrome (34.1% vs 14.8%) and grade 3-4 diarrhea (7.0% vs 3.2%). There was no significant difference in febrile neutropenia (4.2% in FOLFIRI and 2.9% in XELIRI). The addition of bevacizumab did not alter safety profiles between XELIRI and FOLFIRI. There was a treatment-related death in FOLFIRI arm (0.3%). Conclusions: Both FOLFIRI and XELIRI were safe and well tolerated, though there were differences in the rates and toxicity profiles at which adverse events occur. Clinical trial information: NCT01996306. UMIN000012263.

Cost-effectiveness Analysis of Fluorouracil, Leucovorin, and Irinotecan versus Epirubicin, Cisplatin, and Capecitabine in Patients with Advanced Gastric Adenocarcinoma.

No standard treatment has been accepted widely for the first-/second-line therapy for advanced gastric cancer (AGC). The current study aimed to determine a preferred strategy between FOLFIRI (fluorouracil, leucovorin, and irinotecan) and ECX (epirubicin, cisplatin,and capecitabine) for AGC from the cost-effectiveness perspective. According to a French intergroup study, two groups (ECX arm and FOLFIRI arm) and three health states (progression-free survival (PFS), progressive disease (PD) and death) were analyzed in the current Markov model. All the medical costs were calculated from a Chinese societal perspective. Although FOLFIRI was an acceptable first-line therapy in the treatment of AGC with a better time-to treatment failure (TTF) compared to ECX, ECX arm (ECX followed by FOLFIRI) gained 0.08 quality-adjusted life months (QALMs) more effectiveness benefit compared with FOLFIRI arm (FOLFIRI followed by ECX). Additionally, a lower cost was found in ECX arm ($23,813.13 versus $24,983.70). Hence, the strategy of FOLFIRI arm is dominated by ECX arm ($4,125.8 per QALM in FOLIRI arm; $3,879.724 per QALM in ECX arm). ECX followed by FOLFIRI was a preferred strategy with more effectiveness and lower cost compared with FOLFIRI followed by ECX for the treatment of AGC.

Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer

ImportanceMetastatic colorectal cancer (mCRC) is heterogeneous, and primary tumors arising from different regions of the colon are clinically and molecularly distinct.ObjectiveTo examine the prognostic and predictive value of primary tumor location in patients with RAS wild-type (wt) mCRC treated with first-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab in the Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial and FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial.Design, Setting, and ParticipantsIn this retrospective analysis patients with RAS wt metastatic colorectal cancer from the CRYSTAL and FIRE-3 trials were classified as having left-sided or right-sided mCRC, defined, respectively, as patients whose tumors originated in the splenic flexure, descending colon, sigmoid colon, or rectum vs appendix, cecum, ascending colon, hepatic flexure, or transverse colon.Main Outcomes and MeasuresProgression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were assessed according to tumor location and treatment arm.ResultsIn the RAS wt populations of the CRYSTAL and FIRE-3 trials, patients with left-sided tumors (n = 142 and n = 157, respectively) had markedly superior PFS, OS, and ORR compared with patients with right-sided tumors (n = 33 and n = 38, respectively). Among CRYSTAL and FIRE-3 study patients with RAS wt left-sided tumors, FOLFIRI plus cetuximab significantly improved OS relative to the respective comparators (FOLFIRI and FOLFIRI plus bevacizumab); in contrast, in RAS wt patients with poor-prognosis right-sided tumors, limited efficacy benefits were observed upon the addition of cetuximab to FOLFIRI in CRYSTAL, and comparable outcomes were observed between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab arms of FIRE-3. A significant interaction was observed between primary tumor location and treatment for OS (CRYSTAL: hazard ratio [HR], 1.95; 95% CI, 1.09-3.48 and FIRE-3: HR, 0.40; 95% CI, 0.23-0.70) within the RAS wt populations of both studies in multivariable models that also included sex, prior adjuvant therapy, and BRAF mutational status.Conclusions and RelevanceIn the RAS wt populations of CRYSTAL and FIRE-3, patients with left-sided tumors had a markedly better prognosis than those with right-sided tumors. First-line FOLFIRI plus cetuximab clearly benefitted patients with left-sided tumors (vs FOLFIRI or FOLFIRI plus bevacizumab, respectively), whereas patients with right-sided tumors derived limited benefit from standard treatments.Trial Registrationclinicaltrials.gov Identifiers: CRYSTAL, NCT00154102, and FIRE-3, NCT00433927

549P - Gender and chemotherapy-related toxicity in colon cancer: an analysis of the PETACC-3 trial conducted by the EORTC GI-group

Drug metabolism is genetically determined. Gender is one of the factors responsible for the large interpatient variability in the dose-effect relationship of cytotoxics. Comparative data on the effect of gender on chemotherapy (CT)-related toxicity are lacking in colon cancer. This is a retrospective analysis of data from the PETACC-3 trial: 2974 pts (55.7% men (m) and 44.3% women (f)) with stage II and III colon cancer were treated with adjuvant 5-fluorouracil/leucovorin alone (5FU/LV) or with irinotecan (FOLFIRI). Primary aim was to compare CT-related toxicity (according to NCIC-CTCG) in m and f. Clinical and hematologic adverse events (AEs) rates and frequency of dose reductions in m and f were compared by Fisher's exact test; survival outcomes by log-rank test. Subgroup analyses were performed according to age (<50, 50-65, ≥65) and treatment. P-values are 2-sided. No multiple testing adjustments were done. Higher rates of all grade nausea (61.8 vs 53.7%, p < .0001), vomiting (32.5 vs 24.5%, p < .0001), alopecia (41.7 vs 26.0%, p < .0001) and more all grade leucopenia, anemia and neutropenia (p < .0001) were observed in f compared with m. Differences in these AEs between f and m were found significant (p < 0.05) in both arms and in all age groups except for nausea and neutropenia in age <50. Additionally, in the FOLFIRI arm, f had greater risks of stomatitis (40.6 vs 30%, p < .0001), cramping (24.2 vs 16.4%, p = 0.0002), cholinergic syndrome (18.3 vs 12.9%, p = 0.0045) and lethargy (48.9 vs 38.2%, p < 0.0001) as well as more grade 3-4 neutropenia (37.3 vs 21.1%, p < .0001) than m. There was no significant difference in febrile neutropenia between m and f. Dose reductions were more frequent in f (25.9% vs 16.8%, p < .0001) but the mean cumulative doses of CT (mg/m2) were not significantly different between m and f. There were no significant differences in PFS or OS. In this trial, women demonstrated significantly greater rates of various hematological and non-hematological AEs, especially under treatment with FOLFIRI. Thus, AEs need to be reported according to gender in future clinical trials. Further data investigating the relationship between gender and CT efficacy and toxicity is required.