Chibaudel, Benoist

3572 Background: Early onset colorectal cancer (eoCRC: disease diagnosed < 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HRadj], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p<0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]

Abstract Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged &gt;70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status &gt;0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

80 Background: Higher baseline body mass index is associated with improved survival in metastatic CRC (mCRC). Whether weight gain or loss after mCRC diagnosis is associated with survival remains largely unknown. Methods: We analyzed individual patient data from 3504 patients with previously untreated mCRC enrolled in five phase III randomized trials (AVF2017g, AVF2192g, CRYSTAL, N9741, OPUS) conducted between 2000 and 2006. Weight measurements were prospectively collected at 3 months after diagnosis and then up to 5 years. Patients were categorized into three groups based on the percent weight change at 3 months: stable weight or gain, weight loss up to 5% of baseline weight, and ≥5% weight loss of baseline weight. Cox models were used to assess the prognostic associations of weight change at 3 months with overall survival (OS) and progression-free survival (PFS), adjusting for baseline BMI, age, sex, performance score, chemotherapy backbone (oxaliplatin vs. irinotecan), and biologics type (cetuximab vs. bevacizumab). Sub-analyses included Cox models adjusted for additional clinical-pathological factors (primary tumor sidedness [right colon vs. left colon-rectum], and BRAF status; N=1,511). Results: Median percent weight change at 3 months was -0.5% (IQR -4.0 to+1.6%). OS was better in patients with weight stability or gain than in those with weight loss (up to 5% or ≥5%; (Table). Results were consistent for PFS for patients with ≥5% weight loss of baseline weight, as well as for sub-analyses. Conclusions: Patients losing weight during the first 3 months of systemic therapy for metastatic colorectal cancer have significantly shorter overall survival than those with stable or increasing weight. Degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight and obese individuals. Further studies examining possible usefulness of on-treatment early weight loss as a novel intermediary end-point are needed.[Table: see text]

Abstract Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.

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

3575 Background: Pts with mCRC frequently receive ≥1 sequential treatment TL. Approximately 50%-60% of pts receive second-line (L2) and 20%-30% third-line (L3) regimens in routine practice. We investigated the pts clinical/tumor characteristics and their prognostic impact across TL. Methods: Data from 37,560 pts enrolled in 48 randomized trials (34 in first (L1), 9 in L2, and 5 in L3) were analyzed. Candidate variables (VAR) measured at enrollment were sex, age, body mass index, performance status (PS), bilirubin, hemoglobin (Hb), platelets (Pl), derived white blood cells-to-absolute neutrophil counts ratio (WBC/ANC), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), primary tumor location, and number and location of metastatic sites (MS). Missing data were imputed. VAR with significant value at all TL were selected to construct a prognostic score of overall survival (OS) in training set (TS, n=30,050; 80%). For each TL, the score was calculated as the sum on the estimations of the VAR’ coefficients from the common multivariate model; Cox’s model was used to define risk groups. The discrimination capability was assessed using the Harrell’s C-index. External validation was done in the validation set (VS, n=7,510; 20%). Results: A total of 26,974 pts in L1, 7,693 pts in L2 and 2,893 pts in L3 were analyzed. The following characteristics increased continuously over TL: ≥2 MS (57%, 72%, 82%), lung metastases (50%, 74%, 91%), lymph nodes metastases (51%, 61%, 80%), KRAS mutation (37%, 47%, 51%) and elevated ALP (46%, 52%, 61%). BRAF mutation decreased (9%, 7%, 5%). In L1 vs L3 trials, 70% vs 89% of patients had primary tumor resection, 10% vs 80% had at least one metastasectomy and 31% vs 78% had a late metachronous (>12 months) metastasis. 7 independent VAR were retained in the prognostic score (PS, Hb, Pl, WBC/ANC, LDH, ALP, and the number of MS); four pt groups with significantly different prognoses were defined (table). This score remained valid when excluding pts with PS 2. Third-line oral drugs (vs placebo) and subsequent line (L2/L1 or L3/L2) were effective in all prognostic groups. Conclusions: Clinical/tumor pt characteristics significantly varied over subsequent TL in patients included in randomized trials. The same prognostic model using practical clinical and biological variables can be used in all TL.[Table: see text]

Abstract Background Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. Methods PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Results Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P &lt; .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P &lt; .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction &lt; .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P &lt; .001) but not for right-sidedness. Conclusions The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

Abstract Background First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. Methods Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. Results A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). Conclusions Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]