Signifıcant progress has been made in the last decade in the

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1 BIOLOGIC THERAPIES IN COLORECTAL CANCER Biologic Therapies in Colorectal Cancer: Indications and Contraindications Marwan Fakih, MD OVERVIEW The role of antiangiogenic and anti-epidermal growth factor receptor (EGFR) agents has been investigated extensively in colorectal cancer in the palliative, adjuvant, and neoadjuvant settings. Although the role of biologic agents has become well-defined in the first, second, and subsequent lines of treatment of metastatic colorectal cancer (mcrc), considerable debate continues around the optimal sequencing and around optimal patient selection. The benefits from integrating bevacizumab or cetuximab in the adjuvant setting have been investigated in several randomized phase III clinical trials in stage II/III disease, all with disappointing results. Neoadjuvant approaches incorporating biologic therapy in patients with liver metastatic disease have led to mixed results. Although the current evidence does suggest increased down-staging and increased resectability with the addition of cetuximab in patients with initially unresectable or borderline resectable liver metastases, a positive effect of anti-egfr therapy on the overall survival (OS) in this setting is not conclusive. Patients with resectable liver metastases derive no benefit and may experience potential harm from the addition of cetuximab to neoadjuvant chemotherapy. Similarly, there is neither rationale nor adequate data to support the addition of bevacizumab to neoadjuvant chemotherapy in patients with resectable liver metastases. In this review, we examine the role of antiangiogenesis and anti-egfr therapies across the spectrum of adjuvant, neoadjuvant, and metastatic disease. Signifıcant progress has been made in the last decade in the management of mcrc, with median OS of patients with mcrc now at or exceeding 30 months. 1,2 The improvements in outcome are at least partially credited to the integration of biologic therapies, whether antiangiogenic or anti-egfr, in the mainstream treatment of metastatic disease. Although signifıcant progress has been made with the addition of these classes in advanced noncurable disease, their role has been disappointing in the adjuvant setting and continues to evolve in the neoadjuvant setting. In this review, we will summarize the current clinical data for biologic and targeted agents in adjuvant CRC, neoadjuvant, and nonresectable mcrc. BIOLOGIC THERAPY IN THE ADJUVANT TREATMENT OF COLORECTAL CANCER Bevacizumab in Stage II and III Colon Cancer Several randomized phase III clinical trials have evaluated bevacizumab in combination with systemic chemotherapy in the adjuvant treatment of colorectal cancer. The NSABP C-08 clinical trial randomized 2,710 patients with stage II or III colon cancer to receive 6 months (12 cycles) of modifıed FOLFOX6 regimen with or without 1 year of bevacizumab. 3,4 No signifıcant effect on disease-free survival (DFS) or OS was noted in the study population or within the stage II or stage III subgroups. Interestingly, the effect of bevacizumab on DFS was different before and after the 15-month time point from study treatment. The hazard ratio (HR) for recurrence within 15 months from start of study treatment was 0.61 (95% CI, 0.48 to 0.78) in favor of bevacizumab. In contrast, a trend toward increased recurrence rate was noted after 15 months on the bevacizumab arm. A post hoc analysis of the NSABP-CO8 population by mismatch repair status suggested a benefıt from bevacizumab in the mismatch defıcient cohort (HR 0.52; 95% CI, 0.29 to 0.94). 5 The AVANT phase III clinical trial randomized patients with stage II or III colon cancer to receive 6 months of oxaliplatin plus a fluoropyrimidine with or without bevacizumab. 6 Patients were randomly assigned in a 1:1:1 ratio to three arms of treatment: FOLFOX4, FOLFOX4 plus 1 year of bevacizumab, XELOX plus 1 year of bevacizumab. No benefıts in DFS were noted with the addition of bevacizumab to chemotherapy. The HR for DFS for bevacizumab/folfox4 and bevacizumab/xelox compared with FOLFOX4 were 1.17 (95% CI, 0.98 to 1.39) and 1.07 (95% CI, 0.9 to 1.28), respectively. Similar to the NSABP-C08 study, bevacizumab was associated with an improved DFS in the initial period of follow-up. In the fırst year of the study, the HR for DFS was 0.63 and 0.61 on the bevacizumab/folfox4 and bevacizumab/xelox arms in comparison with FOLFOX4. This initial improvement in DFS From the City of Hope Comprehensive Cancer Center, Duarte, CA. Disclosures of potential conflicts of interest are found at the end of this article. Corresponding author: Marwan Fakih, MD, City of Hope Comprehensive Cancer Center, Building 51, Room 127, 1500 E. Duarte Rd., Duarte, CA 91010; mfakih@coh.org by American Society of Clinical Oncology. asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e197

2 MARWAN FAKIH was offset by a detrimental effect of bevacizumab in DFS in years 2 and 3, leading to an overall trend to increased recurrences on the bevacizumab arms. This rebound increase in recurrences in the bevacizumab arms translated into a trend toward a detriment in OS in both the bevacizumab/fol- FOX4 and bevacizumab/xelox arms when compared with FOLFOX4. Finally, the QUASAR2 study randomized 1,941 patients with stage III or high-risk stage II colorectal cancer to receive eight cycles of capecitabine (24 weeks) with or without 16 cycles of every 3-week bevacizumab (48 weeks). 7 An initial trend in improvement in DFS was noted in the bevacizumab arm in the fırst 2 years of follow-up. However, further follow-up after 2 years was associated with an increased recurrence rate in the bevacizumab arm, leading to a fınal HR for DFS of 1.06 in the bevacizumab arm compared with the control arm. Subgroup analysis in the microsatellite stable (MSS) and microsatellite instability (MSI) groups showed a signifıcant detriment with bevacizumab in the MSS group (HR 1.43, p ), whereas no signifıcant difference in outcomes was noted in the MSI group (HR 0.74, p 0.42). No benefıt is expected from the addition of bevacizumab to adjuvant cytotoxic chemotherapy in patients with stage II or III disease. To the contrary, worrisome trends toward increased recurrence rate after completion of bevacizumab therapy have been noted and have translated in a trend toward a worsened OS. The favorable trends noted with bevacizumab in tumors with MSI are hypothesis generating and may warrant further investigation in this subgroup of patients. KEY POINTS There is no role for biologic therapy in the adjuvant treatment of colorectal cancer. In the setting of resectable metastatic disease to the liver, there is no evidence to suggest a benefit from adding either antiangiogenic or anti-epidermal growth factor receptor (EGFR) therapy. The addition of anti-egfr therapy to chemotherapy in the neoadjuvant treatment of KRAS-wild type (WT) resectable liver metastases has been associated with a detrimental effect on disease-free survival. In patients with unresectable but potentially resectable disease, consideration for neoadjuvant FOLFOXIRI/bevacizumab (good performance status) or combination chemotherapy plus anti-egfr agents (RAS-WT) should be made to increase the chances of curative-intent surgery. In RAS-mutant type or BRAF-MT metastatic colorectal cancer (mcrc), the continuum of angiogenesis targeting during the first two lines of treatment is recommended. Bevacizumab or anti-egfr therapy in the first-line therapy of RAS-WT and BRAF-WT mcrc is acceptable with no clear evidence of superiority of one approach compared with another. Cetuximab in the Adjuvant Treatment of Colorectal Cancer The role of anti-egfr therapy in the adjuvant treatment setting has been investigated through the N0147 and PETACC-8 clinical trials. 8,9 The initial design of the N0147 included a randomization to 6 months of FOLFOX, FOLFIRI, or sequential FOLFOX followed by FOLFIRI, with or without cetuximab in patients with stage III colon cancer. Subsequent protocol amendments resulted in the closure of the FOLFIRI and sequential FOLFOX/FOLFIRI arms, as well as the limitation of enrollment to patients with KRAS-wild type (WT) tumors. 8 The study accrued 2,070 patients with KRAS-WT tumors. No benefıt in 3-year DFS in the cetuximab/folfox compared with the FOLFOX arm was noted in the KRAS-WT (HR 1.21; 95% CI, 0.98 to 1.49) or KRAS/ BRAF-WT populations. No advantage to the addition of cetuximab was noted in any of the subgroup analyses. Of note, no defınitive conclusions could be deduced from the FOLFIRI cohorts on N0147 because of the small sample size. However, a trend toward improved DFS and OS was noted in the cetuximab/folfiri compared with FOLFIRI in an exploratory analysis. 10 The PETACC-8 clinical trial randomized patients with stage III colon cancer to 6 months of FOLFOX4 chemotherapy with our without cetuximab. 9 Similar to N0147, the study was subsequently amended to include only patients with KRAS-WT tumors. No benefıt from cetuximab was noted in terms of DFS in the KRAS-WT (HR 1.05; 95% CI, 0.85 to 1.29; p 0.66) or in the KRAS/ BRAF-WT (HR 0.99; 95% CI, 0.76 to 1.28; p 0.92) populations. Interestingly, and in a preplanned subgroup analysis, patients with T4N2 tumors derived a signifıcant benefıt from the addition of cetuximab, whereas, women and patients with right colonic tumors experienced a signifıcant improvement in DFS in the chemotherapy only arm. Based on the N0147 and PETACC-8 studies, there is no current role for cetuximab in the adjuvant treatment of colon cancer. Although subgroup analyses of PETACC-8 suggest a benefıt in more advanced T4N2 disease, this can be considered, at best, hypothesis generating. Clearly, a more predictive signature of response beyond RAS and BRAF mutations will be needed to revisit the role of anti-egfr in the adjuvant treatment of mcrc. The reason for disconnect in benefıts from anti-egfr therapy between adjuvant and metastatic disease studies is not clear but could be explained by a failure to induce complete pathologic sterilization despite an increased antitumor down-staging in metastatic settings. BIOLOGIC THERAPIES IN THE NEOADJUVANT TREATMENT OF MCRC Biologic Therapies in the Neoadjuvant Treatment of Resectable mcrc When considering neoadjuvant treatment in the management of metastatic colorectal cancer, one has to defıne the goal of therapy. The main indications for neoadjuvant treatment for metastatic colorectal cancer are: (1) decrease in the risk for recurrence of disease in the setting of resectable liver e ASCO EDUCATIONAL BOOK asco.org/edbook

3 BIOLOGIC THERAPIES IN COLORECTAL CANCER metastases and (2) down-staging for resection in patients with potentially resectable disease. The EORTC study randomized patients with four or less hepatic colorectal metastases to perioperative FOLFOX chemotherapy or observation. 11 This study met its primary endpoint of 3-year DFS improvement in favor of FOLFOX. No signifıcant improvement in OS was confırmed. 11,12 Since the EORTC control arm did not include postoperative chemotherapy, the benefıts of perioperative chemotherapy compared with adjuvant postoperative chemotherapy are currently not substantiated. Bevacizumab addition to neoadjuvant CAPOX, FOLFOX, FOLFIRI, and FOLFOXIRI has been shown to be feasible in patients with resectable liver mcrc Retrospective analyses suggest an increased likelihood of complete pathologic responses of liver metastases and a lower incidence of sinusoidal damage with the integration of bevacizumab in the preoperative chemotherapy treatment of liver mcrc However, there is no strong evidence to date to support an improvement in DFS or OS with the addition of bevacizumab to preoperative chemotherapy in these settings. Given the discouraging DFS and OS data with bevacizumab in stage III colorectal clinical trials, there is no strong rationale to incorporate bevacizumab in the neoadjuvant or postoperative therapy in patients with resectable mcrc. Indeed, a recent retrospective analysis of patients undergoing hepatectomy with adjuvant chemotherapy with or without bevacizumab failed to show any additional benefıt in the bevacizumab arm. 19 The role of cetuximab as part of a neoadjuvant chemotherapy regimen in resectable mcrc to the liver was investigated through the New EPOC trial. 20 In this randomized phase III clinical trial, patients with resectable or suboptimally resectable KRAS-WT metastatic colorectal cancer to the liver were randomly assigned to perioperative chemotherapy with or without cetuximab. The progression-free survival () was signifıcantly shorter in the chemotherapy/cetuximab compared with the chemotherapy arm (14.1 vs months; HR 1.48; 95% CI, 1.04 to 2.12; p 0.03). Chemotherapy consisted predominantly of oxaliplatin-based therapy (FOLFOX or XELOX), although, 11% of the patient population received FOLFIRI. Given the small number of patients on the irinotecan arm, no defınitive conclusions can be extrapolated from this subgroup. 20 This study was criticized for lack of adequate surgical quality control, imbalance in patient characteristics, variations in chemotherapy backbones, and increased rate of early death without clear attribution. 21 The detrimental effect of cetuximab on the New EPOC trial and the lack of benefıt from adjuvant cetuximab treatment in stage III disease suggest that the addition of cetuximab to chemotherapy in KRAS-WT tumors does not improve the rate of microscopic disease eradication and, hence, does not decrease the risk for disease relapse. This strategy should be avoided in patients with resectable liver metastases. Biologic Therapy in the Management of Potentially Resectable mcrc Down-staging for resection in the setting of metastatic disease that is deemed unresectable at the time of presentation but potentially resectable after a major clinical response should be considered a standard approach. Patients who are converted to resectable disease with chemotherapy achieve a 5-year OS of 30% to 50%, far exceeding any 5-year survival reported with palliative chemotherapy. 22,23 Therefore, it is imperative that the most effective combination chemotherapy is considered in patients with advanced, potentially resectable, mcrc. Since no randomized studies have evaluated the combination cytotoxic chemotherapy compared with cytotoxic chemotherapy/bevacizumab in such settings, one cannot conclusively determine the role of angiogenesis inhibition in down-staging for resection. However, since many of the patients with potentially-resectable disease do not achieve resectability, and given the positive effect of bevacizumab on and OS, the routine implementation of bevacizumab in this setting is considered an acceptable practice, particularly when anti-egfr therapy is not considered or advisable. Additional considerations for the addition of bevacizumab in this setting include retrospective analyses suggesting increased complete pathologic responses and decreased sinusoidal damage to the liver with the addition of bevacizumab to chemotherapy When considering bevacizumab in the management of potentially resectable mcrc, it is important to consider the most effective chemotherapy backbones. To that end, the OLIVIA clinical trial randomized patients with initially unresectable colorectal liver metastases to FOLFOX plus bevacizumab or FOLFOXIRI plus bevacizumab. 15 The FOLFOXIRI arm was associated with an improved response rate, a higher resection rate, higher R0 resection rate, and improved (Table 1). Although the addition of cetuximab to chemotherapy in the setting of resectable hepatic metastatic disease has resulted in disappointing results, the value of cetuximab in unresectable-potentially resectable hepatic metastatic disease has been supported by several studies. A phase III clinical trial randomized patients with KRAS-WT tumors with unresectable hepatic mcrc to receive fırst-line FOLFOX or FOLFOX/cetuximab. 24 Patients assigned cetuximab achieved a higher response rate, R0 hepatic resection rates, and OS (Table 1). Additional support to this strategy comes from several other phase II clinical trials describing a high response rate and resection rates with cetuximab-based combinations. 25,26 In addition, a recent update from CALGB reported that 15.7% of 1,137 patients with KRAS-WT tumors underwent resection after 1:1 randomization to chemotherapy with bevacizumab or chemotherapy plus cetuximab. 27 A higher percentage of patients underwent resection (with no evidence of disease) in the cetuximab arm in comparison with bevacizumab (62% vs. 38%). No OS difference in outcome was noted between arms after resection, suggesting that preoperative cetuximab does not worsen postoperative outlook when compared with a bevacizumab backbone (Table 1). Both bevacizumab and cetuximab are justifıed in the setting of unresectable, potentially-resectable mcrc. Since the majority of these patients do not attain resectability, the integration of biologic therapy in the fırst-line setting is recom- asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e199

4 MARWAN FAKIH TABLE 1. Biologicals in Initially Non-Resectable CRC Liver Metastases Gruenberge et al Ye et al Venook et al Study Design Treatment Arm Comparator Arm RR and Resection Rate /OS Randomized phase II clinical trial 80 patients Primary endpoint: overall resection rate Randomized phase III trial of 138 patients (KRAS-WT) Primary endpoint: conversion rate to radical resection Randomized phase III clinical trial Primary endpoint: OS 1,137 patients KRAS-WT (exon 2) FOLFOX/BV FOLFOXIRI/BV Favors FOLFOXIRI arm RR: 81% vs. 62% Resection rate: 61% vs. 49% R0: 49% vs. 23% FOLFOX FOLFOX/Cmab Favors Cmab arm Resection rate: 29% vs. 13% R0: 26% vs. 7% Chemotherapy/BV Chemotherapy/Cmab 130 patients achieved surgical remission (favors Cmab arm) Cmab arm: 62% vs. 38% Favors FOLFOXIRI arm 18.6 vs months Favors Cmab arm (HR 0.6, p 0.04) OS (HR 0.54, p 0.013) Abbreviations: RR, response rate;, median progression-free survival; OS, median overall survival; HR, hazard ratio; BV, bevacizumab; Cmab, cetuximab; WT, wild type. No difference in OS between arms OS for overall patient population with surgical remission mended in view of its positive effect on and OS. In the setting of RAS-mutant type (MT) or BRAF-MT tumors, one would favor the use of FOLFOXIRI/bevacizumab in younger good performance status (PS) cases. In the setting where a doublet chemotherapy is chosen (more limited PS, older, etc.), an anti-egfr addition is a reasonable choice in RAS-WT tumors given its more pronounced effect on downstaging compared with bevacizumab. BIOLOGIC THERAPY IN NON-RESECTABLE MCRC The choice of biologic therapies in mcrc is often considered in view of the genetic profıle of the tumor. In this review, we will consider the pros and cons for angiogenesis targeting or EGFR targeting based on RAS and BRAF status. Biologic Therapies in RAS-MT and BRAF-MT Tumors Tumors with RAS mutations (exon 2, 3, and 4 of KRAS and NRAS) constitute approximately 50% of tumors; whereas, patients with BRAF mutations constitute 5% to 10% of patients with colorectal cancer. 28,29 Patients with RAS-MT tumors derive no benefıt from the addition of anti-egfr therapy to chemotherapy. 30 To the contrary, the addition of cetuximab to oxaliplatin-based chemotherapy has been associated with worsening in multiple outcome parameters. 28,29,31 The benefıts of bevacizumab in mcrc have been shown to transcend RAS or BRAF mutational status and, therefore, the benefıts reported on from phase III clinical trials from molecularly unselected patients with mcrc can be extrapolated to both RAS-WT and RAS-MT tumors. 32,33 Targeted Therapy in the First-Line Treatment The only angiogenesis-targeting agent to show improvement in and OS in the fırst-line treatment of mcrc is bevacizumab. These studies were performed in RAS and BRAF unselected patients but can be extrapolated to the RAS-MT population. 32,33 The only phase III study to report a signifıcant improvement in OS was the AVF2107 study. AVF2107 randomized patients to irinotecan and 5-FU/leucovorin with or without bevacizumab. 34 Subsequent fırst-line phase III studies have consistently confırmed an advantage to the addition of bevacizumab to several fluoropyrimidine-based backbones, albeit with a primary endpoint The advantage of the incorporation of bevacizumab in fırst-line treatment of mcrc has been particularly notable in the setting of fluoropyrimidine monotherapy. 37 The addition of bevacizumab to FOLFOX or XELOX has resulted in a clinically modest improvement in and insignifıcant improvement in OS. 35 Given the favorable toxicity profıle of bevacizumab and its reproducible positive effect on, it is recommended that this agent is considered in the fırst-line treatment of patients with RAS-MT or BRAF-MT cancer (and as an option for RAS-WT as discussed below). Since anti-egfr therapy is not an option in this setting, this is considered the only viable option for targeted therapy in this population. The reader is directed to our recent review on targeted therapy for further details on this topic. There is no convincing evidence that patients with BRAF-MT mcrc derive a clinically signifıcant benefıt from anti-egfr therapy. 35,38 Signifıcant progress is being made through the concurrent targeting of EGFR and BRAF (with or without MEK) in this population. 39,40 However, such strategies are still considered investigational. Therefore, consideration of front-line addition of bevacizumab should be made in this subgroup of patients. However, the outlook of these patients continues to be dismal. Recent subgroup analysis from the TRIBE clinical trial has suggested a benefıt from FOLFOXIRI/bevacizumab in comparison with FOLFIRI in patients with BRAF-MT disease. 1 Given the aggressive biology of BRAF-MT cancers, consideration for up-front FOLFOXIRI/bevacizumab should be considered in the younger fıt individuals. Targeted Therapy in the Second-Line Treatment The value of bevacizumab in the second-line treatment of patients with previously bevacizumab-naive disease who progressed on a fırst-line therapy of irinotecan plus 5-FU has been confırmed through the ECOG 3200 clinical trial. 41 In this study, patients receiving FOLFOX/bevacizumab experienced a superior response rate,, and OS than the e ASCO EDUCATIONAL BOOK asco.org/edbook

5 BIOLOGIC THERAPIES IN COLORECTAL CANCER FOLFOX control arm (Table 2). However, in clinical practice, most patients who proceed to second-line treatment have had prior bevacizumab exposure. Three randomized phase III clinical trials have now reported on angiogenesis targeting post-bevacizumab progression The results of these studies are summarized in Table 2. Both the ML18147 and RAISE clinical trials mandated prior progression on a bevacizumab-based therapy and resulted in signifıcant improvements in and OS in favor of bevacizumab and ramucirumab. 44 The VELOUR clinical trial included both patients with bevacizumab-naive and bevacizumab pretreated disease and resulted in signifıcant improvement in and OS in the overall population. None of the three trials showed an improvement in response rate in the patients who were bevacizumab-pretreated. The three agents investigated are different biologically with bevacizumab being directed toward VEGF-A, aflibercept toward VEGF-A, VEGF-B and PlGF, and ramucirumab toward VEGFR-2. Although no head-to-head comparison among these agents have been performed to date, bevacizumab has been associated with the most favorable safety profıle, whereas, concerns have been raised regarding the increased toxicity of aflibercept when combined with chemotherapy. 43 All three antiangiogenic agents are considered acceptable options for second-line treatment, with a preference toward bevacizumab given its more established safety profıle. Although bevacizumab can be considered across different backbones in the second-line treatment, aflibercept and ramucirumab should only be considered with FOLFIRI. No clinical or biologic biomarkers have been identifıed to direct treatment toward any of these three biologicals in the setting of second-line FOLFIRI. Targeted Therapy in Chemotherapy-Refractory or Resistant Colorectal Cancer The CORRECT clinical trial 45 enrolled patients with mcrc who progressed after or were intolerant of fluoropyrimidines, oxaliplatin, irinotecan, and anti-egfr therapy (in KRAS-WT). All patients had received prior bevacizumab. The study showed a signifıcant clinically modest improvement in OS (median OS 6.4 vs. 5 months; HR 0.77; 95% CI, 0.64 to 0.94; one-sided p ). Consideration for singleagent regorafenib can therefore be made after progression on all standard chemotherapy. Biologic and Targeted Therapies in RAS-WT Tumors It is important to note that the recommendations regarding antiangiogenesis therapies reported above for the RAS or BRAF-MT populations apply equally to the RAS/BRAF-WT population. On the other hand, the management of the RAS/ BRAF-WT population is complicated by the proven effectiveness of anti-egfr therapy across all lines of treatment. Therefore, treatment decisions in patients with RAS/ BRAF-WT disease have to factor in effıcacy and toxicity data with both classes of targeted agents. In this section we address the effect of anti-egfr agents in this group of patients, and when feasible, put it in context of antiangiogenic therapies. Targeted Therapies in the First-Line Treatment of RAS-WT mcrc The CRYSTAL clinical trial evaluated the combination of FOLFIRI with cetuximab compared with FOLFIRI alone in the fırst-line treatment of mcrc. 46 No benefıt was noted in the KRAS-MT (exon-2) population, whereas, a signifıcant TABLE 2. Angiogenesis Targeting in the Second-Line Treatment of mcrc Giantonio et al 41 ECOG 3200 study Bennouna et al 44 ML18147 Study Van Cutsem et al 43 VELOUR Study Tabernero et al 42 RAISE Study Study Design Second-line randomized phase III clinical in BV-naive disease 829 patients Second-line randomized phase III clinical trial in patients post- BV first-line progression 820 patients Second-line randomized phase III clinical trial 1,226 patients (70% of patients without prior BV) Second-line randomized phase III clinical trial in patients post- BV first-line progression 1,072 patients Control Arm Experimental Arm Efficacy Objectives Primary Efficacy Endpoint Other Efficacy Endpoints FOLFOX4 FOLFOX4/BV Primary: OS Chemotherapy Chemotherapy/BV Primary: OS FOLFIRI FOLFIRI/ ziv-aflibercept Primary: OS FOLFIRI FOLFIRI/RAM Primary: OS OS: 12.9 (FOLFOX4/BV) vs months (FOLFOX4) (HR 0.75, p 0.001) OS: 11.2 (chemotherapy/bv) vs. 9.8 months (chemotherapy) (HR 0.81, p ) OS: 13.5 (FOLFIRI/ziv-aflibercept) vs months (FOLFIRI) (HR 0.817, p ) OS: 13.3 (chemotherapy/ram) vs months (chemotherapy) (HR 0.84, p ) Abbreviations: OS, overall survival; RR, response rate;, progression-free survival; HR, hazard ratio; BV, bevacizumab; RAM, ramucirumab. : 7.3 (FOLFOX4/BV) vs. 4.7 months (FOLFOX4) (HR 0.61, p ) RR: 22.7% (FOLFOX4/BV) vs. 8.6% (FOLFOX4) (p ) : 5.7 (chemotherapy/bv) vs. 4.1 months (chemotherapy) (HR 0.68, p ) No difference in RR : 6.9 (FOLFIRI/zivaflibercept) vs. 4.7 months (FOLFIRI) (HR 0.758, p ) RR: 19.8% (FOLFIRI/zivaflibercept) vs. 11.1% (FOLFIRI) (p 0.001) No difference in RR in patients with prior BV : 5.7 (chemotherapy/bv) vs. 4.5 months (chemotherapy) (HR 0.79, p ) No difference in RR asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e201

6 MARWAN FAKIH TABLE 3. EGFR Targeting in the First-Line Treatment of mcrc Maughan et al 29 COIN Study Tveit et al 48 NORDIC VII Study Douillard et al 28 PRIME study Van Cutsem et al 46,47 CRYSTAL Study Study Design Randomized phase III clinical trial (KRAS-WT for codons 12, 13, and 61) 815 patients per arm Randomized phase III clinical trial 566 patients Randomized phase III clinical trial 1,183 patients Randomized phase III clinical trial 1,198 patients KRAS exon 2 WT: 676 patients Control Arm Arm A: oxaliplatin/ fluoropyrimidine (FOLFOX or XELOX) FLOX (bolus 5-FU, leucovorin, and oxaliplatin) (Arm A) Experimental Arm(s) Arm B: oxaliplatin/ fluoropyrimidine/ Cmab FLOX/Cmab (Arm B) Efficacy Objectives Primary Efficacy Endpoint Other Efficacy Endpoints Primary: OS RR, Primary: RR, OS FOLFOX4 FOLFOX4/Pmab Primary: RR, OS FOLFIRI FOLFIRI/cetuximab Primary: OS OS: 17 (Arm B) vs months (Arm A) (HR 1.04, p 0.67) in the KRAS- WT population KRAS-WT population: : 7.9 (Arm B) vs. 8.6 months (Arm A) (HR 1.06, p 0.66) KRAS exon 2 WT: : 9.6 (FOLFOX4/Pmab) vs. 8 months (FOLFOX4) (HR 0.8, p 0.02) RAS-WT: : 10.8 (FOLFOX4/ Pmab) vs. 9.2 months (FOLFOX4) (HR 0.72, p 0.004) KRAS exon 2 WT: : 9.9 (FOLFIRI/Cmab) vs. 8.4 months (FOLFIRI) (HR 0.696, p ) RAS-WT: : 11.4 (FOLFIRI/ Cmab) vs. 8.4 months (FOLFIRI) (HR 0.56, p ) : 8.6 months (Arms A and B) (HR 0.96, p 0.6) HR for the FOLFOX arm favored Cmab (HR 0.72, p 0.037) KRAS-WT population: RR: 49% (Arm B) vs. 41% (Arm A) (p 0.15) No difference in OS (Arm A 22 months, Arm B 20.1 months) KRAS exon 2 WT: OS: 23.8 (FOLFOX4/Pmab) vs months (FOLFOX4) (HR 0.83, p 0.03) RAS-WT: OS: 25.8 (FOLFOX4/Pmab) vs months (FOLFOX4) (HR 0.77, p 0.009) KRAS exon 2 WT: OS: 23.5 (FOLFIRI/Cmab) vs months (FOLFIRI) (HR 0.797, p ) RAS-WT: FOLFIRI/Cmab OS 28.4 vs. FOLFIRI 20.2 months (HR 0.69, p ) KRAS exon 2 WT: RR: 55% (FOLFOX4/Pmab) vs. 48% (FOLFOX4) (OR 1.35, p 0.068) KRAS exon 2 WT: RR: 57.3% (FOLFIRI/Cmab) vs. 39.7% (FOLFIRI) (OR 2.069, p 0.001) RAS-WT: FOLFIRI/Cmab RR 66.3% vs. FOLFIRI 38.6% (OR 3.11, p ) Abbreviations: mcrc, metastatic colorectal cancer; OS, overall survival; Cmab, cetuximab; Pmab, panitumumab; RR, response rate;, progression-free survival; HR, hazard ratio; EGFR, epidermal growth factor receptor; OR, odds ratio; WT, wild type. improvement in response rate,, and OS was noted in the KRAS-WT subgroup. 46 Subsequent analysis based on RAS-WT (no KRAS or NRAS exon 2 4 mutations) showed even more robust improvements in and OS than the KRAS-WT population (Table 3). 47 Similar benefıts were noted with panitumumab with a FOLFOX backbone on the PRIME clinical trial (Table 3). 28 Two other phase III clinical trials failed to show a survival advantage for cetuximab in KRAS-WT tumors in the fırst-line setting (Table 3). 29,48 The NORDIC trial used a nonconventional bolus fluoropyrimidineoxaliplatin regimen. 48 The COIN trial included XELOX as a chemotherapy backbone, which was associated with increased toxicities when combined with cetuximab and, therefore, potentially confounding cetuximab effıcacy. 29 In addition, the lack of benefıt on the NORDIC trial may have been confounded by a detrimental effect for cetuximab in the patients with KRAS (exon 3 and 4) and NRAS mutations who were included in the study analysis. Three randomized fırst-line studies investigated bevacizumab compared with anti-egfr therapy in the fırst-line treatment of KRAS-WT tumors (Table 4). 2,31,49 All three studies have reported effıcacy data based on RAS-MT. The FIRE-3 and CALGB studies confırmed an improved response rate in favor of anti-egfr therapy, no difference in among arms, but diverted in the OS results. The FIRE-3 clinical trial showed an improvement in OS in RAS-WT tumors favoring cetuximab, whereas, no difference was noted in the CALGB study (Table 4). 2,49,50 The reason behind this difference in OS is unclear. A difference in postprogression salvage rate with anti-egfr therapy in the bevacizumab arms could very well have contributed to these variations in outcome. Other contributing factors could be variations in treatment compliance, dose intensity, and early treatment discontinuation because of toxicity, all of which are yet to be reported on CAALGB The PEAK clinical trial is a smaller randomized phase II clinical trial of FOLFOX/panitumumab compared with FOLFOX/bevacizumab. 31 The results from this study were somewhat consistent with the FIRE-3 clinical trial (Table 4). For further review, please refer to our recent review on this topic. Both bevacizumab and anti-egfr therapy are considered appropriate options in the fırst-line treatment of metastatic cancer. Given the increased down-staging potential of anti- EGFR therapy in the fırst-line setting compared with bevacizumab, this may be the more preferable biologic agent in the potentially resectable cases, especially when FOLFOXIRI (with or without bevacizumab) is contraindicated. In addition, anti-egfr therapy is preferred in patients with higher risk for perforation (bulky primary, signifıcant carcinomatosis) or with known risk factors for arterial thrombotic events. Bevacizumab is more preferable in patients who want to avoid skin toxicity. Targeted Therapies in the Second-Line Treatment of RAS-WT mcrc Although anti-egfr therapy clearly increases the response rate andinpatientswithras-wtmcrc, nostudieshavereported an improvement in OS in this setting (Table 5). 38,51,52 Two studies e ASCO EDUCATIONAL BOOK asco.org/edbook

7 BIOLOGIC THERAPIES IN COLORECTAL CANCER TABLE 4. Anti-EGFR Versus Bevacizumab Plus Chemotherapy Studies in the First-Line Treatment of Metastatic Colorectal Cancer Author/Study Schwartzberg et al 31 PEAK Study Heinemann et al 49 Stintzing et al 50 FIRE-3 Study Venook et al 2 Lenz et al 27 CALGB Study Design Randomized phase II clinical trial in KRAS-WT (exon 2) 285 patients Randomized phase III clinical trial in KRAS-WT WT (exon-2) 592 patients RAS-WT: 400 patients Randomized phase III clinical trial 1,137 patients KRAS- WT (exon 2) RAS-WT: 526 patients Control Arm Experimental Arm(s) FOLFOX/BV FOLFOX/Pmab Primary: OS, RR FOLFIRI/BV FOLFIRI/Cmab Primary: RR (FOLFOX or (FOLFOX or FOLFRI)/BV FOLFIRI)/ Cmab Efficacy Objectives Primary Efficacy Endpoint Other Efficacy Endpoints, OS Primary: OS KRAS-WT : 10.9 (Pmab) vs months (BV) (HR 0.87, p 0.353) RAS-WT : 13 m (Pmab) vs. 9.5 months (BV) (HR 0.65, p 0.029) KRAS-WT (independent review): RR: 66.5% (Cmab) vs. 55.6% (BV) (OR 1.58, p 0.016) RAS-WT (independent review): RR: 72% (Cmab) vs. 56% (BV) (OR 2, p 0.003) KRAS-WT: OS: 29.9 (Cmab) vs. 29 months (BV) (HR 0.92, p 0.3) RAS-WT: OS: 30.8 (Cmab) vs months (BV) (HR 0.9, p 0.4) KRAS-WT RR: 57.8% (Pmab) vs. 53.5% (BV) OS: 34.2 (Pmab) vs months (BV) (HR 0.62, p 0.009) RAS-WT RR: 63.6% (Pmab) vs. 60.5% (BV) OS: 41.3 (Pmab) vs months (BV) (HR 0.63, p 0.058) KRAS-WT: OS: 28.7 (Cmab) vs. 25 months (BV) (HR 0.77, p 0.017) 10 (Cmab) vs months (BV) (HR 1.06, p 0.55) RAS-WT: OS: 33.1 (Cmab) vs. 25 months (BV) (HR 0.7, p ) 10.3 (Cmab) vs months (BV) (HR 0.97, p 0.77) KRAS-WT: RR: 65.6% (Cmab) vs. 57.2% (BV) (p 0.002) KRAS-WT: : 10.4 (Cmab) vs months (BV) (HR 1.04, p 0.55) RAS-WT: RR: 68.8% (cetuximab) vs. 56% (BV) (p 0.001) RAS-WT: : 10.9 (Cmab) vs m (BV) (HR 1.1, p 0.31) Abbreviations: EGFR, epidermal growth factor receptor; Pmab, panitumumab; Cmab, cetuximab; BV, bevacizumab;, progression-free survival; OS, overall survival; RR, response rate; HR, hazard ratio; OR, odds ratio; WT, wild type. evaluated cetuximab and panitumumab in the setting of singleagent irinotecan. 38,51 The EPIC trial did not select patients based on RAS status but reported improvements in response rate and. 51 The PICCOLO study excluded patients with KRAS codon 12, 13, and 61 mutations and showed an improvement in response rate and, but no benefıt in OS. 38 The study randomized patients to FOLFIRI plus panitumumab compared with FOLFIRI in patients with KRAS (exon-2) WT disease. 52 A signifıcant improvement in response rate and was noted on the panitumumab arm. A recent update on this study showed further accentuation of benefıt in favor of panitumumab in the RAS-WT population (Table 5). 53 It is unclear at this time what the best strategy is for a biologic therapy in the second-line setting of RAS-WT tumors after progression on fırst-line bevacizumab-based combinations. The continuation of bevacizumab or a switch to anti-egfr based therapy (in the setting of irinotecan-based backbone) is acceptable. However, in the setting where down-staging is important, anti-egfr therapy is more appropriate. Targeted Therapies in the Third-Line Treatment of RAS-WT mcrc There is no current data to support the continuation of bevacizumab in the third-line treatment in mcrc. In patients who have progressed on all cytotoxic chemotherapies, the combination of anti-egfr plus irinotecan is considered the most appropriate choice in patients with good PS who are irinotecan tolerant. 54 The use of cetuximab or panitumumab monotherapy in this setting is also considered appropriate based on the C017 and the ASPECCT trials (Table 6). 55,56 Regorafenib should only be considered after failure (or intoler- TABLE 5. EGFR Targeting in the Second-Line Treatment in KRAS-WT Metastatic Colorectal Cancer Peeters et al Study Seymour et al 38 PICOLLO Study Study Design Second-line randomized phase III clinical trial KRAS exon 2 WT: 597 patients Second-line randomized phase III clinical trial KRAS WT (codon 12, 13, 61) 460 allocated to irinotecan with or without panitumumab Control Arm Experimental Arm(s) Efficacy Objectives FOLFIRI FOLFIRI Pmab Primary: OS Irinotecan 300 mg/m 2 to 350 mg/m 2 every 3 weeks Irinotecan/panitumumab (9 mg/kg every 3 weeks) Primary: OS, RR Primary Efficacy Endpoint : 5.9 m (FOLFIRI Pmab) versus 3.9 m (FOLFIRI) (HR 0.73, p 0.004) OS: 10.4 (irinotecan/ Pmab) vs months (irinotecan) (HR 1.01, p 0.91) Other Efficacy Endpoints OS: 14.5 m (FOLFIRI Pmab) versus 12.5 m (FOLFIRI) (HR 0.85, p 0.12) : Pmab/irinotecan arm was superior to irinotecan (HR 0.78, p 0.015) Abbreviations: EGFR, epidermal growth factor receptor; OS, overall survival; RR, response rate;, progression-free survival; HR, hazard ratio; OR, odds ratio; WT, wild type. RR: 35% (FOLFIRI Pmab) versus 10% (FOLFIRI) (p 0.001) RR: 33% (Pmab/irinotecan) vs. 12% (irinotecan) (OR 4.12, p ) asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e203

8 MARWAN FAKIH TABLE 6. EGFR Targeting in Chemotherapy Resistant KRAS-WT mcrc Karapetis et al 56 NCI-CO17 Study Price et al 55 ASPECCT Study Study Design Randomized phase III clinical trial KRAS-WT (exon 2), 230 patients Randomized phase III noninferiority clinical trial in patients with KRAS-WT 1,010 patients Control Arm Experimental Arm(s) Efficacy Objectives Primary Efficacy Endpoint Other Efficacy Endpoints BSC Cmab Primary: OS Cmab Pmab Primary: OS OS: 9.5 (Cmab) vs. 4.8 months (BSC) (HR 0.55, p 0.001) OS: 10.4 (Pmab) vs. 10 months (Cmab) Pmab non-inferior to Cmab : 3.7 (Cmab) vs. 1.9 months (BSC) (HR 0.40, p 0.001) RR: 12.8% (Cmab) vs. 0% (BSC) : 4.1 (Pmab) vs. 4.4 months (Cmab) (HR 1.0; 85% CI, 0.88 to 1.14) RR: 22% (Pmab) vs. 19.8% (Cmab) Abbreviations: mcrc, metastatic colorectal cancer; OS, overall survival; RR, response rate;, progression-free survival; HR, hazard ratio; EGFR, epidermal growth factor receptor; Cmab, cetuximab; Pmab, panitumumab; OR, odds ratio; BSC, best supportive care; WT, wild type. ance) of all cytotoxic and anti-egfr therapy. It is important to note that no randomized data have reported on anti-egfr recycling and that the above recommendations in the second- and third-line treatment with anti-egfr therapy are based on clinical trials of patients with anti-egfr naive disease. The question of recycling is an important research question given the RAS-mutation emergence in the setting of anti-egfr therapy. It is possible that prolonged breaks after anti-egfr progression allow for tumor reconstitution with anti-egfr sensitive clones resulting in further benefıt from anti-egfr rechallenge. A small phase II clinical trial supports this concept; however, more studies are needed to confırm these fındings and to identify the patients who would best benefıt from this strategy. 57 Disclosures of Potential Conflicts of Interest Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate family member; those marked B are held by the author and an immediate family member. Institutional relationships are marked Inst. Relationships marked U are uncompensated. Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Marwan Fakih, Amgen, Genentech, Sanofi, Sirtex Medical. Consulting or Advisory Role: Marwan Fakih, Amgen, Sanofi, Sirtex Medical, Taiho Pharmaceutical. Speakers Bureau: Marwan Fakih, Amgen, Bayer, Genentech, Sanofi, Sirtex Medical. Research Funding: Marwan Fakih, Amgen (Inst), Novartis (Inst). Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None. References 1. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014; 371: Venook A, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-fu/leucovorin (FOLFIRI) or oxaliplatin/5-fu/ leucovorin (mfolfox6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s (suppl; abst LBA4). 3. Allegra CJ, Yothers G, O Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29: Allegra CJ, Yothers G, O Connell MJ, et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J Clin Oncol. 2013;31: Pogue-Geile K, Yothers G, Taniyama Y, et al. Defective mismatch repair and benefıt from bevacizumab for colon cancer: fındings from NSABP C-08. J Natl Cancer Inst. 2013;105: de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012; 13: Midgley R, Love S, Tomlinson I, et al. Final results from QUASAR2, a multicentre, international randomised phase III trial of capecitabine (CAP) /- bevacizumab (BEV) in the adjuvant setting of stage II/III colorectal cancer (CRC). Paper presented at: ESMO 2014 Congress; September 2014; Madrid, Spain. 8. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012; 307: Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15: Huang J, Nair SG, Mahoney MR, et al. 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9 BIOLOGIC THERAPIES IN COLORECTAL CANCER tastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371: Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14: Nasti G, Piccirillo MC, Izzo F, et al. Neoadjuvant FOLFIRI bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial. Br J Cancer. 2013;108: Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008;26: Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mfolfox-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. Epub 2014 Dec Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110: Gruenberger T, Arnold D, Rubbia-Brandt L. Pathologic response to bevacizumab-containing chemotherapy in patients with colorectal liver metastases and its correlation with survival. Surg Oncol. 2012;21: Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35: Turan N, Benekli M, Koca D, et al. 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Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25: Tabernero J, Cohn A, Obermannova R, et al. RAISE: a randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and asco.org/edbook 2015 ASCO EDUCATIONAL BOOK e205