KRAS Wild-type Metastatic Colorectal Cancer Research Articles

Abstract 2355: SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies

Abstract SGN-EGFRd2 is an investigational bispecific antibody comprised of two camelid-derived humanized variable heavy chain only (VHH) domains, one targeting Vγ9Vδ2 (gamma delta) T cells and the other targeting the epidermal growth factor receptor (EGFR). Selective antitumor activity occurs when two conditions are met: 1) the molecule engages both EGFR-expressing tumor cells and gamma delta T cells and 2) butyrophilins, in complex with phosphoantigens (pAgs), are expressed by EGFR-positive tumor cells, resulting in gamma delta T cell directed tumor cell killing by activation, degranulation and secretion of cytolytic molecules. The tumor specific proximity of gamma delta T cells and expression of the butyrophilins/pAgs complex results in the killing of EGFR-expressing tumor cells but not EGFR-expressing normal cells. EGFR is an oncogenic receptor tyrosine kinase and target of several classes of therapeutic modalities, including antibodies. Two antibodies are currently approved for the treatment of EGFR-expressing, KRAS wild-type metastatic colorectal cancer (mCRC): cetuximab (CET) and panitumumab (PAN). Although these anti-EGFR therapies provide significant survival benefits to patients, the duration of response is transient, and most patients progress and develop secondary resistance [1]. One such escape mechanism is the acquisition of mutations in the extracellular domain (ECD) of EGFR, which prevent binding of therapeutic antibodies [2]. Because SGN-EGFRd2 will be tested on patients previously exposed to anti-EGFR therapeutic antibodies, it is paramount to assess its binding to EGFR ECD mutations identified in antibody resistant mCRC patients. EGFR-negative A2058 cells were transduced to express wild type EGFR and a panel of EGFR ECD resistance mutations (N=16). The binding specificity and kinetics of SGN-EGFRd2 were compared to CET and PAN by flow cytometry on engineered cell lines and biolayer interferometry, respectively. Results indicated SGN-EGFRd2 maintained the ability to bind to all tested EGFR ECD mutants, whereas CET and PAN were unable to bind several ECD mutants, as previously described [3,4]. SGN-EGFRd2 binding to EGFR ECD mutant cell lines induced the production of interferon gamma and expression of cell surface CD107a on gamma delta T cells, confirming functional engagement. In contrast to current anti-EGFR therapeutic antibodies, SGN-EGFRd2 binding and activity was unaffected by commonly identified EGFR ECD mutations. These findings highlight SGN-EGFRd2 as a novel molecule targeting wild-type EGFR and common EGFR ECD mutations identified in the mCRC setting. Citation Format: Liem Nguyen, Chun-Shu Wong, Serena Wo, Bryan Grogan, Daniel Diolaiti, Maria Corinna Palanca-Wessels, Astrid Clarke. SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2355.

Treatment outcome comparisons of first-line targeted therapy in patients with KRAS wild-type metastatic colorectal cancer: A nationwide database study.

The first-line systemic therapy for metastatic colorectal cancer (mCRC) is a combination of one targeted therapy agent and a chemotherapy doublet. Whether bevacizumab or anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) is the more effective addition to a chemotherapy doublet as the first-line treatment for inoperable KRAS wild-type mCRC remains controversial in prior clinical trials. Moreover, the association between the sidedness of primary tumors and the efficacy of anti-EGFR mAb needs to be addressed. We established a cohort of patients with KRAS wild-type mCRC who were treated with first-line targeted therapy plus doublet chemotherapy between 2013 and 2018 using Taiwan's National Health Insurance Research Database. Secondary surgery was defined as either resection of primary tumors, liver metastases, lung metastases, or radiofrequency ablation. A total of 6482 patients were included; bevacizumab and anti-EGFR mAb were the first-line targeted therapies in 3334 (51.4%) and 3148 (48.6%) patients, respectively. Compared with those who received bevacizumab, patients who received anti-EGFR mAb exhibited significantly longer overall survival (OS; median, 23.1 vs. 20.2 months, p = 0.012) and time to treatment failure (TTF; median, 11.3 vs. 10 months, p < 0.001). Among left-sided primary tumors, the OS and TTF benefits of anti-EGFR mAb remained. Among right-sided primary tumors, the OS and TTF were similar regardless of the type of targeted therapy. In multivariate analyses, first-line anti-EGFR mAb therapy remained an independent predictor of longer OS and TTF for left-sided primary tumors. Patients who received anti-EGFR mAb were more likely to receive secondary surgery (29.6% vs. 22.6%, p < 0.0001) than patients who received bevacizumab. For patients who received first-line doublet chemotherapy for KRAS wild-type mCRC, adding anti-EGFR mAb was associated with significantly longer OS and TTF, especially for left-sided primary tumors.

Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer

BackgroundIn 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients. MethodsEmploying cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC. ResultsIC reduced costs by £ 35,763 (PSM; p < 0.001) or £ 30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£ 1.2 billion over this cohort’s lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic. ConclusionsOur results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic.

P-71 Treatment outcome comparisons of first-line targeted therapy in patients with KRAS wild-type metastatic colorectal cancer: A nationwide database study

It remains controversial regarding whether bevacizumab or anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) is the better companion of a chemotherapy doublet as the first-line treatment for inoperable KRAS wild-type metastatic colorectal cancer (mCRC).

Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS.

This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant metastatic colorectal cancer.

Efficacy and Safety of Cetuximab Dosing (biweekly vs weekly) in Patients with KRAS Wild-type Metastatic Colorectal Cancer: A Meta-analysis.

Cetuximab 500mg/m2 biweekly (Q2W) plus chemotherapy is commonly used and recommended by NCCN guidelines. This meta-analysis compares efficacy and safety between Q2W versus weekly (Q1W) cetuximab dosing. A systematic literature review was performed on Pubmed and RightFind (2007-2017) for patients with KRAS wild-type mCRC who received Q2W or Q1W cetuximab and other treatments. Observational studies and case reports were excluded. Randomized trials comparing Q2W and Q1W dosing, and single-arm trials with only Q2W schedule were included. CRYSTAL, a phase 3 randomized study with Q1W cetuximab dosing was paired with each single-arm study with a Q2W schedule and reweighted to achieve similar demographic/baseline characteristics. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HR), overall response rate (ORR) with odds ratios, and risk difference of adverse events of special interest (AESI) between Q2W versus Q1W cetuximab were analyzed. Five phase 2 studies with cetuximab Q2W/Q1W dosing schedules were identified: CECOG (phase 2; Q2W, n = 77; Q1W, n = 75), NORDIC 7.5 (phase 2; Q2W, n = 152) and NORDIC 7 (arm C of phase 3; Q1W, n = 109), CELINE (n = 60), OPTIMIX (n = 99), and APEC (n = 289) all phase 2, Q2W, single-arm studies paired with CRYSTAL Q1W dosing (n = 303). Efficacy was similar between Q2W versus Q1W administration; OS HR = 0.96, 95% confidence interval (CI) [0.89, 1.04]; PFS HR = 0.96, 95% CI [0.87, 1.05]; ORR odds ratio 1.16, 95% CI [0.96, 1.41]. Mean differences (Q2W-Q1W) across AESI rates were not clinically meaningful with no obvious directionality. This meta-analysis demonstrated no significant differences in efficacy and safety between Q2W versus Q1W cetuximab administration in mCRC patients.

Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

P-136 Detecting panitumumab/FOLFOX responders in K-Ras wild-type metastatic colorectal cancer through an artificial intelligence-based analytical tool

Patients with K-RAS wild-type (WT) metastatic colorectal cancer (mCRC) are currently considered the optimal candidates for upfront treatment with combinations of chemotherapy and EGFR inhibitors. These combinations significantly extend overall survival (OS) compared to chemotherapy alone. However, a proportion of patients would not achieve this goal. This study has investigated the ability of an artificial intelligence-based analytical tool that, based on patients clinical parameters, can identify those on which the addition of EGFR inhibitors to initial chemotherapy is likely to be effective.

Random survival forests identify pathways with polymorphisms predictive of survival in KRAS mutant and KRAS wild-type metastatic colorectal cancer patients

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene–gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/β-catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways.

Cost-Effectiveness of Anti-Epidermal Growth Factor Receptor Therapy Versus Bevacizumab in KRAS Wild-Type (WT), Pan-RAS WT, and Pan-RAS WT Left-Sided Metastatic Colorectal Cancer

ObjectivesWe aimed to compare the economic value of chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) against chemotherapy with bevacizumab (Bev, an anti-vascular endothelial growth factor mAb) as first-line treatment in KRAS wild-type (WT), pan-RAS WT and pan-RAS WT left-sided metastatic colorectal cancer (mCRC) patients from the Hong Kong societal perspective.Materials and MethodsWe developed Markov models and 10-year horizon to estimate costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of chemotherapy plus anti-EGFR therapy against chemotherapy plus Bev in KRAS WT, pan-RAS WT, and pan-RAS WT left-sided mCRC. We considered two times of the local gross domestic product per capita (GDPpc) as the willingness-to-pay (WTP) threshold (2× GDPpc; US$97,832).ResultsAdding anti-EGFR mAb to chemotherapy provides additional 0.24 (95% confidence interval [CI] 0.19–0.29), 0.32 (95% CI 0.27–0.37), and 0.57 (95% CI 0.49–0.63) QALY compared to adding Bev in KRAS WT, pan-RAS WT, and left-sided pan-RAS WT mCRC populations respectively. The corresponding ICER is US$106,847 (95% CI 87,806–134,523), US$88,565 (95% CI 75,678–105,871), US$76,537 (95% CI 67,794–87,917) per QALY gained, respectively.ConclusionsAnti-EGFR therapy is more cost-effective than Bev as a first-line targeted therapy in left-sided pan-RAS WT and pan-RAS WT, with ICER <US$100,000/QALY, compared to KRAS WT mCRC population.

Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway

BackgroundCetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells.MethodsEx vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity.ResultsWe first confirmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway.ConclusionsThis study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC.

Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes

AimCetuximab is a standard-of-care treatment for KRAS wild-type metastatic colorectal cancer (mCRC), but it may also be effective in a subgroup of KRAS mutant patients by its immunomodulatory activity. Here,...

Cost-minimization analysis of biweekly dosing of cetuximab and FOLFIRI compared with panitumumab and FOLFOX for first-line treatment of patients with KRAS wild-type metastatic colorectal cancer in the United States

Aim To compare the cost of biweekly regimens of first-line (1L) treatments of cetuximab-folinic acid, fluorouracil, and irinotecan (FOLFIRI) versus panitumumab-folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients with Kirsten’s rat sarcoma wild type (KRAS WT) metastatic colorectal cancer (mCRC) in the United States, across varying weights and body surface areas (BSAs). Materials and methods Cost-minimization analysis (CMA) was performed to estimate per-patient cost differences of cetuximab-FOLFIRI versus panitumumab-FOLFOX. The CMA estimated the costs of RAS testing, premedication, drug acquisition, treating infusion reactions (IRs), supportive therapy, and biweekly administration of chemotherapy, cetuximab (500 mg/m2), and panitumumab (6 mg/kg) over 43 weeks (median progression-free survival). To calculate dose and cost, weight and height data were gathered from an electronic health record-derived de-identified database (n = 7,669; January 2013–October 2020). Base case analysis utilized mean weight/BSA of the overall cohort (82.04 kg/1.92 m2), and alternate scenarios were based on 88.18 kg/2.03 m2 (men, n = 4,477) and 73.43 kg/1.76 m2 (women, n = 3,192). Results For the base case, total treatment costs were $167,853 for cetuximab-FOLFIRI and $168,254 for panitumumab-FOLFOX; cost savings per patient receiving cetuximab-FOLFIRI was $400. Cost savings in alternate scenarios (men, $15,138; women, $15,004) resulted from lower drug acquisition costs for cetuximab (men, $14,833; women $14,854) and administration cost ($440) versus panitumumab. Cost savings of cetuximab-FOLFIRI in treating IR ($353) were similar across all scenarios. Limitations With no head-to-head clinical trial data in the 1L setting, assumptions of similarity in efficacy and safety of cetuximab versus panitumumab were based on published network meta-analysis and the ASPECCT trial. This model did not consider a lifetime horizon. Costs of managing all adverse events (except IR) were not included. Conclusions Biweekly cetuximab-FOLFIRI offers cost savings compared with panitumumab-FOLFOX for 1L therapy of patients with KRAS WT mCRC in the United States. These cost differences were observed for the overall population and across different BSA and weights for men and women.

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial

BackgroundCetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.MethodsThe intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.ResultsMedian OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.ConclusionsFOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases.ClinicalTrials.gov identifierNCT00433927.

Cetuximab versus bevacizumab maintenance following prior 8-cycle modified FOLFOXIRI plus cetuximab in Asian postmenopausal women with treatment-naive KRAS and BRAF wild-type metastatic colorectal cancer.

ObjectiveTo assess the efficacy and safety of cetuximab (CE) versus bevacizumab (BE) maintenance treatment after prior 8-cycle modified 5-fluorouracil, folinate, oxaliplatin, and irinotecan (FOLFOXIRI) plus CE induction therapy in treatment-naive KRAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).MethodsFrom 2012 to 2017, prospectively maintained databases were reviewed to assess Asian postmenopausal women with treatment-naive KRAS and BRAF wt mCRC who underwent modified FOLFOXIRI plus CE induction therapy, followed by CE or BE maintenance until disease progression or death. Co-primary clinical endpoints were progression-free survival (PFS) and overall survival (OS).ResultsA total of 222 women were included (CE n = 110 and BE n = 112). At a median follow-up of 27.0 months (interquartile range, 6.5–38.6 months), median PFS was 21.9 months (95% confidence interval [CI] 16.4–24.4) and 17.7 months (95% CI 11.3–19.0) for CE and BE groups, respectively (hazard ratio [HR] 0.31, 95% CI 0.15–0.46); median OS was 26.0 months (95% CI 23.4–28.7) and 22.7 months (95% CI 21.2–24.3) for CE and BE groups, respectively (HR 0.22, 95% CI 0.11–0.37).ConclusionsCE maintenance treatment is more poorly tolerated but has a slightly more modest survival benefit compared with BE maintenance treatment in mCRC.

Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08

BackgroundRegorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC).MethodsThis Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses.ResultsAmong 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group.ConclusionsIrinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial.Clinical trial registrationUMIN000010638

P-365 Association between baseline serum levels of miRNA-143 and hepatocyte growth factor in patients with RAS wild type metastatic colorectal cancer treated with first-line anti-EGFR therapy

Recently the prognostic role of microRNA-143 has been proven by ours and several studies and one meta-analysis. Additionally, high serum levels of hepatocyte growth factor (HGF) were found to be associated with resistance to anti-EGFR antibodies in KRAS wild-type metastatic colorectal cancer (mCRC). The possible interplay between miRNA-143 and HGF as predictive factors in RAS wild mCRC is unknown.

P-293 Overall survival according to mutation frequency of BRAF, NRAS genes, and MSI status in patients with wild-type KRAS metastatic colorectal cancer treated with cetuximab

The treatment of colorectal cancer (CRC) has been progressively based on its molecular profile. This study was justified by the prognostic relevance of BRAF and NRAS genes and microsatellite instability (MSI) status in CRC, and the small number of studies evaluating the mutation frequency of these genes as well as the status of MSI in colorectal tumors in Brazil. In addition, it is one of the first studies in the Brazilian population that aimed to confirm previous findings regarding the efficacy of cetuximab in the treatment of advanced CRC in an enriched population of refractory poly-treated patients.

Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial

BackgroundThe multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC). Patients and methodsPatients received FOLFOX6 with cetuximab (500 mg/m2) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location. ResultsIn total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months. ConclusionsThis study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer.

BACKGROUNDAnti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown.AIMTo assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management.METHODSPatients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up.RESULTSOverall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low.CONCLUSIONThe rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.