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Abstract Background Synthetic control arms (SCAs) derived from historical trial data can complement randomized controlled trials (RCTs), particularly in oncology where feasibility, ethical, and cost constraints may limit conventional trial designs. However, their validity for overall survival (OS) remains uncertain. We evaluated the feasibility and limitations of constructing SCAs from the ARCAD metastatic colorectal cancer (mCRC) database across multiple treatment lines. Methods Seven landmark RCTs representing first-, second-, and third-line settings were selected. External control arms were constructed from ARCAD individual patient-level data using propensity score matching based on key clinical and biological variables from a validated ARCAD prognostic score, with adjustment for geographic region and time era when needed. A prespecified two-step benchmarking framework assessed: (1) control-arm OS reproducibility and (2) virtual trial comparisons between matched synthetic controls and original RCT experimental arms. Agreement was evaluated using hazard ratios (HRs) and Z-tests. Results A total of 28,022 patients met the inclusion criteria. ARCAD-derived SCAs were successfully constructed for all selected RCTs and closely reproduced control-arm OS. After matching, baseline characteristics were well balanced, with minimal differences between included and excluded patients. Virtual trials showed concordant treatment-effect estimates with the original RCTs, with a median absolute HR deviation of 0.05 and no significant differences by Z-tests (P>.05). Survival outcomes were consistently reproduced across treatment lines. Conclusion ARCAD-derived SCAs reliably reproduced control-arm OS and benchmark treatment-effect estimates from landmark RCTs in mCRC. Despite limitations related to residual confounding and missing data, this framework supports benchmarking, trial design, and exploratory analyses when conventional control arms are impractical.

PURPOSE Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to develop an overall prognostic score (OPS). PATIENTS AND METHODS Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox's model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices. Internal validation was done in the validation set. RESULTS A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs ( v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups. CONCLUSION The same prognostic model using practical variables can be used before all treatment lines. The OPS could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.

PURPOSE The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; P int = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P < 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT<.001). Conclusions: In pts with multiple sites mCRC, a statistically sig OS bnf of BEV added to CT was observed mainly among pts without lung mets. The overall effect of CT partner choice when combined with BEV can be different. In pts with single site, BEV did not seem to improve OS but the evaluation of efficacy of BEV in presence or absence lung mets was based on small number of pts and needs to be evaluated in trials with larger pts sample, especially trials including pts with single site lung mets. [Table: see text]

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

3606 Background: Standard adjuvant CT for stage III CC are FOLFOX and CAPOX. Recently, IDEA study separated stage III patients (pts) into low risk (T1 to 3, N1) and high risk (T4 or N2). We recently confirmed benefit of OX in both risk groups. However, we observed a difference in the two high-risk subgroups, with benefit in N2 but not in T4 (Margalit O et al; Clin Colorectal Cancer 2021). This prompted us to compare outcomes (OS/TTR) between treatment with OX vs. without OX within sub-stage III CC groups defined by T and N. Methods: We pooled 4941 stage III CC pts from the three studies evaluating 6 months of CT with fluoropyrimidine (FP) ± OX: MOSAIC, C-07 and XELOXA. Baseline characteristics were compared using χ2 and t-test. OS was compared between OX and no OX in T and N subgroups. Kaplan-Meier analyses, adjusted and unadjusted Cox models stratified by study were used. Sub-groups classification was done according to OX benefit and verified by interaction test (Int) considered as significant with a P<0.1. We considered for recommendation of using OX-based adjuvant CT, 1) significant benefit in OS, 2) significant Int between substage and adjuvant therapy, and 3) the three individual trials showing similar results (benefit or non-benefit of OX). Results: In stage III population, T3 pts were 74.9%, T1-2 12.4%, T4 13.1%, while N stage was N1 64.7% and N2 35.3%. Population was well balanced according to treatment allocation in most subgroups. A significant benefit of OX was only observed in T3N1 and T3N2 (OS HR 0.76). Whatever N stage, there was no significant benefit of OX in the T1-2 and T4 subgroups. The effect of OX+FP vs FP alone in OS of the three studies differed between T3 and T1-2 subgroups (P = 0.047). Interaction was borderline between T3 and T4 subgroups (P = 0.10) but there was no interaction between T1-2 and T4 subgroups (P = 0.429). A benefit of OX in TTR remained in the T4 population. Discrepancy between advantage in time to relapse (TTR) and no advantage in OS was not explained by survival post relapse. Conclusions: Our analysis suggested that pts with T1-2N1-2 and T4N1-2 disease had no OS benefit of addition of OX to FP. The good survival achieved with FP alone in T1-2N1-2 pts (5-yr OS 89%) question the addition of OX. In the T4 population our results suggested that benefit of OX was limited and that further studies should assess this issue or at least stratify pts on T stage in the future adjuvant trials in CC. [Table: see text]

3578 Background: Monoclonal antibodies (mab) targeting EGFR are recommended in L1 treatment (trt) for mCRC in patients (pts) with RAS wild-type (WT) tumor and primary left CRC. ARCAD database contains individual data of randomized trials that evaluated anti-EGFR mab plus chemotherapy (CT). In this analysis we aimed to evaluate anti-EGFR benefit in mCRC with lung mets, either as single site or multiple sites. Methods: Individual pts data from four trials (PRIME, CRYSTAL, COIN, OPUS) comparing CT +/- anti-EGFR were pooled. KRAS status was not required at inclusion to these studies. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method, prognostic value of lung mets was evaluated by stratified Cox models in pts groups defined by KRAS status. The predictive value was evaluated by interaction test (Int) between trt and lung mets status in pts group defined by KRAS status and considered as significant with a P < 0.1. Results: 3681 pts with known KRAS status were included, 2171 WT and 1510 mutant (MT). Pts characteristics were well balanced. Significant median OS benefit of anti-EGFR was observed in the whole KRAS WT population and in the left colon and rectum subgroup but not in the right colon subgroup. In pts with KRAS WT single site mets, a non-significant benefit of anti-EGFR was observed only among pts without lung mets (N = 642). In pts with lung single site mets (N = 129), a significant benefit ( P= 0.018) in the KRAS MT population (N = 55) was observed, but Int was non-significant ( P =0.157). In pts with KRAS WT and multiple without lung mets sites (N = 673), no benefit of anti-EGFR was observed and Int was significant ( P= 0.054). Pts with KRAS MT multiple sites with (N = 656) or without (N = 397) lung mets, had no benefit of anti-EGFR. The same findings were found in the left primary pts and in the two fluoropyrimidine backbone. PFS analyses confirm the OS results. Conclusions: In this ARCAD analysis pts with lung mets as a single site appear to benefit from anti-EGFR L1 therapy in case of KRAS MT. This unexpected result based on a limited sample size cannot be explained on the knowledge of anti-EGFR therapy. Furthermore, pts with multiple mets sites have a benefit of anti-EGFR therapy only in the presence of lung mets even in KRAS WT left primary tumor. These findings need further confirmation and may initiate the search for a specific molecular phenotype associated with lung mets in CRC pts. [Table: see text]

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]

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.