FOLFIRI In Metastatic Colorectal Cancer Research Articles

Abstract 3700: Genomic alterations on first-line panitumumab plus FOLFIRI in metastatic colorectal cancer

Abstract Background: IMPROVE is a randomized, non-comparative multicenter, phase 2 study evaluating continuous or intermittent FOLFIRI/PANI, in first-line in patients (pts) with unresectable RAS/BRAF wild-type metastatic colorectal cancer (mCRC). In this trial intermittent FOLFIRI/PANI strategy produced a longer progression-free survival (PFS) on treatment, 17.6 months (mts) vs 11.3 mts, a reduced skin severe toxicity, 18% vs 30%, without any detrimental effect on overall survival (OS), 36.2 mts vs 36.2 mts. The trial also included a prospective genomic alterations (GAs) analysis on circulating tumor DNA with the aim to explore emergence of GAs under the selective pressure of FOLFIRI/PANI. Methods: We analyzed paired plasma samples (basal and PD) by a commercially available NGS panel enabled to simultaneously analyze KRAS, NRAS, BRAF and PIK3CA hotspot mutations from blood samples. Among them, inspecting default calling parameters on proprietary analysis software (Ion Reporter software 5.2.0), only variants with ⩾5X allele coverage and a quality score ⩾20, within an amplicon that covered at least 1000X alleles was considered. As clonality, the threshold of 0.5% of variant allele frequency (VAF) was established to classify mutations as clonal (VAF⩾0.5%) or subclonal (VAF<0.5%). Results: Of the 137 pts enrolled in the trial, GAs basal analyses were available for 84 pts. Among these, in 55 (65.5%) no GAs were detected (ND). In the remaining cases, the analysis relieved the presence of mutations for PIK3CA (N=14), KRAS (N=12), NRAS (N=2) and BRAF (N=1). According to the clonality threshold, these GAs were classified as subclonal (SC) in 12 cases (14.3%) and clonal (CL) in 17 (20.2%) cases. Survival analysis according to basal GAs clonality showed a median PFS of 16.6 mts (95% IC 13.0-20.2), 12 mts (95% IC 9.1-14.9) and 25.8 mts (95% IC 17.2-34.5) for ND, CL and SC group, respectively. Median OS was 47.7 mts for ND group (95% IC 34.9-60.5), 26.8 mts for CL (95% IC 25.8-27.8) and not reached for SC group. Moreover, we performed GAs analysis on 61 cases of which basal and PD samples were available. Forty-two cases (68.9%) resulted ND, 7 (11.5%) with SC and 12 (19.7%) with CL GAs.At PD, among 42 ND basal cases, 29 remained ND (69%), 8 (19%) and 5 cases (11.9%) developed SC and CL GAs, respectively. In the SC group, 1 kept SC (14.3%), 4 (57.1%) and 2 (28.6%) cases became ND and CL GAs, respectively. In the CL group, 10 (83.3%) kept CL GAs, 1 (8.3%) case became ND and 1 (8.3%) CL. Conclusions: These findings suggest that classical GAs associated with anti-EGFR resistance are infrequent with up-front use of anti-EGFR/chemotherapy. Moreover, our data show that basal SC GAs rarely evolve to CL GAs at progression disease and do not affect survival of pts with anti-EGFR/chemotherapy treatment. An update will be provided at the congress. NCT04425239 Citation Format: Antonio Avallone, Francesco Giuliani, Guglielmo Nasti, Vincenzo Montesarchio, Giuseppe Santabarbara, Silvana Leo, Umberto Malapelle, Gerardo Rosati, Claudio Lotesoriere, Emiliano Tamburini, Alfredo Colombo, Francesco Pepe, Claudia Cardone, Alessandra Leone, Carlo Vitagliano, Gianluca Russo, Giancarlo Troncone, Diana Giannarelli, Alfonso De Stefano, Alfredo Budillon. Genomic alterations on first-line panitumumab plus FOLFIRI in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3700.

P-342 Prospective, observational study evaluating the effectiveness and safety of aflibercept plus FOLFIRI in metastatic colorectal cancer (mCRC) according to Polish reimbursement criteria

P-342 Prospective, observational study evaluating the effectiveness and safety of aflibercept plus FOLFIRI in metastatic colorectal cancer (mCRC) according to Polish reimbursement criteria

493P Impact of age on the activity of aflibercept plus FOLFIRI in metastatic colorectal cancer (mCRC): Real world data from the QoLiTrap study

Median ages at CRC diagnosis and death are 67 and 72 years, respectively. Older patients (pts) are underrepresented in clinical trials and often undertreated in daily practice. Here, we report the impact of age on effectiveness, quality of life (QoL) and safety of aflibercept plus FOLFIRI in mCRC pts previously treated with an oxaliplatin-containing regimen.

Optimizing FOLFIRINOX tolerability in patients with colorectal cancer through dosing irinotecan in the morning for men and in the afternoon for women.

120 Background: Irinotecan (IRI) toxicity was worse in female (F) than in male (M) patients (pts) on FOLFIRI for metastatic colorectal cancer (MCC). This finding could reflect different optimal administration timing of IRI in M and F pts along the 24 hours. IRI pharmacology is regulated by the circadian clock, and its least toxic daily time (LTT) occurred ~6 hours later in F as compared to M mice. The relevance of sex for the LTT of IRI is addressed here using data from an international randomized trial, whose primary endpoint was not met for all the 193 pts with MCC (EORTC 05011). Methods: 130 M and 63 F were randomized to receive chronomodulated IRI (180 mg/m2 over 6-h, with peak delivery in the morning (at 5:00 or 9:00), in the afternoon (at 13:00 or 17:00) or at night (at 21:00 or 01:00) on day (d) 1, followed by fixed-time chronomodulated oxaliplatin-5-fluorouracil-leucovorin for 4 d. Triplet combination was given q3 weeks as 1st or 2nd line, without prophylactic G-CSF. The relevance of IRI timing for main toxicities was determined separately in M and F, using Cosinor and Fisher Exact tests. Results: Baseline characteristics of M or F pts did not differ significantly according to IRI timing group. Main worse grade 3-4 toxicities per pt after 6 courses were diarrhea (M, 40.2%; F, 51.9%) neutropenia (M, 12.6%; F, 18.4%), fatigue (M, 13.4%; F, 17.3%) and anorexia (M, 8.2%; F, 9.6%). These toxicities were reduced following IRI delivery in the morning for M, but in the afternoon for F, with statistically significant rhythms (p < 0.05 from cosinor) and sex*timing interactions (Fischer Exact, diarrhea, p = 0.023; neutropenia, p = 0.015; fatigue, p = 0.062; anorexia, p = 0.032). IRI timing was most critical for F, with Grade 3-4 toxicities ranging from 55.2% of the pts (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. IRI timing did not significantly influence efficacy. Conclusions: The present study results supports the administration of irinotecan in the morning for M and in the afternoon for F in order to minimize adverse events of triplet chemotherapy without impairing efficacy. Prospective trials testing sex specific timing issues are warranted. Clinical trial information: 05011.

Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab.

Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS). Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC). Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis. Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42days of ramucirumab plus FOLFIRI therapy and OS (grade 1-2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66-1.24]; grade 3+, HR 1.02 [95% CI 0.67-1.55]; P = 0.803) or PFS (grade 1-2, HR 0.98 [95% CI 0.74-1.28]; grade 3+, HR 0.93 [95% CI 0.64-1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1-2, HR 0.96 [95% CI 0.76-1.20]; grade 3+, HR 2.72 [95% CI 1.67-4.44]; P = 0.001) and PFS (grade 1-2, HR 1.01 [95% CI 0.83-1.23]; grade 3+, HR 2.22 [95% CI 1.43-3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS. Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS. No. NCT01183780.

595P - Quality of life (QoL) in patients with aflibercept (AFL) and FOLFIRI for metastatic colorectal cancer (mCRC): Interim analysis with focus on mutational status of the non-interventional study QoLiTrap (AIO-LQ-0113)

BackgroundThe anti-angiogenic fusion protein AFL targets VEGF-A, VEGF-B and PlGF. It is approved in combination with FOLFIRI for treatment of mCRC that is resistant to or has progressed after oxaliplatin-containing therapy. MethodsQoLiTrap is an ongoing non-interventional study conducted in the DACH region to evaluate Quality of Life in 1500 mCRC patients treated with AFL+FOLFIRI using the EORTC-QLQ C30 questionnaire at baseline and before every cycle. ResultsFor this interim analysis (cut-off: 02 Jan 2019) 839 patients (mean age: 64.7±9.8 years; 64.4% male, 50.9% with documented RAS mutation, ECOG 0-1: 86.0%) who completed the baseline and at least 2 post-baseline EORTC-QLQ C30 questionnaires were evaluated. AFL was administered for a median of 7 cycles to RAS-wild-type (wt) (range: 1-61) and RAS-mutated (mut) (range 1-44) patients. Of those 772 patients with a previous therapy, 56.7 % received bevacizumab (BEV), 15.3% anti-EGFR antibodies (cetuximab and/or panitumumab) and 14.6 % both agents. 42.1% of RAS-wt and 56.7% of RAS-mut patients received AFL in second line setting. Median global health score at baseline was 58.3 and decreased moderately (mean change -3.4%, p<0.0001) within the first 12 weeks of therapy. Reduction was greater in RAS-mut compared to RAS-wt (mean change -5.1% vs. -1.1%). Among evaluable patients receiving AFL in second line after anti-EGFR or BEV, 25.0% exhibited CR+PR and 51.6% had SD as best response. RAS mutational status had an impact on the rate of disease control in these patients (85.7% disease control in RAS-wt vs. 69.8% in RAS-mut; p=0.0242). Median PFS in these patients was 7.6 months (95% CI 6.3- 12.4) for RAS-wt patients and 8.2 months (95% CI 5.9- 9.0) for RAS-mut patients. Toxicity was in line with the known safety profile. ConclusionsThe current interim analysis suggests that FOLFIRI + AFL administered in routine conditions after either BEV or anti-EGFR is an active second-line therapy. Both RAS-wt and RAS-mut patients benefited from this combination. No clinically relevant decrease in global health status was observed during study treatment. Supported by Sanofi-Aventis Deutschland GmbH. Clinical trial identificationAIO-LQ-0113. Editorial acknowledgementSandra Baumgart (Alcedis GmbH Gießen, Germany), funded by Sanofi-Aventis Deutschland GmbH. Legal entity responsible for the studySanofi-Aventis Deutschland GmbH. FundingSanofi-Aventis Deutschland GmbH. DisclosureR. von Moos: Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Sanofi Aventis; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Vifor; Travel / Accommodation / Expenses: Pfizer. F. Scholten: Honoraria (self), Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Eli-Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Sanofi-Aventis. H. Derigs: Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Roche. R.D. Hofheinz: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Research grant / Funding (self): Medac; Honoraria (self): Boehringer; Honoraria (self): Celgene; Honoraria (self): Saladax; Honoraria (self): AstraZeneca; Speaker Bureau / Expert testimony: Deutsche Krebshilfe. All other authors have declared no conflicts of interest.

Quality of life in patients treated with aflibercept and FOLFIRI for metastatic colorectal cancer: interim analysis with focus on therapy lines of the non-interventional study QoLiTrap (AIO-LQ-0113)

Quality of life in patients treated with aflibercept and FOLFIRI for metastatic colorectal cancer: interim analysis with focus on therapy lines of the non-interventional study QoLiTrap (AIO-LQ-0113)

Impact of the prior chemotherapy with two different fluoropyrimidines on the efficacy of CapeIRI or FOLFIRI in metastatic colorectal cancer: An exploratory analysis of the phase III AXEPT trial.

711 Background: Modified CapeIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1–14 every 3 weeks) with or without bevacizumab (± BV) has shown non-inferiority of overall survival compared with FOLFIRI ± BV based on the phase III study, AXEPT, as second-line chemotherapy for patients with mCRC. In this exploratory analysis of the AXEPT trial, we evaluated the impact of the prior chemotherapy with two different fluoropyrimidine backbones (fluorouracil and leucovorin vs oral fluoropyrimidine) on the efficacy of CapeIRI and FOLFIRI. Methods: Patients were randomized to receive standard FOLFIRI ± bevacizumab or modified CapeIRI ± bevacizumab after failure to fluoropyrimidine-based chemotherapy in the AXEPT study. Prior fluoropyrimidine backbones were categorized into oral fluoropyrimidine-based (eg, capecitabine or S-1) regimen (oral 5-FU group) and fluorouracil and leucovorin-based regimen (infusional 5-FU group). Assessed endpoints included overall survival, progression-free survival, response rate, and safety. Results: Prior fluoropyrimidine backbone was available for 642 patients among all 650 randomized patients (oral 5-FU group in 291, and infusional 5-FU group in 351). Median overall survival was 17.0 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 14.9 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Median progression-free survival was 7.9 and 8.6 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 6.8 and 8.3 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Conclusions: There was no significant difference in the efficacy of CapeIRI or FOLFIRI regardless of prior fluoropyrimidine backbones. Therefore, CapeIRI ± BV could also be effective for patients after failure of oral fluoropyrimidine-based chemotherapy (eg, CapeOX ± BV). Clinical trial information: NCT01996306. [Table: see text]

Blood-based biomarkers in metastatic colorectal cancer patients treated with FOLFIRI plus regorafenib or placebo: Results from LCCC1029.

587 Background: The LCCC1029 trial demonstrated that addition of the multitargeted kinase inhibitor regorafenib (Rego) to FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) modestly prolonged progression-free survival (PFS). In this preplanned analysis, circulating angiogenic and inflammatory proteins were explored as potential prognostic and predictive biomarkers of Rego benefit. Methods: Plasma samples from 149 mCRC pts (107 in Rego + FOLFIRI and 42 in placebo + FOLFIRI) were evaluated for 20 markers at baseline (n = 149) and cycle 1 day 21 (C1D21, n = 81). Predictive and prognostic values of each marker at baseline were analyzed for both PFS and overall survival (OS) using Cox proportional hazard models. On-treatment changes were quantified as fold change [log2(C1D21/baseline)] and differences between arms were evaluated using the Mann-Whitney test. Results: The primary objective of this study was to determine whether any marker was predictive of benefit with Rego for PFS. Although no treatment by marker interactions were significant after adjusting for multiple testing, the top three markers of interest were OPN (unadjusted p-values of 0.02), VCAM-1 (0.02), and PDGF-AA (0.04). VCAM-1 was also predictive for OS benefit in pts treated with Rego (unadjusted p = 0.01). Baseline levels of multiple markers (including HGF, IL-6, PlGF, VEGF-R1, OPN) were prognostic for both PFS and OS. Higher levels of these markers were associated with worse survival. Biomarker changes in response to treatment were explored and compared between arms. Fold change of three markers (PlGF, VEGF-A, VCAM-1) were significantly different between arms (p &lt; 0.0001), all being markedly up-regulated in the Rego arm compared to the placebo after treatment. Conclusions: In this hypothesis generating report, VCAM-1, OPN, and PDGF-AA were the top biomarkers when analyzing the potential predictive association with PFS, where a lower hazard was observed for pts receiving Rego. Candidate prognostic markers were identified, including PlGF and VEGF-R1, key factors in VEGF biology. Biomarker changes observed here may offer insights into potential combinatorial strategies with Rego for future studies.

Abstract 404: Development of a RSPO3 CLIA-validated assay as a predictive biomarker for response to anti-RSPO3 antibody treatment in patients with solid tumors

Abstract R-Spondin (RSPO) proteins bind to LGR receptors and potentiate Wnt/β-catenin signaling. We have identified a therapeutic anti-RSPO3 antibody targeting the RSPO-LGR pathway. In preclinical studies, RSPO3 gene expression has shown correlation with anti-RSPO3 antibody efficacy in multiple solid tumor types. A qPCR-based RSPO3 assay has been developed as a predictive biomarker for response to the anti-RSPO3 antibody. In addition, RSPO gene fusions may play a role in the activation of Wnt signaling. A gene fusion detection workflow consisting of a RSPO3 CLIA assay, a RSPO3 RUO assay and next generation sequencing (NGS) has also been developed. We designed 6 qPCR-based assays for the RSPO3 CLIA assay development and 2 assays for the RUO assay. These assays were designed to span exon-exon junctions or target microarray probe set sequences. Amplification sensitivity and specificity were assessed for assay selection. The analytic performance of the candidate RSPO3 CLIA assay and quality control measures were established in a validation study. The validation study included: 1) performance specifications of the RSPO3 assay including analytical sensitivity, linearity, and precision, 2) determination of a reportable range, 3) establishment of a cut-off for the RSPO3 CLIA assay for patient selection, and 4) establishment of quality control procedures. 104 human cancer tissues and 24 independent patient-derived tumor xenografts (PDX) were used in these studies. To evaluate the fusion detection workflow, the RUO assay was performed on samples that tested above the CLIA assay cut-off. The delta Ct difference between the CLIA and RUO assays was calculated to identify potential fusions. The limit of quantification was established for the RSPO3 CLIA assay. The 95% reference interval was estimated to be (-2.44, 16.02) with 90% confidence interval for the lower bound (-3.45, -2.12) and upper bound (15.26, 16.57). The delta Ct cut-off for the RSPO3 CLIA assay was set based on sensitivity, specificity and prevalence. No statistically significant difference in the total variance across the tested samples was observed. A549 and OV56 were identified to be cell line controls with established acceptable delta Ct limits. Using NGS, RSPO3 fusions were identified in 6 PDX tumors with delta Ct RUO - delta Ct CLIA&amp;gt;7, including a novel fusion. This cut-off was further refined with NGS of 9 clinical samples. Prevalence of the RSPO3 expression and fusions will be presented. A qPCR based RSPO3 assay was developed and CLIA-validated for use as a potential predictive biomarker for response to anti-RSPO3 therapy. This RSPO3 CLIA assay, together with the fusion detection workflow, will be evaluated in a Phase 1a/b dose escalation study of anti-RSPO3 (OMP-131R10) in advanced solid tumors and in combination with FOLFIRI in metastatic colorectal cancer (NCT02482441). Citation Format: Chun Zhang, Yuwang Liu, Min Wang, Gilbert OYoung, Joy Kavanagh, Cheryl McFarlane, Fiore Cattaruzza, Pete Yeung, Jennifer Cain, Wan-Ching Yen, Marcus Fischer, Belinda Cancilla, Edwina Dobbin, Michelle McCarthy, Austin Gurney, Leonardo Faoro, John Lewicki, Tim Hoey, Ann M. Kapoun. Development of a RSPO3 CLIA-validated assay as a predictive biomarker for response to anti-RSPO3 antibody treatment in patients with solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 404.

Expression of amphiregulin (AREG) and response to first-line panitumumab (pmab) + FOLFIRI in metastatic colorectal cancer (mCRC).

3536 Background: Biomarker analyses have shown that patients (pts) with RASwild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers ma...

Amphiregulin (AREG) expression and response to first-line panitumumab (pmab) plus FOLFIRI in metastatic colorectal cancer (mCRC).

731 Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]

528P - Aflibercept + Folfiri for Treatment of Metastatic Colorectal Cancer After Oxaliplatin Failure: 4Th Interim Safety Data from the Global Aflibercept Safety and Quality-Of-Life Program (Asqop/Afeqt Studies)

ABSTRACT Aim: In VELOUR, aflibercept (ziv-aflibercept in the US) + FOLFIRI demonstrated a statistically significant improvement in overall survival vs placebo + FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) previously treated with an oxaliplatin-containing regimen. Results supported initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of 2 clinical studies (ASQoP; AFEQT) to capture utility values from QoL instruments and collect safety data from a population similar to that in VELOUR in a real-life setting. We report safety data from the 4th interim analysis of these ongoing studies. Methods: ASQoP and AFEQT are single-arm, open-label trials in mCRC pts previously treated with an oxaliplatin-containing regimen. Eligible pts received aflibercept 4 mg/kg every 2 weeks on day 1 of each cycle followed by FOLFIRI. FOLFIRI starting dose and subsequent additional dose modifications are at discretion of the treating physician. Results: At data cut-off for this interim analysis, the safety population (n = 688) was compared with VELOUR. In 44% of ASQoP vs 33.5% of VELOUR, pts were ≥65 years; 10.8% of ASQoP vs 5.4% of VELOUR were ≥75 years. ASQoP pts received a median of 6 treatment cycles while VELOUR pts received a median of 9. Grade (G) 3/4 adverse events (AEs) were experienced by 72.2% of ASQoP pts vs 83.5% in VELOUR. Most were G3. G4 hypertension or diarrhea was not reported. Table shows selected G3/4 AEs. ASQoP/AFEQT VELOUR Adverse Events, % Aflibercept + FOLFIRI (n = 688) Aflibercept + FOLFIRI (n = 611) Grade 3/4 (%) Grade 3/4 (%) Proteinuria 3.6 7.9 Stomatitis and ulceration (high level term) 9.6 13.8 Diarrhea (preferred term) 14.1 19.3 Infections and infestations (system organ class) 9.6 12.3 Hypertension 23.0 19.3 Arterial thromboembolic event 0.6 1.8 Venous thromboembolic event 4.4 7.9 Fistula (gastrointestinal [GI] origin) 0.6 0.3 GI perforation 1.3 0.5 Conclusions: Interim safety analysis from ASQoP/AFEQT has identified no new safety signals. Despite a greater % of elderly pts in ASQoP/AFEQT, reported incidence of toxicity is generally similar or less than VELOUR. Differences in AE incidence in ASQoP/AFEQT vs VELOUR may be related to the VELOUR protocol requirement of full-dose FOLFIRI initiation and current overall exposure differences. Disclosure: J. Taieb: has conflicts of interest related to advisory boards for Sanofi and for corporate-sponsored research for Sanofi; Y. Moore: formerly held a leadership position at Sanofi at the time this study was conducted and has stock ownership in Sanofi; C. Zilocchi: is an employee of Sanofi and has stock ownership; S. Brette: is an employee (biostatistician) of Lincoln, which is a consultant for Sanofi. A. Sobrero: has received honoraria for participating in advisory boards for Bayer, Roche, Sanofi, Celgene, Merck, and Amgen. All other authors have declared no conflicts of interest.

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)

BackgroundThe FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12–13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. Patients and methodsWe conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, and folinate 200 mg/m2 on day 1, followed by fluorouracil 3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12–13–61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m2 after two of the first three patients reported grade 3–4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). ResultsEighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7–12.9 months). After amendment, most common grade 3–4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. ConclusionsAdding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras–BRAF wild-type patients are promising.

Phase II trial of irinotecan, S-1, and bevacizumab (IRIS/Bev) combination chemotherapy as second line for advanced colorectal cancer (NCCSG04).

496 Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853-860) previously demonstrated the non-inferiority of Irinotecan plus S-1 (IRIS) to FOLFIRI for metastatic colorectal cancer (mCRC), with progression-free survival as the primary endpoint. IRIS plus bevacizumab (IRIS/Bev) was reported an active and generally well-tolerated first-line treatment for mCRC (Yuki et al. ASCO 2012 #3593). We planned a Phase II trial to evaluate the efficacy and safety of IRIS/Bev as second-line therapy for patients with mCRC. Methods: The study design was multicenter, single-arm, open-label phase II study. Eligible patients had to have mCRC with confirmed diagnosis of adenocarcinoma, history of oxaliplatin containing regimen as first-line therapy, an age from 20 to 80 years, ECOG performance status (PS) of 0-1. S-1 65 mg/m2 daily p.o. was given on days 1-14 and Irinotecan 75mg/m2 and Bevacizumab 10mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (OR), overall survival (OS), time to treatment failure (TTF) and safety. Results: From 08/12 until 11/06, 35 patients were enrolled. One patient did not start therapy. Thirty-four patients were investigated. Median age was 63 years (range, 38 to 82). Twenty-five patients were male. The mean of relative dose intensity of TS-1/Irinotecan/Bev were respectively 92.1%/87.0%/86.2%. The OR was 21.1% (7/33) and disease control rate was 84.8% (28/33). Median PFS was 9.3 months, median TTF was 8.2 month and median survival time 23.1 month. On safety analysis, the incidence of grade 3 or 4 adverse reactions were as follows: neutropenia, 14.7%; fatigue, 14.7%; white blood cell decreased, 11.8%; anorexia, 8.8%; anemia, 8.8%; diarrhea, 2.9%; proteinuria, 5.9%; thromboembolic event, 2.9%. Conclusions: IRIS/Bev is an active and well-tollarated second-line treatment for patients with mCRC. Clinical trial information: UMIN000001631.

WS1-4 - Updated Analysis: Phase II Trial of Combined Chemotherapy with Irinotecan, S-1, and Bevacizumab (IRIS/Bev) in Patients with Metastatic Colorectal Cancer: Hokkaido Gastrointestinal Cancer Study Group (HGCSG) Trial

ABSTRACT Background The FIRIS study (Muro K et al. Lancet Oncol 2010; 11: 853–860) previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS) to FOLFIRI for metastatic colorectal cancer (mCRC), with progression-free survival (PFS) as the primary end point. We previously reported that IRIS plus bevacizumab (IRIS/bev) is very effective as first-line treatment (Komatsu Y et al. ESMO 2010). We now report the updated results of this study. Methods Eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1–14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary end point was safety. The secondary end points included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results The target number of 53 patients was enrolled as of March 2009. The results are reported for 52 patients with evaluable lesions. The clinical characteristics of the patients were as follows. The median age was 63.5 years (range, 48 to 82). The male:female ratio was 3:2. The performance status on the Eastern Cooperative Oncology Group scale was 0. In January 2012, on safety analysis, the incidence of grade 3 or 4 neutropenia was 27%. The incidences of other grade 3 or 4 adverse reactions were as follows: diarrhea, 17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and gastrointestinal perforation, 0%. The overall response rate was 63.5%. Three patients had complete response. Thirty patients had partial response, 16 had stable disease, none had progressive disease, and 3 were not evaluable. Median progression-free survival was 17.0 months and the median survival time was 39.6 months. Seven patients (13.5%) treated with IRIS/Bev underwent surgery with curative intent. Conclusions IRIS/Bev is a remarkably active and generally well-tolerated first-line treatment of patients with mCRC. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. Randomized control trial comparing IRIS/Bev with oxaliplatin containing regimen (XELOX or mFOLFOX6 plus bevacizumab) is being planned.

592P - Phase II Trial of Combined Chemotherapy with Irinotecan, S-1, and Bevacizumab (IRIS/BEV) In Patients with Metastatic Colorectal Cancer -Updated Analysis-. Hokkaido Gastrointestinal Cancer Study Group (HGCSG) Trial

ABSTRACT Background The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–860) previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS) to FOLFIRI for metastatic colorectal cancer(mCRC), with progression-free survival (PFS) as the primary endpoint. We previously reported that IRIS plus bevacizumab (IRIS/bev) is very effective as first-line treatment (Komatsu Y et al. ESMO 2010). We now report the updated results of this study. Methods Eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results The target number of 53 patients was enrolled as of March 2009. The results are reported for 52 patients with evaluable lesions. The clinical characteristics of the patients were as follows. The median age was 63.5 years (range, 48 to 82). The male:female ratio was 3:2. The performance status on the Eastern Cooperative Oncology Group scale was 0. In January 2012, on safety analysis, the incidence of grade 3 or 4 neutropenia was 27%. The incidences of other grade 3 or 4 adverse reactions were as follows: diarrhea, 17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and gastrointestinal perforation, 0%. The overall response rate was 63.5%. Three patients had complete response. Thirty patients had partial response, 16 had stable disease, none had progressive disease, and 3 were not evaluable. Median progression-free survival was 17.0 months and median survival time was 39.6 months. Conclusions IRIS/Bev is a remarkably active and generally well-tolerated first-line treatment for patients with mCRC. Randomized control trial comparing this regimen with oxaliplatin containing regimen (XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Disclosure All authors have declared no conflicts of interest.

Bevacizumab every 4 weeks is as effective as every 2 weeks in combination with biweekly FOLFIRI in metastatic colorectal cancer

The efficacy and tolerability of bevacizumab every 2 or 4 weeks using the same dosage in combination with biweekly FOLFIRI were retrospectively evaluated in metastatic colorectal cancer (mCRC) patients in the first-line and second-line therapy. A total of 332 patients from six centers were evaluated. The patients had received biweekly FOLFIRI in combination with bevacizumab 5 mg/kg every 2 weeks or every 4 weeks schedule for various reasons in individual patients. Approximately 70 % of all patients had 2-week treatment schedule. In the first-line therapy (n = 240), the overall response rate (ORR) was 34.1 % in 2-week and 36.3 % in 4-week groups. Median progression-free survival (PFS) was 8 months (95 %CI, 6.8-9.2) and 9 months (95 %CI, 6.6-11.4) (p = 0.074), and median overall survival (OS) was 22 months (95 %CI, 15.8-28.2) and 20 months (95 %CI, 8.1-31.9) (p = 0.612) in 2- and 4-week groups, respectively. One-year survival rate was 76.2 % for 2-week group and 73.2 % for 4-week group. In the second-line therapy (n = 92), the ORR was similar between the groups (24.5 vs 25.9 % in 2- and 4-week groups, respectively). Median PFS was 6 months (95 %CI, 4.7-7.3) and 11 months (95 %CI, 6.3-15.7) (p = 0.074), and median OS was 15 months (95 %CI, 9.6-20.4) and 17 months (95 %CI, 13.7-20.3) (p = 0.456) for 2-week and for 4-week groups, respectively. One-year survival rate was 61.3 % for 2-week and 71.3 % for 4-week groups. Toxicity profile was similar in 2- and 4-week groups and included neutropenia, febrile neutropenia, nausea and vomiting, diarrhea, mucositis, bleeding, hypertension, thromboembolism and fistulization. Bevacizumab 5 mg/kg every 2 weeks or every 4 weeks in combination with biweekly FOLFIRI had similar efficacy and tolerability in mCRC. Because of the retrospective nature of our study, the data should be examined cautiously. However, our study clearly points out the need for determination of optimum biological dosing interval of bevacizumab in well-designed, prospective, randomized trials.

PD-0022 Aflibercept Versus Placebo in Combination with Folfiri in Previously Treated Metastatic Colorectal Cancer: Mean Overall Survival for Subgroups from Velour

ABSTRACT Introduction The VELOUR phase III trial evaluated the efficacy and safety of the novel fusion protein aflibercept (VEGF Trap) in combination with FOLFIRI in metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Median overall survival (OS) showed significant improvement with 13.50 months in the aflibercept arm vs. 12.06 months in the placebo arm (p = 0.0032; HR = 0.82 [95.34% CI: 0.71 to 0.94]). Treatments were allocated through a 1:1 randomization stratified by ECOG PS (0, 1 or 2) and prior bevacizumab use. The purpose of this analysis was to estimate mean OS in ITT population and stratified subgroups of VELOUR for populating cost-effectiveness analysis. Methods Because some patients were alive at the time of the final analysis, mean OS must be estimated by extrapolating the trial Kaplan-Meier curve using a survival function. Five standard parametric distributions were tested: exponential, Weibull, lognormal, log-logistic and Gompertz. Akaike’s Information Criteria (AIC), Bayesian Information Criteria (BIC) and graphical methods were used to evaluate the goodness of fit of the distributions. Survival functions were fit to each treatment arm separately or by combining the two arms and using treatment as covariate to control for variation. Mean OS was estimated for the ITT population and stratification subgroups accordingly. The subgroup of patients with PS = 2 is not presented as it represents only 27 patients (2.2% of the 1226 ITT patients). Results The log-logistic function provided the best fit of the VELOUR data for the ITT population and for all subgroups except in the placebo arm for the PS = 0 subgroup and for the prior bevacizumab subgroup where the lognormal and Weibull distributions respectively fit best. Using the best fits, mean survival was greater in the aflibercept arm compared to placebo arm in all subgroups, by an amount ranging from 1.4 to 9.8 months. Conclusion These additional analyses of mean OS in the ITT population and stratification subgroups support the primary VELOUR analyses demonstrating a survival benefit across patient subgroups of Aflibercept/FOLFIRI over Placebo/FOLFIRI. These results have important implications in terms of informing consistent clinical and economic benefit of aflibercept across general, as well as clinically relevant patient subpopulations in second-line mCRC. Study NCT00561470 was funded by sanofi, in partnership with Regeneron. Table 1 .

O-0024 Phase 2 Randomized, Noncomparative, Open-Label Study of Aflibercept and Modified Folfox6 in the First-Line Treatment of Metastatic Colorectal Cancer (AFFIRM)

ABSTRACT Introduction Aflibercept is a recombinant human fusion protein that acts as a decoy receptor preventing VEGF-A, VEGF-B, and PlGF from interacting with their receptors. The phase 3 VELOUR study demonstrated a statistically significant survival benefit with the combination of aflibercept + FOLFIRI in metastatic colorectal cancer (mCRC) patients who had progressed during or after prior oxaliplatin-based chemotherapy. Modified (m) FOLFOX6 is an established first-line regimen for patients with mCRC. Preclinical and clinical evidence supported the evaluation of aflibercept + mFOLFOX6 for the first-line treatment of patients with mCRC. An mFOLFOX6 study arm was included as a calibrator; the study was not powered for a statistical comparison. Methods The primary endpoint was progression-free survival rate at 12 months (PFS12). A secondary objective was to explore biomarkers. Patients with previously untreated mCRC, ECOG PS 0-2, and adequate organ function were randomized 1:1 to receive aflibercept 4 mg/kg + mFOLFOX6 (A) or mFOLFOX6 (B), every 2 weeks, and were stratified by ECOG PS (0-1/2), prior adjuvant therapy (yes/no), and metastases confined to liver (yes/no). Patients were to be treated to disease progression. PFS12 rate and objective response rate were assessed according to RECIST criteria by an Independent Review Committee blinded to treatment allocation. Results From March 2009 to April 2010, 236 patients (median age, 62.5 years; male, 61% PS 0-1, 97.5% prior adjuvant therapy, 10.2% liver metastases only, 28.4%) were randomized to A (n = 119) or B (n = 117). Baseline characteristics were similar in both arms. PFS12 was 25.8% (95% CI: 17.2-34.4) for A and 21.2% (95% CI: 12.2-30.3) for B. Response rate was 49.1% (95% CI: 39.7-58.6) in arm A and 45.9% (95% CI: 36.4-55.7) in arm B, and median PFS was 8.48 months (95% CI: 7.89-9.92) in arm A and 8.77 months (95% CI: 7.62-9.27) in arm B. Overall survival data had limited maturity, with less than 43% death events in each arm. Grade 3-4 adverse events with >5% higher incidence in arm A relative to arm B were hypertension, proteinuria, neutropenia, diarrhea, and infections. Biomarker data will be presented at the meeting. Conclusion In this phase 2 study, PFS12 with aflibercept + mFOLFOX6 appeared to be similar to mFOLFOX6, although the study was not powered for comparison. The biomarker analyses and clinical interpretation will be presented at the meeting. The safety profile of aflibercept was consistent with that seen in prior studies.