ABCG2 Protein Levels and Association to Response to First-Line Irinotecan-Based Therapy for Patients with Metastatic Colorectal Cancer

In this study we investigated the use of cancer cell protein expression of ABCG2 to predict efficacy of systemic first-line irinotecan containing therapy in patients with metastatic colorectal cancer (mCRC). From a Danish national cohort, we identified 119 mCRC patients treated with irinotecan containing therapy in first-line setting. Among these, 108 were eligible for analyses. Immunohistochemistry (IHC) analyses were performed on the primary tumor tissue in order to classify samples as high or low presence of ABCG2 protein. Data were then associated with patient outcome (objective response (OR), progression free survival (PFS) and overall survival (OS)). ABCG2 protein expression in the basolateral membrane was high (score 3+) in 33% of the patients. Exploratory analyses revealed a significant interaction between ABCG2 score, adjuvant treatment and OR (p = 0.041) in the 101 patients with evaluable disease. Patients with low ABCG2 (score 0–2) and no prior adjuvant therapy had a significantly higher odds ratio of 5.6 (Confidence Interval (CI) 1.68–18.7; p = 0.005) for obtaining OR. In contrast, no significant associations between ABCG2 expression and PFS or OS were found. These results suggest that measurement of the ABCG2 drug efflux pump might be used to select patients with mCRC for irinotecan treatment. However, additional studies are warranted before conclusions regarding a clinical use can be made. Moreover, patients with high ABCG2 immunoreactivity could be candidates for specific ABCG2 inhibition treatment in combination with irinotecan.

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Response-Independent Survival Benefit in Metastatic Colorectal Cancer: A Comparative Analysis of N9741 and AVF2107

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.8099 ◽

2008 ◽

Vol 26 (2) ◽

pp. 183-189 ◽

Cited By ~ 124

Author(s):

Axel Grothey ◽

Eric E. Hedrick ◽

Robert D. Mass ◽

Somnath Sarkar ◽

Sam Suzuki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Survival Benefit ◽

Tumor Response ◽

Objective Response ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

First Line Therapy ◽

Phase Iii Study

PurposeIn the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response.Patients and MethodsFor these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy.ResultsCompared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders.ConclusionIn both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

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EFFECTIVENESS OF MAINTENANCE THERAPY AFTER THE END OF THE FIRST LINE OF TREATMENT FOR PATIENTS WITH METASTATIC COLORECTAL CANCER – THE RESULTS OF A POPULATION-BASED STUDY

Malignant tumours ◽

10.18027/2224-5057-2018-8-3-57-67 ◽

2018 ◽

Vol 8 (3) ◽

pp. 57-67

Author(s):

M. Yu. Fedyanin ◽

Sh. A. Aliyeva ◽

L. Y. Vladimirova ◽

A. N. Ivanov ◽

A. A. Katkov ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Maintenance Therapy ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Progression Free Survival ◽

Observation Group ◽

First Line ◽

Free Survival ◽

Maintenance Group

Aim.To evaluate the effectiveness of different regimens of maintenance chemotherapy after the first line of treatment for patients with metastatic colorectal cancer.Materials and methods.We performed retrospective analyses of the data from 432 patients from 17 clinics in 14 regions of the Russian Federation who started systemic therapy for metastatic cancer in 2013. The main inclusion criterion was objective response or stabilization after the first 16 weeks of first-line therapy. Four groups of patients were compared, depending on the nature of maintenance therapy: those receiving fluoropyrimidines, a combination of fluoropyrimidines with bevacizumab, monotherapy of bevacizumab and monotherapy of anti-EGFR antibodies. The main criteria for assesment of the effectiveness of treatment were progression-free survival and overall survival. The statistical analysis was performed with the SPSS 20.0 sof tware package.Results.Maintenance therapy after completion of the first 16 weeks of the 1st line of chemotherapy was administered in 126 patients, most of them were treated with fluoropyrimidines (53.1 %). The median overall survival in the maintenance group was 27 versus 21 months in the observation group, p=0.01, HR=0.78 (95 % CI 0.6–1.02) Median progression-free survival in the maintenance group was 11 vs 7 months in the observation group (p<0.001, HR=0.6, 95 % CI 0.5–0.8). The worst results of progression-free survival were observed in the group with monotherapy of bevacizumab – median was 10 months versus 12 months in the fluoropyrimidine monotherapy group, 10 months for the combination of fluoropyrimidine with bevacizumab and 14 months for monotherapy of the anti-EGFR (p=0,9, HR=1.0, 95 % CI 0.9–1.2).Conclusions.There were no statistical differences in survival with different regimens of maintenance therapy. Monotherapy of bevacizumab in maintenance treatment was associated with the worst sur vival rates.

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Bevacizumab associated calcifications might be a prognostic marker in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16108 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16108-e16108

Author(s):

Yuwen Zhou ◽

Qiu Meng

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Prognostic Marker ◽

Cox Regression ◽

Objective Response ◽

Progression Free Survival ◽

Hazard Ratio ◽

First Line ◽

Cox Regression Analysis ◽

First Line Therapy

e16108 Background: Cetuximab associated calcifications is a positive predictive factor in metastatic colorectal cancer (mCRC). In patients with glioblastoma, bevacizumab-induced calcifications are also related to a better prognosis. However, tumor calcifications are rarely recognized in mCRC patients treated with bevacizumab. This study was to investigate the correlation between clinical outcome and calcification in mCRC who received bevacizumab and chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy in our hospital from January 2016 to January 2019. Clinical variables were retrieved from medical records and tumor calcification were evaluated independently by radiologists on the basis of computed tomography scans. A univariate and multivariate COX regression analysis was performed to evaluate the association between calcification and outcome. Results: 159 patients with an average age of 59.0 years were included. Median follow-up was 29.6 months. Among all enrolled patients, 31 had tumor calcification [31/159 (19.5%)]. The median overall survival (OS) and progression-free survival (PFS) was significantly better in patients with calcification than those without calcification (28.0 vs. 24.9 months, p= 0.024; 12.0 vs. 10.0 months, p= 0.026). A higher objective response rate (61.3% vs. 50.0%) was also observed in calcification group. On multivariate analysis, tumor calcification was independently associated with OS (hazard ratio 1.799, 95% CI 1.002–3.230) and PFS (hazard ratio 1.609, 95% CI 1.013–2.557). Conclusions: Tumor calcification was independently associated with improved prognosis in colorectal cancer. It might be a potential prognostic marker.

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Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3570 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3570-3570

Author(s):

Josep Tabernero ◽

Axel Grothey ◽

Dirk Arnold ◽

Michel Ducreux ◽

Peter J. O'Dwyer ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Maintenance Treatment ◽

Predictive Biomarkers ◽

Experimental Treatment ◽

Progression Free Survival ◽

Phase 2 ◽

First Line ◽

Tissue Samples ◽

First Line Therapy

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC > 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

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Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.1.136 ◽

2000 ◽

Vol 18 (1) ◽

pp. 136-136 ◽

Cited By ~ 954

Author(s):

S. Giacchetti ◽

B. Perpoint ◽

R. Zidani ◽

N. Le Bail ◽

R. Faggiuolo ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Sensory Neuropathy ◽

Phase Iii ◽

Line Treatment ◽

Survival Times ◽

First Line ◽

Grade 3 ◽

First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

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Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer

BMC Cancer ◽

10.1186/s12885-020-07576-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hironaga Satake ◽

Koji Ando ◽

Eiji Oki ◽

Mototsugu Shimokawa ◽

Akitaka Makiyama ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Ii Study ◽

Progression Free Survival ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Free Survival ◽

First Line Therapy ◽

Line Therapy

Abstract Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003. Registered April 18, 2019.

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Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.2106 ◽

2010 ◽

Vol 28 (15) ◽

pp. 2556-2564 ◽

Cited By ~ 108

Author(s):

Valérie Boige ◽

Jean Mendiboure ◽

Jean-Pierre Pignon ◽

Marie-Anne Loriot ◽

Marine Castaing ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Response ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

First Line ◽

Free Survival ◽

Increased Risk ◽

Grade 3 ◽

Cancérologie Digestive

Purpose The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Patients and Methods Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. Results The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). Conclusion A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

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Randomized, Controlled Trial of Irinotecan Plus Infusional, Bolus, or Oral Fluoropyrimidines in First-Line Treatment of Metastatic Colorectal Cancer: Results From the BICC-C Study

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.3357 ◽

2007 ◽

Vol 25 (30) ◽

pp. 4779-4786 ◽

Cited By ~ 510

Author(s):

Charles S. Fuchs ◽

John Marshall ◽

Edith Mitchell ◽

Rafal Wierzbicki ◽

Vinod Ganju ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Controlled Trial ◽

Progression Free Survival ◽

Phase Iii ◽

Primary Study ◽

Line Treatment ◽

First Line ◽

Double Blind ◽

First Line Treatment

PurposeThis phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI).Patients and MethodsA total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity.ResultsMedian PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of ≥ grade 3 hypertension than mIFL+Bev.ConclusionFOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.

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Safety, efficacy, and time to clinical response with bevacizumab plus FOLFIRI regimen in metastatic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15138 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15138-e15138

Author(s):

S. Tomao ◽

G. Spinelli ◽

L. Rossi ◽

G. Pasciuti ◽

G. Arcangeli ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Clinical Response ◽

Median Time ◽

Progression Free Survival ◽

Phase Iii ◽

Clinical Activity ◽

Efficacy And Safety ◽

First Line ◽

Ecog Ps

e15138 Background: Bevacizumab (BEV) has shown clinical activity in metastatic colorectal cancer patients (mCRC)and randomised phase III trials have demonstrated that this agent significantly improves overall and/or progression-free survival when added to first-line irinotecan based chemotherapy (CT) regimens. We evaluated the efficacy and safety of BEV plus FOLFIRI (irinotecan, 5- fluorouracil, and leucovorin) as first line treatment in 27 consecutive metastatic colorectal cancer cases, with the primary end point to calculate the median time to clinical response with this chemotherapeutic schedule. Methods: Between October 2007 and January 2008 we collected the data on 27 patients with mCRC treated with first line chemotherapy with BEV plus FOLFIRI. Elegibility criteria had to be: mCRC; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. The treatment consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI schedule; BEV (5mg/kg) was given on day 1 with CT and then every 2 weeks until disease progression. Safety and response were assessed at the time of first CT and every 4 weeks thereafter. Results: 27 pts were evaluable (male 18; median age 61 years (range 45–77), ECOG PS 0: 52%, PS 1: 48%. The sites of metastases were: liver (15 pts), lung (5 pts), liver and lung (5 pts), peritoneal wall (2 pts).Median follow-up was 18 weeks. Two patients had complete response(CR) and 13 pts partial response (PR), with an overall response rate of 57.7%. Five patients had stable disease and 6 patients showed progressive disease. A clinical benefit was demonstrated in 77 % of pts. We observed a median time to clinical response of 11 weeks, evaluated with tumor markers and with CT/NMR/US examinations. A grade 3 or 4 neutropenia was detected in 39% of pts and grade 2 or 3 hypertension in 9%. We did’nt observe cases of thrombosis, bleeding and gastrointestinal perforation, sometimes related to the use of BEV. Conclusions: In this little experience the efficacy and safety of BEV associated with FOLFIRI schedule, a first line therapy in mCRC,is consistent with results from other previous studies, showing moreover a short time to clinical response with this association. No significant financial relationships to disclose.

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Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.561 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 561-561

Author(s):

S. Yuki ◽

K. Shitara ◽

M. Yoshida ◽

D. Takahari ◽

S. Utsunomiya ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Combination Chemotherapy ◽

Response Rate ◽

Standard Dose ◽

Objective Response ◽

Progression Free Survival ◽

Wild Type ◽

Standard Regimen ◽

Free Survival

561 Background: Weekly cetuximab and irinotecan is a standard regimen in heavily pretreated patients with metastatic colorectal cancer (MCRC). The aim of this study was to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pretreated MCRC harboring wild-type KRAS. Methods: Patients with wild- type KRAS MCRC that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included in this study. Cetuximab was administered at 500 mg/m2 biweekly with irinotecan. The primary endpoint was response rate. The secondary endpoints included adverse events, progression-free survival, and overall survival. The pharmacokinetics of cetuximab was also evaluated in five patients. Results: From May, 2009 to February, 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 assessable patients, ECOG PS was 0 in 12, 1 in 16, and 2 in two patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4), and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95%CI, 61.4-92.3). The median progression-free survival was 5.3 months (95%CI, 3.4-7.3). Grade 3 skin toxicity was observed in 3 patients (10%), and treatment related death due to pneumonia occurred in one patient. Conclusions: The efficacy data are similar to those of standard dose of cetuximab plus irinotecan. Combination chemotherapy with biweekly cetuximab and irinotecan is effective for pretreated metastatic wild-type KRAS MCRC. No significant financial relationships to disclose.

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