KRAS Wild-type mCRC Research Articles

Model-informed Evidence for Clinical Non-inferiority of Every-2-Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer.

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every-2-weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non-inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I-III clinical trials in 852 patients with KRAS wild-type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure-tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi-mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration-time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model-based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non-inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non-inferiority in 94% of cases. Taken together, these analyses provide model-based evidence for clinical non-inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.

Impact of Systemic Treatments on Outcomes and Quality of Life in Patients with RAS-Positive Stage IV Colorectal Cancer: A Systematic Review.

This systematic review critically evaluates the impact of systemic treatments on outcomes and quality of life (QoL) in patients with RAS-positive stage IV colorectal cancer, with studies published up to December 2023 across PubMed, Scopus, and Web of Science. From an initial pool of 1345 articles, 11 relevant studies were selected for inclusion, encompassing a diverse range of systemic treatments, including panitumumab combined with FOLFOX4 and FOLFIRI, irinotecan paired with panitumumab, regorafenib followed by cetuximab ± irinotecan and vice versa, and panitumumab as a maintenance therapy post-induction. Patient demographics predominantly included middle-aged to elderly individuals, with a slight male predominance. Racial composition, where reported, showed a majority of Caucasian participants, highlighting the need for broader demographic inclusivity in future research. Key findings revealed that the addition of panitumumab to chemotherapy (FOLFOX4 or FOLFIRI) did not significantly compromise QoL while notably improving disease-free survival, with baseline EQ-5D HSI mean scores ranging from 0.76 to 0.78 and VAS mean scores from 70.1 to 74.1. Improvements in FACT-C scores and EQ-5D Index scores particularly favored panitumumab plus best supportive care in KRAS wild-type mCRC, with early dropout rates of 38-42% for panitumumab + BSC. Notably, cetuximab + FOLFIRI was associated with a median survival of 25.7 months versus 16.4 months for FOLFIRI alone, emphasizing the potential benefits of integrating targeted therapies with chemotherapy. In conclusion, the review underscores the significant impact of systemic treatments, particularly targeted therapies and their combinations with chemotherapy, on survival outcomes and QoL in patients with RAS-positive stage IV colorectal cancer, and the need for personalized treatment.

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [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 925.

Real-world clinical efficacy of epidermal growth factor receptor inhibitors (EGFRi) in patients with early-onset (eo), metastatic colorectal cancer (mCRC).

36 Background: The incidence of eo CRC (age of onset: <50 years) is rising globally, although specific reasons remain unknown. In a prior study using the ARCAD database, the addition of EGFRi to chemotherapy (chemo) significantly improved progression-free survival (PFS) in late-onset (lo) KRAS wild-type (wt) left-sided mCRC patients (pts); however, no such effect was observed in eo mCRC pts (Jin Z et al., 2022). Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database of adult patients diagnosed with mCRC on/after January 1, 2013 with data cut-off on June 30, 2023. The cohort included pts with RAS/BRAF wt and left-sided primary tumors who were treated with first-line (1L) chemo+EGFRi, chemo+bevacizumab (bev), or chemo alone. Associations of disease onset and 1L therapy with real-world overall survival and time to next treatment (rwOS, rwTTNT) were assessed using Kaplan-Meier methods and hazard models adjusted for clinical confounders including year of metastatic diagnosis, group stage at initial diagnosis, site of disease, gender, race/ethnicity, and ECOG performance status. Results: Among 895 left-sided RAS/BRAF wt mCRC pts, 216 and 679 pts had eo and lo mCRC, respectively. In pts treated with chemo+EGFRi vs chemo alone, the adjusted hazard ratio (HR) (95% CI) of rwTTNT was 0.93 (0.56-1.53) and 0.77 (0.58-1.02) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.96 (0.51-1.83) and 0.78 (0.57-1.07) in eo and lo pts, respectively. In pts treated with chemo+bev vs chemo alone, the adjusted HR (95% CI) of rwTTNT was 1.00 (0.62-1.60) and 0.75 (0.58-0.97) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.97 (0.54-1.75) and 0.78 (0.58-1.03) in eo and lo pts, respectively. Conclusions: Adding EGFRi to chemotherapy suggested potential improvements in rwTTNT and rwOS in lo pts but not in eo pts, similar to findings from the prior ARCAD database study. Such differences in outcomes, similarly observed in pts treated with chemo+bev, underscore the need for tailored therapeutic strategies. Given the wide confidence intervals in this study, future research with larger patient cohorts or longer follow-up may yield more precise estimates of these differences. [Table: see text]

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

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.

Predictive potential of angiopoietin-2 in a mCRC subpopulation treated with vanucizumab in the McCAVE trial.

Angiopoetin-2 (Ang-2) is a key mediator of tumour angiogenesis. When upregulated it is associated with tumour progression and poor prognosis. Anti-vascular endothelial growth factor (VEGF) therapy has been widely used in the treatment of metastatic colorectal cancer (mCRC). The potential benefit of combined inhibition of Ang-2 and VEGF-A in previously untreated patients with mCRC was evaluated in the phase II McCAVE study (NCT02141295), assessing vanucizumab versus bevacizumab (VEGF-A inhibitor), both in combination with mFOLFOX-6 (modified folinic acid [leucovorin], fluorouracil and oxaliplatin) chemotherapy. To date, there are no known predictors of outcome of anti-angiogenic treatment in patients with mCRC. In this exploratory analysis, we investigate potential predictive biomarkers in baseline samples from McCAVE participants. Tumour tissue samples underwent immunohistochemistry staining for different biomarkers, including Ang-2. Biomarker densities were scored on the tissue images using dedicated machine learning algorithms. Ang-2 levels were additionally assessed in plasma. Patients were stratified by KRAS mutation status determined using next generation sequencing. Median progression-free survival (PFS) for each treatment group by biomarker and KRAS mutation was estimated using Kaplan-Meier plots. PFS hazard ratios (and 95% confidence intervals) were compared using Cox regression. Overall low tissue baseline levels of Ang-2 were associated with longer PFS, especially in patients with wild-type KRAS status. In addition, our analysis identified a new subgroup of patients with KRAS wild-type mCRC and high levels of Ang-2 in whom vanucizumab/mFOLFOX-6 prolonged PFS significantly (log-rank p=0.01) by ~5.5 months versus bevacizumab/mFOLFOX-6. Similar findings were seen in plasma samples. This analysis demonstrates that additional Ang-2 inhibition provided by vanucizumab shows a greater effect than single VEGF-A inhibition in this subpopulation. These data suggest that Ang-2 may be both a prognostic biomarker in mCRC and a predictive biomarker for vanucizumab in KRAS wild-type mCRC. Thus, this evidence can potentially support the establishment of more tailored treatment approaches for patients with mCRC.

Predictive and prognostic features of metastatic colorectal cancer arising from the transverse colon: A pooled analysis of the CCTG/AGITG CO.17 and CO.20 randomized trials.

124 Background: Primary tumour location is predictive of anti-EGFR benefit and prognostic in metastatic colorectal cancer (mCRC). Transverse colon cancers are often categorized as right sided, but the optimal cut point is unclear. Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group ( AGITG) CO.17 compared Cetuximab (Cet) vs. best supportive care (BSC) in mCRC. CCTG/AGITG CO.20 studied the addition of Brivanib Alaninate to Cet in pre-treated KRAS wildtype (WT) mCRC. We investigated the predictive and prognostic features of transverse colon primary location in a pooled cohort from these trials. Methods: Data from patients with RAS WT mCRC from CO.17 and KRAS WT mCRC from CO.20 randomized to cetux were analyzed for treatment outcomes according to location - right, transverse and left. The cecum to transverse colon was considered right sided, while the splenic flexure to rectum was considered left sided. Results: 553 patients were included, 201 (36.3%) from CO.17 and 352 (63.7%) from CO.20. Primary site distribution was: 32 (5.8%) transverse, 101 (18.3%) right and 420 (75.9%) left. On multivariate analysis from 457 (82.6%) patients treated with Cet, left side was associated with superior OS (HR, 0.40; 95% CI, 0.24-0.68, p=0.0006) and PFS (HR, 0.48; 95% CI,0.29-0.79, p=0.004) compared to transverse colon. No significant difference was noted in OS (HR, 0.74; 95% CI, 0.41-1.31, p=0.30) and PFS (HR, 0.79; 95% CI, 0.46-1.36, p=0.40) between right side versus transverse colon. Sidedness was not associated with prognostic difference in OS or PFS in the 96 (17.4%) patients receiving BSC alone. Outcomes according to primary site and treatment are shown. Conclusions: Transverse mCRC has comparable prognostic and predictive features to right sided mCRC. In keeping with previous studies, left side was predictive of greater Cet benefit and presented better overall prognosis when single agent Cet was used after 5-FU, oxaliplatin and irinotecan. [Table: see text]

KRAS Mutation: Characterization and Its Impact on Survival Outcome of Patients with Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancer types, with rising incidence due to imbalanced lifestyle and dietary habit. Association between CRC cases and KRAS mutation has been established recently. Brunei Darussalam, located within the Borneo island, is of diverse ethnicity which could represent the genome of Southeast Asia population. Our study, for the first time, determined the survival outcome of metastatic colorectal cancer (mCRC) and established the link with KRAS mutation by modelling the population in Brunei Darussalam. We collected data of 76 metastatic CRC (mCRC) patients undergoing treatment at The Brunei Cancer Centre, the national centre for cancer treatment in Brunei. These patients were diagnosed with Stage 4 CRC between 1 January 2013 and 31 December 2017. Age, gender, ethnicity, date of diagnosis, site of primary tumour, metastatic sites and molecular analysis of KRAS mutation status (either KRAS mutated or KRAS wild-type) of tumour were recorded. The survival outcomes of these mCRC patients were analysed. The end of this study period recorded 73.1% deceased mutant KRAS mCRC patients and 46.0% deceased wild-type KRAS mCRC patients, contributing to death rates of 45.2% and 54.8%, correspondingly. Chi-squared analysis showed a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients (p-value = 0.024). There is a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients in the Brunei population. In addition, we found that mutations in codon 12 of KRAS gene on mutant KRAS mCRC patients have shorter survival median periods than those with mutations within codon 13 of KRAS gene. This is the first study in Brunei Darussalam to analyse both the survival outcomes of mCRC patients and those of mutant KRAS mCRC patients.

NSABP FC-11: A phase II study of neratinib (N) plus trastuzumab (T) or N plus cetuximab (C) in patients (pts) with "quadruple wild-type" metastatic colorectal cancer (mCRC) based on HER2 status.

3564 Background: Patients (pts) with KRAS wild-type (WT) mCRC treated with single agent anti-EGFR therapy (tx) have improved OS compared to BSC but only a 10-15% response rate. Prior EGFR tx may upregulate HER amplification. For pts with quadruple WT mCRC (KRAS, NRAS, BRAF, PIC3KA), data suggest that dual targeting of the MAPK pathway, specifically EGFR and HER2, may be more effective. The purpose of this study was to evaluate the activity of dual MAPK pathway inhibition based on HER2 status: amplified (amp), non-amplified (non-amp), or mutated (mt). Methods: This 2-arm phase II trial enrolled pts with quad WT mCRC with ECOG PS 0-2, adequate organ function, prior oxaliplatin- and irinotecan-based regimens, and known HER2 status. Arm 1: HER2 amp (confirmed as &gt;2.14 copy number by Guardant 360) and prior anti-EGFR tx or HER2 mt (with qualifying mt) with or without prior anti-EGFR tx; Arm 2: HER2 non-amp or HER2 amp without prior anti-EGFR tx. Tx included T 4 mg/kg IV loading dose → 2 mg/kg/wk and N 240 mg po daily (Arm 1) or C 400 mg/m2 IV loading dose → 250 mg/m2/wk and N 240 mg po daily (Arm 2). Imaging was performed every 8 wks with response per RECIST 1.1. Primary end point (EP) of each arm was 6 mo PFS (PFS6). Secondary EPs: Response rate (ORR), clinical benefit rate (CBR), toxicity and exploratory assessments of N pharmacokinetics, genetic and molecular analyses, and evaluation of multiple drug combinations in PDX/PDXO models. We tested H0: PFS6 &lt;0.13 v HA: PFS6 &gt;0.47 (α=0.05; power=0.90 to reject HA). Treating 15 pts in each arm, if ≥5 pts are alive and progression free (PFS6 0.33), the arm is worth further testing. Results: From Jul 2018 - Mar 2021, 25 pts enrolled from 9 different centers. Arm 1 closed due to poor accrual (n=4). Those pts have been excluded from further analysis. Arm 2 enrolled 21 pts. with 15 evaluable for response by imaging. Early discontinuation occurred in 6 of 21 pts: 2 withdrew consent, 3 due to toxicity, and 1 physician withdrawal. Of the 15 evaluable pts, there were 6 PR, 5 of 13 HER2 non-amp, 1 of 2 HER2 amp, (duration 120-171 days; mean 140) and 5 SD (duration 59-231 days; mean 124). The ORR (CR/PR) in all pts who received at least one dose of tx is 33% (6/20). 8 of 15 evaluable pts (53%) were progression free at cycle 6. Common grade 3+ AEs (&gt;5%) included diarrhea (24%), rash (8%), and abdominal pain/distension (8%), without any grade 5 AEs. Conclusions: The combination of C+N was reasonably well tolerated with expected toxicities of diarrhea and rash. The ORR, CBR, and PFS compare favorably to pts previously relapsed following oxaliplatin and irinotecan and treated with single-agent anti-EGFR tx. Upon entry, biopsies for PDX implantation had an engraftment success rate of ̃80%. We anticipate using these grafts to establish PDXO models for molecular analyses and further drug testing. Support: NSABP Foundation, Puma Biotechnology. Clinical trial information: NCT03457896.

Development and validation of a predictive score to identify K-Ras wild-type (WT) metastatic colorectal cancer (mCRC) patients who are likely to benefit from Panitumumab (P) treatment.

e15526 Background: Practice guidelines recommend using P to treat K-Ras WT mCRC patients where it was shown to significantly extend overall survival (OS). Still, a proportion of patients will not achieve this goal. We propose a simplified predictive score to identify patients who are likely to benefit from P treatment. Methods: NCT00364013 was used as training dataset (TRS) (n = 460) with NCT00339183 (TES1) (n = 479) and NCT00113763 (TES2) (n = 191) as validations sets. Datasets were obtained from www.projectdatasphere.org and included K-Ras WT mCRC patients treated with P in combination or not with FOLFOX4 (FOL) or FOLFIRI as 1st, 2nd, or 3rd line therapy. TRS was used to generate synthetic representations (SRs) for each patient through the integration of 36 clinical and analytical features collected, respectively, during the screening phase and the first month of inclusion. These SRs were then input into a deep learning framework (DLF) to identify subgroup of patients based on their similarities. The resultant subpopulations were correlated with OS. Differential variables between subgroups were identified through feature contribution analysis and included in a multivariable logistic regression model. Independent predictive factors found to be statistically significant were used to generate a predictive score of P response at baseline that was validated in the test sets. Results: DLF identified two different subpopulations: SPA (n = 162) and SPB (n = 298). Patients in SPA had a lower risk of death when treated with P/FOL compared to FOL (HR 0.68 95%CI 0.48-0.99; p = 0.04). Patients in SPB showed no significant differences between P/FOL and FOL (p = 0.27). Feature contribution analysis identified 15 differential features between both subpopulations. From these, CEA &gt; 174 ng/ml, ALP &gt; 131 IU, LDH &gt; 703 IU, and platelets &gt; 374 109/L were selected to create a simplified predictive score for P response ranging 0-18 (if &gt; than the depicted values: 6.5 points for CEA, 5.5 for LDH, and 3 points for each other characteristic). When applied to TRS, this score yielded an area under the curve of 0.87 (95%CI: 0.84-0.91). A score ≥8.5 was positively correlated to a longer OS after P/FOL compared to FOL (HR 0.65 95%CI 0.43-0.98; p = .04). No significant differences were observed between P/FOL and FOL in patients with a score &lt; 8.5 (p = 0.89). The predictive score was then validated in the two test sets with similar results (score ≥8.5, TES1: HR 0.59 95%CI 0.40-0.88 p = .009; TES2: HR: HR 0.58 95%CI 0.35-0.96 p = .03; score &lt; 8.5, TES1: p = .5; TES2: p = .1). Conclusions: Based on CEA, ALP, LDH and platelet baseline levels, this easily applicable predictive score might be helpful to accurately select K-Ras WT mCRC patients who would benefit from P treatment. Further work is required to validate this approach in prospective cohorts of patients.

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.

Cost-effectiveness of preemptive skin treatment to prevent skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type metastatic colorectal cancer in Japan

BackgroundClinical management of skin-toxicity associated with the use of anti-Epidermal Growth Factor Receptor (EGFR) antibodies to treat colorectal cancer maintains quality of life of patients with colorectal cancer. Results of clinical trials have recommended the efficacy of prophylactic treatment, but the cost-effectiveness is unclear. This study examined the cost-effectiveness of preventive skin care for skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type metastatic colorectal cancer from the perspective of the Japanese healthcare payer.MethodsThe data source was J-STEPP trial, which compared preemptive skin treatment with reactive treatment in third-line panitumumab therapy for KRAS wild type metastatic colorectal cancer in Japan. The costs and effectiveness of preemptive treatment was compared with reactive treatment in a 3-year time horizon using a 4-state partitioned survival analysis. The health outcome was quality-adjusted life-years (QALYs). The costs were 2020 revisions to the drug prices. The robustness of the model was verified by one-way sensitivity analysis and a probabilistic sensitivity analysis (PSA). A 2% annual discount was applied to the expenses and QALYs. Willingness-to-pay (WTP) threshold of 5 million JPY was used.ResultsPreemptive treatment had incremental effects of 0.0029 QALYs, incremental costs of 5300 JPY (48.6 USD), and incremental cost-effectiveness ratios (ICER) of 1,843,395 JPY (16,912 USD) per QALY. The variability of preemptive and reactive treatment costs for skin-toxicity and the disutility of skin-toxicity had a large impact on ICER. From PSA, the cost-effectiveness rate of preemptive treatment was 75.0%.ConclusionsThe cost to effectiveness of preemptive treatment to prevent skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type mCRC is not high.

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.

The Spectrum, Tendency and Predictive Value of PIK3CA Mutation in Chinese Colorectal Cancer Patients.

Background PIK3CA is a high-frequency mutation gene in colorectal cancer, while its prognostic value remains unclear. This study evaluated the mutation tendency, spectrum, prognosis power and predictive power in cetuximab treatment of PIK3CA in Chinese CRC cohort.MethodsThe PIK3CA exon 9 and 20 status of 5763 CRC patients was detected with Sanger sequencing and a high-resolution melting test. Clinicopathological characteristics of 5733 patients were analyzed. Kaplan-Meier method and nomogram were used to evaluate the overall survival curve and disease recurrence, respectively.ResultsFifty-eight types of mutations in 13.4% (771/5733) of the patients were detected. From 2014 to 2018, the mutation rate of PIK3CA increased from 11.0% to 13.5%. At stage IV, exon 20 mutated patients suffered shorter overall survival time than wild-type patients (multivariate COX regression analysis, HR = 2.72, 95% CIs = 1.47-5.09; p-value = 0.012). At stage III, PIK3CA mutated patients were more likely to relapse (multivariate Logistic regression analysis, exon 9: OR = 2.54, 95% CI = 1.34-4.73, p = 0.003; exon 20: OR = 3.89, 95% CI = 1.66-9.10, p = 0.002). The concordance index of the nomogram for predicting the recurrence risk of stage III patients was 0.685. After cetuximab treatment, the median PFS of PIK3CA exon 9 wild-type patients (n = 9) and mutant patients (n = 5) did not reach a significant difference (3.6 months vs. 2.3 months, Log-rank test, p-value = 0.513).ConclusionsWe found that PIK3CA mutation was an adverse predictive marker for the overall survival of stage IV patients and recurrence of stage III patients, respectively. Further more, we suggested that PIK3CA exon 9 mutations are not negative predictors of cetuximab treatment in KRAS, NRAS, and BRAF wild-type mCRC patients.

PULSE: A randomized phase II open label study of panitumumab rechallenge versus standard therapy after progression on anti-EGFR therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency &gt; 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

Continuing Cetuximab vs Bevacizumab plus chemotherapy after first progression in wild-type KRAS, NRAS and BRAF V600E metastatic colorectal cancer: a randomized phase II trial.

To evaluate the clinical efficacy of continuing cetuximab vs bevacizumab plus chemotherapy crossover after first progression to cetuximab regimen in wild-type KRAS, NRAS and BRAF V600E mCRC, we conducted this prospective, open-label and randomized phase 2 trial in three cancer centers from Oct 1, 2016 to July 1, 2020. Eligibility criteria included documented progressive disease during or after first-line treatment with cetuximab regimen; second biopsy confirmed as KRAS, NRAS and BRAF V600E wild-type mCRC. Patients were randomized to arm A (cetuximab+chemo) or arm B (bevacizumab+chemo) with second-line chemotherapy crossover. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS) and toxicity. Tissue VEGFA, ERBB2 and MET mRNA were examined by real time RT-PCR.A total of 104 patients (53 in arm A and 51 in arm B) were enrolled. Median PFS was 7.7 months (95% CI: 6.5-8.9) for arm A and 6.3 months (95% CI: 4.5-8.1) for arm B (p=0.931). Median OS was 18.2 months (95% CI: 14.5-21.9) for arm A and 16.4 months (95% CI: 14.2-18.6) for arm B (p=0.339). The ORR was 28.3% and 19.6% in arm A and arm B (p=0.31), respectively. MET mRNA was highly expressed in the cetuximab-progressed tumors, but treatment responsiveness to cetuximab or bevacizumab in each arm was not correlated with the MET expression level. The results showed no significant difference in PFS, OS and ORR between the two arms, but a trend in favor of the cetuximab continuation plus chemotherapy crossover was examined in all end points. High expression of MET in cetuximab-progressed tumors may indicate an existence of MET-dependent tumor cell population.

The effectiveness of cetuximab and panitumumab when combined with FOLFIRI in second-line treatment of KRAS wild type metastatic colorectal cancers. Single centre experience

Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.

RAS Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer.

Several trials have evaluated the efficacy of rechallenge treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type 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