Overall Survival for Bevacizumab Therapy in Metastatic Colorectal Cancer: An Updated Analysis of the TRAVASTIN Study.

To assess the efficacy and safety of first-line standard chemotherapy plus bevacizumab in metastatic colorectal cancer and to explore how to optimize therapeutic efficacy. First, meta-analysis and pooled analysis of three randomized, controlled trials were used to compare response rate (RR), progression-free survival (PFS), overall survival (OS), and grade 3 or 4 adverse events (G3/4AEs) of chemotherapy plus bevacizumab (n = 1169) with those of chemotherapy alone (n = 1148). Second, using six different regimens plus bevacizumab, the Spearman method was used to analyze the correlation between these regimens and OS. Finally, one-way ANOVA was used to compare OS in these regimens. Overall, chemotherapy plus bevacizumab increased RR by 3.8%, prolonged PFS by 3.0 months and OS by 3.3 months, and increased G3/4AEs by 7.6%. Significant differences were found in PFS (hazard ratio [HR] = 0.65; p = 0.000), OS (HR = 0.79; p = 0.000), and G3/4AEs (risk ratio = 1.12; p = 0.006). However, no statistical difference was found in RR (odds ratio = 1.32; p = 0.17). The optimal regimens with regard to mean OS were capecitabine and irinotecan (CAPIRI) plus bevacizumab (24.00 months) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (23.97 months). First-line standard chemotherapy plus bevacizumab conferred a significant improvement in OS. In combination with bevacizumab, both CAPIRI and FOLFOX are favorable regimens, though further studies are needed to confirm these results.

3580 Background: Trifluridine/tipiracil (FTD-TPI; Lonsurf) is an oral antineoplastic agent approved for 3 rd -line use in combination with or without bevacizumab (BEV) in metastatic colorectal cancer (mCRC). In the Phase III SUNLIGHT trial, the addition of BEV to FTD-TPI was associated with a significant improvement in overall survival (OS) and progression-free survival (PFS) compared to FTD-TPI monotherapy. However, data on the use of FTD-TPI in combination with BEV in the real-world community setting are currently limited. Methods: This was a retrospective observational study involving electronic medical records and (where available) chart reviews from mCRC patients treated by the Texas Oncology community practice from Jan 2020 to Oct 2024. Patients had to have received FTD-TPI with or without BEV after progressing on a prior line of therapy with oxaliplatin and irinotecan. Variables included patient characteristics, clinical characteristics, treatment patterns and clinical outcomes. OS and time to next treatment or death (TTNTD) were analyzed using the Kaplan-Meier method. Results: In total, 265 patients were included (166 FTD-TPI + BEV; 99 FTD-TPI monotherapy), with the majority receiving FTD-TPI as 3 rd -line (83%; n = 220) or 4 th -line (14%; n = 38) therapy. The population was 59% male, 66% white, and 35% were ≥65 years of age. The most common previous 1 st - and 2 nd -line treatment for 3 rd -line FTD-TPI patients was chemotherapy + an antiangiogenic (1 st -line, 67%; 2 nd -line, 74%), which was similar regardless of current BEV use. Median duration of therapy was 2.8 months (range 0.3 to 12.5) with FTD-TPI + BEV and 2.8 months (range 0.1 to 10.4) with monotherapy. Median OS was 11.6 months with FTD-TPI + BEV and 6.2 months with monotherapy (hazard ratio [HR] = 2.1; 95% confidence interval [CI]: 1.5-3.0; p < 0.001). At 6 months, OS probability was 0.69 (95% CI: 0.61-0.77) with FTD-TPI + BEV and 0.50 (95% CI: 0.40-0.63) with monotherapy; 12-month OS probability was 0.49 (0.39-0.61) and 0.15 (0.07-0.28), respectively. Median TTNTD was 9.4 months for FTD-TPI + BEV and 5.8 months for FTD-TPI alone (HR = 1.7, 95% CI: 1.2-2.4; p < 0.001). The safety/tolerability profile was generally similar irrespective of BEV use, with the most common adverse events being fatigue/asthenia (73%), abdominal discomfort/pain (55%), and nausea (54%). The most notable difference was neutropenia (37% FTD-TPI + BEV, 27% monotherapy). Conclusions: In this large real-world community practice setting in the US, FTD-TPI use in mCRC was mostly in the 3 rd -line setting and approximately two-thirds of use was in combination with BEV. Patient characteristics were similar to the SUNLIGHT trial, with high rates of previous antiangiogenic use. A statistically significant and clinically relevant OS benefit was seen with the addition of BEV versus monotherapy consistent with the results of the SUNLIGHT trial.

Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab

e15580 Background: Regorafenib improves progression-free survival (PFS) and overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC). Here, we report the treatment patterns of regorafenib in the third- or late-line setting for mCRC in four centers in China. Methods: Patients with refractory mCRC in four centers in China administered regorafenib from February 1, 2018 to June 31, 2021 were enrolled. Patients were grouped into 3 cohorts, including the monotherapy (regorafenib alone), chemo (regorafenib plus chemotherapy) and immune (regorafenib plus anti-PD1 (programmed cell death 1) antibodies) groups. Demographic, clinical, survival and safety data were retrospectively analyzed. Results: A total of 177 patients were included in this study. Of them, 116 (65.5%) were treated with regorafenib alone, while 28 (15.9%) and 33 (18.6%) were administered regorafenib plus chemotherapy and anti-PD1 antibodies, respectively. The median followedup time was 9.2 months. The disease control rate (DCR) was 40.7%. The median PFS (mPFS) was 2.43 months and the median OS (mOS) was 12.2 months. The immune group had longer median PFS (3.5 m vs. 2.2 m, p = 0.043) compared with the monotherapy group. Patients administered regorafenib plus chemotherapy had longer median OS (15.9 m vs. 8.4 m, p = 0.032) compared with the monotherapy group. Patients who began regorafenib treatment at 120 mg had longer median PFS and OS compared with those who began at 80 mg (PFS: 3.7 m vs. 2.0 m; p < 0.001; OS: 13.4 m vs. 10.2 m; p = 0.005). Patients with a final dose of 120 mg had longer median PFS and OS compared with the 80 mg or less group (PFS: 5.0 m vs. 2.3 m; p = 0.045; OS: UR (unreach) vs. 10.9 m; p = 0.003). There were 87.0% (154/177) patients experience AEs. Three groups had similar rates of AEs (86.2% vs. 89.3% vs. 87.9%; p = 0.89). Conclusions: Patients administered regorafenib alone or regorafenib in combination with other agents were relieved to some extent, with a disease control rate of 40.7%. Regorafenib plus anti-PD1 antibodies showed better PFS, while regorafenib plus chemotherapy had the most benefit in OS. There was no significant difference among three groups in terms of AEs.

Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.

Background and importanceUncertainty exists regarding the comparative effectiveness of cetuximab versus bevacizumab in metastatic colorectal cancer (mCRC) due to conflicting evidence of efficacy of previous randomised clinical trials and the...

522 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study that investigated 115 patients (pts) treated with 1st line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS and OS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for KRAS. Sixty-two pts (62.6%) had KRAS wild-type (wt) and 37 pts (37.4%) had mutation (mt). The pts characteristics between those with wt and with mt were generally balanced except for PS 0 (91.9% in wt, 75.7% in mt; p = 0.036) and lung metastasis (33.9% in wt, 62.2% in mt; p = 0.007). RR was 70.0% in wt versus 65.7% in mt. Adverse events related to BV were almost balanced except for bleeding (any grade) (30.6% in wt, 13.5% in mt; p = 0.088). The median PFS and OS was 9.9 and 26.8 months in wt versus 7.9 and 17.5 months in mt (PFS ; HR 1.519, p = 0.064 and OS ; HR 1.944, p = 0.005). In Cox multivariate analysis, KRAS mt showed significantly shorter PFS and OS (PFS ; HR 1.637, p = 0.045 and OS ; HR 2.132, p = 0.005). Conclusions: In this cohort, depending on the KRAS Exon2 mutational status, severe adverse events were no significant difference. The multivariate analysis showed that PFS and OS were significantly longer in the KRAS Exon2 wild-type patients. So, KRAS Exon2 mutational status can be a predictive and prognostic marker in bevacizumab combined 1st line chemotherapy. Clinical trial information: UMIN000018935.

BackgroundRegorafenib improves progression-free survival (PFS) and overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC). Here, we report the treatment patterns of regorafenib in the third- or late-line setting for mCRC in four centers in China.Patients and MethodsPatients with refractory mCRC in four centers in China administered regorafenib from February 1, 2018 to June 31, 2021 were enrolled. Patients were grouped into 3 cohorts, namely, the monotherapy (regorafenib alone), chemo (regorafenib plus chemotherapy), and immune [regorafenib plus anti-PD1 (programmed cell death 1) antibodies] groups. Demographic, clinical, survival and safety data were retrospectively analyzed.ResultsA total of 177 patients were included in this study. Of them, 116 (65.5%) were treated with regorafenib alone, while 28 (15.9%) and 33 (18.6%) were administered regorafenib plus chemotherapy and anti-PD1 antibodies, respectively. The median followed-up time was 9.2 months. The disease control rate (DCR) was 40.7%. The median PFS (mPFS) was 2.43 months and the median OS (mOS) was 12.2 months. The immune group had longer median PFS (3.5 m vs. 2.2 m, p = 0.043) compared with the monotherapy group. Patients administered regorafenib plus chemotherapy had longer median OS (15.9 m vs. 8.4 m, p = 0.032) compared with the monotherapy group. Patients who began regorafenib treatment at 120 mg had longer median PFS and OS compared with those who began at 80 mg (PFS: 3.7 m vs. 2.0 m; p <0.001; OS: 13.4 m vs. 10.2 m; p = 0.005). Patients with a final dose of 120 mg had longer median PFS and OS compared with the 80 mg or less group (PFS: 5.0 m vs. 2.3 m; p = 0.045; OS: UR (unreach) vs. 10.9 m; p = 0.003). There were 87.0% (154/177) patients who experienced AEs. Three groups had similar rates of AEs (86.2% vs. 89.3% vs. 87.9%; p = 0.89).ConclusionPatients administered regorafenib alone or regorafenib in combination with other agents were relieved to some extent, with a disease control rate of 40.7%. Regorafenib plus anti-PD1 antibodies showed better PFS, while regorafenib plus chemotherapy had the most benefit in OS. There was no significant difference among three groups in terms of AEs.

652 - Primary Resistance to First-Line Bevacizumab in Metastatic Colorectal Cancer: Implications on Prognosis

Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21-53 months) and right-sided (median first PFS = 13 months, 95% CI 9-17 months; median OS = 37 months, 95% CI 22-52 months) disease. These results raised questions regarding the true significance of primary tumor location when selecting bevacizumab or cetuximab for first-line therapy, particularly the current thought of using cetuximab for left-sided tumors. While the superiority of bevacizumab over cetuximab in rightsided disease remained evident upon comparison of our analysis with historical controls, survival outcomes with the agent in our analysis appeared to be similar to that of cetuximab in CRYSTAL, FIRE- 3, and CALGB/SWOG 80405 in left-sided disease. Further study is required to determine if bevacizumab truly does produce similar outcomes to cetuximab in left-sided primary tumors.

BackgroundAnti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally.MethodsVALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance.DiscussionThere is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test.Trial registrationClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020.

152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.

IntroductionTargeting angiogenesis in metastatic colorectal cancer (mCRC) using bevacizumab is a standard of care. The addition of this targeted biological agent to first-line infusional fluoropyrimidine-based chemotherapy was associated with superior overall survival (OS) in several randomized and controlled studies for CRC patients in the metastatic setting. However, access to this therapy in countries with limited resources is challenging. In Morocco, bevacizumab was introduced for this indication after considerable efforts of the Ministry of Health and Lalla Salma Foundation to support cancer patients with a limited income. In this report, the real-world efficacy and safety of the combination of bevacizumab with chemotherapy in mCRC are reported based on a retrospective cohort in Eastern Morocco.Material and methodsThe archives of the medical records of 98 mCRC patients treated with first-line bevacizumab at the Hassan II Regional Cancer Center (Oujda, Morocco) were sampled from 1st January 2014 to 31st December 2019 and analyzed using descriptive statistics, Kaplan-Meier estimation, and a multivariable Cox regression model for a time-to-event study.ResultsThe toxicity profile was dominated by grade I–II proteinuria (10%), bleeding events (10%), thromboembolic events (9%), grade I–III hypertension (3%), and other rare events such as delayed healing of the stoma, scar dehiscence, intestinal perforation, and heart failure deterioration. In terms of survival, median OS and progression-free survival in the whole cohort were 22 and 13 months respectively. Patients who benefited from a metastasectomy after bevacizumab treatment had 31 months of median OS as compared to 14 months in the matched cohort with non-resectable liver metastasis. Notably, we demonstrated that tumor sidedness is a predictive factor of OS [hazard ratio (HR) = 2.452; 95% CI: 1.434–4.191, p = 0.001]. Moreover, the median OS for patients who received between 10 and 20 or more than 20 bevacizumab administrations was 24 and 33 months respectively as compared to those who received less than 10 cures (17 months) (log rank p < 0.0001). These markedly improved outcomes were also confirmed in multivariate Cox regression. A highly significant association of bevacizumab use and OS was found after adjusting for covariates (HR = 0.518, 95% CI: 0.374–0.717; p < 0.0001).ConclusionsThe current study confirmed the important place of this therapeutic strategy in mCRC. Additional studies with prospective enrollment are awaited to validate these findings.

During the past 20 years, median overall survival (OS) for patients with metastatic colorectal cancer (CRC) has steadily improved from 10 to 12 months to greater than 24 months, due in large part to approval of eight new therapeutic agents. Yet, as we have observed in other diseases, the benefits of empiric therapies without regard to molecular subtype has limits, and CRC remains a leading cause of cancer-related death in the United States. In the article that accompanies this editorial, results of the PEAK (Panitumumab Efficacy in Combination With mFOLFOX6 Against Bevacizumab Plus mFOLOFOX6 in Metastatic CRC Subjects With Wild-Type KRAS Tumors) trial are reported. In this phase II study, 285 patients with previously untreated, KRAS exon 2 wild-type, metastatic CRC were randomly assigned to receive FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) plus panitumumab versus FOLFOX plus bevacizumab. The specified primary objective was to estimate progression-free survival (PFS) for panitumumab relative to bevacizumab in combination with FOLFOX. In this regard, PFS was similar between the panitumumab and bevacizumab arms, with median PFS times of 10.9 and 10.1 months, respectively. Thus, the primary result of this trial does not suggest a difference in controlling disease progression for one regimen versus the other in the primary analysis population. However, further results of interest are provided in secondary analyses, including evaluation of additional end points and examination of patient subgroups stratified by extended RAS testing (KRAS and NRAS exons 2-4, but not BRAF exon 15). In the first-line treatment of metastatic CRC, studies have demonstrated similar efficacy for FOLFIRI (infusional fluorouracil, leucovorin, irinotecan), FOLFOX, and CAPOX (capecitabine and oxaliplatin). However, whether to add an inhibitor of angiogenesis, such as bevacizumab, or a monoclonal antibody to the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, to first-line treatment programs has remained unclear. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor A that has demonstrated improved PFS and OS when added to IFL (bolus fluorouracil, leucovorin, irinotecan) and improved PFS with a trend toward improved OS when added to FOLFOX or CAPOX in the first-line treatment of metastatic CRC. Given that validated predictive biomarkers are not available for antiangiogenic therapy, bevacizumab-containing treatment programs have been widely adopted for patients with metastatic CRC, independent of tumor mutations identified by genomic profiling. The efficacy of anti-EGFR monoclonal antibodies first emerged in the setting of previously treated metastatic CRC, and two randomized trials demonstrated modest improvements in survival for cetuximab or panitumumab as monotherapy compared with placebo. Soon after these results became available, mutations in exon 2 (codons 12 and 13) of the KRAS oncogene emerged as predictive biomarkers for intrinsic resistance to anti-EGFR therapy. KRAS encodes a small GTPase protein that integrates signals from cell surface receptors such as EGFR to regulate cell growth and division. Mutations in KRAS lead to persistent binding of GTP and constitutive activation of the protein. In a multitude of studies, the presence of these mutations was noted to confer resistance to anti-EGFR therapy, rapidly leading to a change in practice whereby these agents were limited to patients without KRAS exon 2 mutations. Nevertheless, clinical trials have not consistently demonstrated benefit to anti-EGFR antibodies in the first-line setting, even among patients with KRAS exon 2 wild-type tumors. The CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial evaluated the addition of cetuximab to FOLFIRI, demonstrating improved PFS and OS among patients with KRAS exon 2 wild-type tumors receiving cetuximab. The PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study randomly assigned patients to FOLFOX with or without panitumumab, demonstrating improved PFS and a trend toward improved OS for the panitumumab arm among patients with KRAS exon 2 wild-type tumors. However, the NORDIC-VII and MRC COIN studies demonstrated no improvements in outcome measures for the addition of cetuximab to a fluoropyrimidine and oxaliplatin in this same molecularly defined patient subgroup (NORDIC-VII: 5-Fluorouracil/Folinate/Oxaliplatin [FLOX Regimen], Given Continuously or Intermittently, in Combination With Cetuximab, in First-Line Treatment of Metastatic Colorectal Cancer; and MRC COIN: Medical Research Council Continuous Chemotherapy Plus Cetuximab or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer). Given that anti-EGFR monoclonal antibodies clearly have activity against CRC, the mixed results from these studies have left us to ponder whether more comprehensive analysis of the CRC genome JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 21 JULY 2

Colorectal cancer trial endpoints: time for dynamic thinking?