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Abstract Purpose Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. Patients and Methods We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. Results Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8–157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21–0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72–6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. Conclusions Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.

Summary Background Colorectal cancer (CRC) results from the accumulation of mutations and epigenetic changes in gut epithelial cells likely due to gut microbiota dysbiosis. However, limited research has been done to explore the link between host tumour dysbiosis and disease outcome. Methods The mechanisms influencing outcomes of 97 colorectal cancer (CRC) patients, including 13 with Lynch syndrome, 20 with inflammatory bowel disease (IBD), and 64 sporadic cases, were analyzed using a multiomics approach. These patients were categorized into two groups: “disease-free/stable disease” and “progression disease” survival outcomes. The analysis included tumor adherent microbiota composition (16S rRNA), somatic gene mutations (WES), gene expression (RNAseq), immune markers (RNAscope), and immune infiltrate cells (immunohistochemistry). Results IBD-CRC patients had worse outcomes than those with Lynch or sporadic CRC, regardless of TNM staging or treatment. Symbiotic bacteria like Lactococcus lactis were significantly reduced in IBD-CRC tissues. Patient outcomes were influenced by the abundance of virulent ( Escherichia coli ) relative to beneficial bacteria ( Lactococcus lactis ). Although no significant increase in deleterious somatic mutations was found in IBD-CRC. 16sRNA revealed increased virulent- and decreased anti-inflammatory symbiotic-bacteria correlating with the upregulation of oncogenes and downregulation of anti-oncogenes like PHLPP1. The multiplex in situ hybridization of CD8, IFNγ and PHLPP1 an anti-oncogene revealed significant decrease of immune cells with detectable PHLPP1 expression in IBD-CRC tumour tissues as compared to sporadic CRCs. Conclusion The poor outcomes in IBD-CRC patients are likely due to gut dysbiosis and immune cell alterations, possibly triggered by microbiota-related epigenetic pathways. What You Need to Know BACKGROUND AND CONTEXT Colorectal cancer (CRC) is associated with gut microbiota dysbiosis. Inflammatory bowel disease-related CRC (IBD-CRC) is classified as an environment-related condition. NEW FINDINGS In relation with patient outcomes, tumour tissues from three types of CRC (Sporadic-, IBD-, and Lynch syndrome-CRC) were analyzed using a multiomic approach. This included examining tissue adherent virulent bacteria, gene analyses, and quantifying immune cell infiltration in the mucosa. IBD-CRC patients had the worst outcomes, associated with the down regulation of PHLPP1 gene, virulent/symbiotic imbalance, and immune response failure. LIMITATIONS Lack of animal experiments using FMT of fresh stool from IBD-CRC patients. CLINICAL AND TRANSLATIONAL RESEARCH RELEVANCE Among the different types of CRC, IBD-CRC patients showed a greater imbalance between harmful and beneficial bacteria, along with immune response failure. Lay summary This study compares the pathological and clinical characteristics of patients with colorectal cancer (CRC) across three distinct etiologies: sporadic CRC, inflammatory bowel disease (IBD)-associated CRC, and Lynch syndrome-associated CRC (LS-CRC). Distinct differences in tumor-adherent microbiota, gene expression and immune response profiles were observed. Notably, IBD-CRC patients demonstrated the poorest prognosis depending on microbe-host gene interaction highlighting potential biomarkers for disease prognosis and treatment strategies.

TPS3616 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US for NSCLC harboring MET exon 14 skipping. Tepotinib + gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp NSCLC and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary safety and tolerability, antitumor activity, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). A safety run-in (6–12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint: dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis ( RAS/BRAF wild-type), documented previous anti-EGFR therapy and acquired resistance on most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific heterogenecity in reported METamp incidence. Approximately 42 pts are planned to receive study treatment: ̃22 in Cohort A (second-line, outside US) and 20 in Cohort B (≥third-line, US only). Primary endpoint: investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR), PFS (RECIST 1.1) and OS, tolerability and safety (NCI-CTCAE v5.0), and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles, and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.

3610 Background: Chronic lower grade adverse events (AE) can negatively affect a patient’s quality of life but it is difficult to capture using a traditional toxicity reporting approach. A novel AE reporting method was recently developed to describe, summarize, and present longitudinal AE profiles(Lopes et al, 2021). We leveraged this method to describe and compare the AE profiles of doublet chemotherapy (DC) + Cetuximab and DC alone in mCRC patients. Methods: This AE reporting method utilizes two additional AE metrics to complement the maximum (max) toxicity grade usually reported in clinical trials. Onset time indicates the time period in which max grade for an AE occurred for the first time, defined here as “early” (i.e. within first 42 days) and “late” (i.e. after the 42nd day). AE Load (AEL) indicates the overall severity of an AE in the entire treatment. AEL varies from 0 to 1. Higher AEL indicates a worse overall severity of that AE over time. AEL is the key metric for describing chronic AE. We included patients receiving DC + cetuximab (n = 738) and DC alone (n = 564 [ref group]) from two randomized first-line trials in the ARCAD database. Diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis were examined and adjusted for backbone (FOLFOX vs. FOLFIRI), ECOG PS, sex, site location, dose reduction, and treatment length. Results: For rash, DC + cetuximab had a higher risk of G3+ (21% vs. 0.5%; odds ratio {OR} [95% confidence interval {CI}] = 50 [16,157], p < 0.001), increased overall severity over the entire treatment (AEL = 0.257 vs. 0.069; Adjusted difference in means–Mdiff [95% CI] = 0.22 [0.21,0.23], p < 0.001), and increased risk of early onset (67% vs. 33%; OR [95% CI] = 4.3 [2.7,6.7], p < 0.001). DC + cetuximab also had higher AEL for rash across max grades (p < 0.001 within G1, G2, and G3+). For HFS, DC + cetuximab had a higher risk of G3+ (OR [95% CI] = 6.0 [2.5,14], p < 0.001), increased overall severity (AEL = 0.139 vs. 0.087; Mdiff [95% CI] = 0.03 [0.03,0.04], p < 0.001), and slightly earlier onset (12.4 vs. 13.9 weeks; Mdiff, weeks [95% CI] = -4.9 [-0.80,-9.0], p = 0.021). Within each max grade, DC + cetuximab did not have higher AEL of HFS. No associations were found for diarrhea, fatigue, anorexia, or mucositis. Conclusions: The addition of cetuximab is associated with higher grade, more persistent, and more immediate rash. The higher severity in HFS with the addition of cetuximab appears to be related to higher grade but not chronic HFS. This method may be useful to describe different strategies, e.g. intermittent cetuximab. It provided a comprehensive view of acute and chronic toxicity profiles supporting its potential interest as new metrics in clinical trials. Lopes GS, Tournigand C, Olswold CL, et al. Adverse event load, onset, and maximum grade: A novel method of reporting adverse events in cancer clinical trials. Clinical Trials. 2021;18(1):51-60

Background Current adverse event reporting practices do not document longitudinal characteristics of adverse effects, and alternative methods are not easily interpretable and have not been employed by clinical trials. Introducing time parameters in the evaluation of safety that are comprehensive yet easily interpretable could allow for a better understanding of treatment quality. In this study, we developed and applied a novel adverse event reporting method based on longitudinal adverse event changes to aid describing, summarizing, and presenting adverse event profile. We termed it the “Adverse Event Load, Onset, and Maximum Grade” method. Methods We developed two adverse event summary metrics to complement the traditional maximum grade report. Onset time indicates the time period in which the maximum grade for a specific adverse event occurred and was defined as “early” (i.e. maximum grade happened for the first time before 6 weeks) or “late” (i.e. after the 6 th week). Adverse event load indicates the overall severity of a specific adverse event over the entire treatment. Higher adverse event load indicates a worse overall experience. These metrics can be calculated for adverse events with different maximum grades, in treatments with planned changes (e.g. dosage changes), using data sets with different number of adverse event data points between treatments (e.g. treatments with longer cycle lengths may have less adverse event data points) and on data sets with different adverse event data availability (e.g. cycle basis and patient-outcome reports). We tested the utility of this method using individual patient data from two major backbone therapies (“Irinotecan” and “Oxaliplatin”) from the N9741 trial available in the Fondation ARCAD database ( fondationarcad.org ). We investigated profiles of diarrhea, neutropenia/leukopenia, and nausea/vomiting. Results Our method provided additional information compared to traditional adverse event reports. For example, for nausea/vomiting, while patients in Irinotecan had a higher risk of experiencing maximum grade 3–4 (15.6% vs 7.6%, respectively; p < 0.001), patients in both groups experienced similar severity over time (adverse effect load = 0.102 and 0.096, respectively; p = 0.26), suggesting that patients in Oxaliplatin experienced a lower-grade but more persistent nausea/vomiting. For neutropenia/leukopenia, more patients in Irinotecan experienced their maximum grade for the first time early in the treatment compared to patients in Oxaliplatin (67.9% vs 41.7%; p < 0.001), regardless of maximum grade. Longitudinal information can help compare treatments or guide clinicians on choosing appropriate interventions for low-grade but persistent adverse event or early adverse event onset. Conclusion We developed an adverse event reporting method that provides clinically relevant information about treatment toxicity by incorporating two longitudinal adverse event metrics to the traditional maximum grade approach. Future research should establish clinical benchmarks for metrics included in this adverse event reporting method.

4029 Background: The clearance of 5-FU differs significantly between men (M) and women (W). Adjuvant chemotherapy (CT) for CRC has a higher toxicity in W. The impact of sex on efficacy and toxicity in first-line trials of metastatic CRC (mCRC) is unknown. Methods: We analyzed patient (pt) and tumor characteristics, toxicities (nausea (AE1), vomiting (AE2), diarrhea, neutropenia (AE3)) and efficacy (overall survival (OS), progression-free survival (PFS)) according to sex in the following treatment groups: A: CT alone, B: CT + bevacizumab, C: CT + EGFR-antibodies, with subgroup analyses in the CT alone group for single-agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. Pts from trials with treatments still used today and all relevant data available were eligible. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS). Results: We included 28 trials with 18.399 pts (11.352 M and 7.047 W). W were younger (61 vs. 63 years), had more often a PS of 1 (49 vs 45%), BRAF mutations (10 vs. 7%), right-sided tumors (42 vs. 35%) and less often rectal tumors (26 vs. 32%). Significant differences in toxicity are reported in table. Rates of diarrhea were similar. There was no sex disparity in OS in the predefined subgroups except for pts receiving triplets where OS was better in M (HRadj=1.39 (1.05 - 1.85)). Median (interquartile range) OS in months for M and W was 16.7 (9.2-27.4) and 16.2 (8.9-27.2) in group 1, 21.9 (12.7-37.5) and 22.3 (12.9 – 39.0) in group 2, and 26.8 (14.6-45.3) and 24.8 (12.3-49.2) in group 3. HRsadj (W vs M) (95% CI), p values for OS were 1.02 (0.96-1.09), .557, 0.92 (0.83-1.03), .142, 0.99 (0.85-1.14), .866. Conclusions: M and W with mCRC differ significantly regarding patient and tumor characteristics. The significant higher toxicity in W does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated. [Table: see text]

Abstract Background Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in metastatic colorectal cancer (mCRC). We sought to identify a threshold for CEA change from baseline to predict progressive disease (PD) in mCRC patients receiving first-line therapy. Methods Patients from trials collected in the ARCAD database were included if baseline CEA was at least 10 ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by receiver operating characteristic analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value. Analyses were conducted by treatment class: chemotherapy alone, chemotherapy with anti-VEGF antibody, and chemotherapy with anti-EGFR antibody. Results A total of 2643 mCRC patients treated with systemic therapy were included. Median percent change of CEA from baseline to first restaging for patients with complete response, partial response, or stable disease (non-PD) and PD was −53.1% and +23.6% for chemotherapy alone (n = 957) and −71.7% and −45.3% for chemotherapy with anti-VEGF antibody (n = 1355). The optimal area under the curve cutoff for differentiating PD from non-PD on first restaging was −7.5% for chemotherapy alone and −62.0% for chemotherapy with anti-VEGF antibody; chemotherapy alone, adjusted odds ratio = 6.51 (95% CI = 3.31 to 12.83, P &lt; .001), chemotherapy with anti-VEGF antibody, adjusted odds ratio = 3.45 (95% CI = 1.93 to 6.18, P &lt; .001). A 99% negative predictive value clinical cutoff for prediction of non-PD would avoid CT scan at first restaging in 21.0% of chemotherapy alone and 16.2% of chemotherapy with anti-VEGF antibody–treated patients. Among patients with stable disease on first restaging, those with decreased CEA from baseline had statistically significantly improved progression-free and overall survival. Conclusions Change in CEA from baseline to first restaging can accurately predict non-progression and correlates with long-term outcomes in patients receiving systemic chemotherapy.

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

3517 Background: The combination of oxaliplatin, fluorouracil, and leucovorin is effective in many patients with colon cancer treated in either the advanced or adjuvant disease setting. To better identify the risks & benefits of this regimen for elderly patients we compared safety & efficacy data for the FOLFOX4 regimen (oxaliplatin plus fluorouracil/leucovorin administered bimonthly) in patients over & under 70 years of age. Methods: We conducted a retrospective analysis of 3742 patients (614 aged ≥ 70) with colorectal cancer enrolled in four clinical trials using the same FOLFOX4 regimen as adjuvant therapy, or as first- or second-line therapy in advanced disease. Endpoints included grade ≥ 3 adverse events, response rate (RR) (in studies of advanced disease), progression (metastatic)/relapse free (adjuvant) survival (P/RFS), overall survival (OS), and dose intensity. Results: Age ≥ 70 was associated with slightly higher rates of neutropenia and thrombocytopenia but no other grade ≥ 3 adverse events (see table). There was no difference in 60-day mortality (1.1% vs 2.3%, p=0.20). We observed no significant difference in any measure of therapeutic impact of FOLFOX based on age, including P/RFS, OS, response rate, or dose intensity (see table). Conclusions: The FOLFOX4 regimen maintains its efficacy/safety ratio in elderly patients with colorectal cancer, and was administered per protocol at similar drug doses compared to the younger patients enrolled on these trials. Age alone should not be a factor limiting the use of FOLFOX4 provided patients are carefully evaluated and monitored. This analysis was supported by Sanofi-Aventis [Table: see text] [Table: see text]

89 Background: Monitoring of adverse events (AE) is crucial in clinical trials. Maximum grade per patient (pt) is commonly used but better metrics are needed to aid describing and comparing AE profiles. Methods: We developed and evaluated 2 longitudinal AE summary metrics. 1) Onset time of max grade refers to whether a pt has max grade within pre-specified timeframes for an AE, e.g. onset can be defined as “early” (max grade before the 6th cy) or “late” (≥ 6th cy). 2) Adverse effect load (AEL) is a longitudinal score of worst grade possible excluding death over the entire treatment for an AE. Higher AEL means worst overall experience of AE. We applied these metrics to real trial data. Pts were from 6 mCRC trials included in ARCAD database and received Irinotecan-based (n = 1,119) or Oxaliplatin-based (n = 1,230) treatments that did not include biologicals. AEs were diarrhea, nausea/vomiting, neutropenia/leukopenia, and neuropathy. We used linear model to AEL and logistic model to the other metrics, adjusting for age, sex, and number of metastases. Results: For nausea/vomiting, pts in Oxali-based chemo showed a higher AEL compared to patients in Iri-based (mean (M) [standard deviation (SD)] = 0.04 [0.06] vs. 0.02 [0.04]; p < 0.001) even though less pts had gr ≥ 3 (10.4% vs. 16.2%, resp.; p < 0.001), suggesting a lower-grade but persistent nausea/vomiting for Oxali-based. Among pts with diarrhea max gr 2, pts in Iri-based had higher AEL than with Oxali-based (M [SD] = 0.11 [0.11] vs. 0.08 [0.09]; p = 0.008), indicating more persistent diarrhea for Iri-based trts even among pts with same max grade. For neutropenia/leukopenia, pts in Oxali-based trts experienced higher AEL (M [SD] = 0.09 [0.13] vs. 0.05 [0.11], p < 0.001), and more pts in Oxali-based trts had gr ≥ 3 (70.1% vs. 64.4%; p = 0.002), suggesting that pts in Oxali-based trts experienced worst overall and max grade neutropenia/leukopenia compared to pts in Iri-based. Conclusions: To improve toxicity assessment in clinical trials, AEL and onset time of max grade are new measures that describe the evolution of adverse events over time. Further validation is warranted.