Misumi, Toshihiro

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.

e15557 Background: In metastatic colorectal cancer (mCRC), systemic chemotherapy can enable conversion surgery in a subset of patients with initially unresectable disease. Although R0 resection considered a key determinant of long-term survival, its clinical impact across heterogeneous trial populations and treatment strategies remains insufficiently defined. We aimed to clarify the survival benefit of R0 resection after first-line chemotherapy using large-scale individual patient data. Methods: Using the ARCAD database, which comprises 67 randomized clinical trials and approximately 47,000 patients, we conducted a pooled analysis of individual patient data from six first-line randomized clinical trials (COIN, COIN-B, 03-TTD-01, ATOM, SOFT and PARADIGM) for which data on R0 resection were available. Patients with initially unresectable mCRC and available surgical data were categorized into three groups: R0 resection, non-R0 resection, and no surgery. All R0 cases were included, comprising liver-only, lung-only, combined liver and lung metastases, and peritoneal dissemination or other metastatic sites. Overall survival (OS) and progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards models adjusted for age, sex, and performance status. Pre-specified subgroup analyses examined the consistency of outcomes according to tumor response, metastatic site, primary tumor sidedness, RAS status, and targeted therapy class. Results: Among 4,445 eligible patients, 263 underwent R0 , 233 underwent non-R0 resection, and 3,949 received no surgical intervention. The R0 resection group comprised patients with liver-only metastases (n = 176), lung-only metastases (n = 23), and combined liver and lung metastases (n = 27). R0 resection was associated with significantly improved OS and PFS compared with both non-R0 resection and no surgery. These survival benefits were consistently observed across key clinical subgroups, including patients achieving complete or partial response to chemotherapy, those with liver or lung metastases, left- and right-sided primary tumors, and both RAS wild-type and mutant disease. Importantly, the benefit of R0 resection was maintained irrespective of anti-EGFR– or anti-VEGF–based first-line therapy. Conclusions: R0 resection following systemic chemotherapy is strongly associated with durable survival benefits in patients with initially unresectable mCRC across diverse clinical settings. These findings support the pivotal role of conversion strategies and highlight the importance of multidisciplinary evaluation to identify appropriate candidates for curative-intent resection.

Abstract Background Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti–epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. Methods We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. Results Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR–based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. Conclusions Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

Abstract Background: Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain. Methods: Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment, if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT scans and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml. Results: Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, which did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05; P = 0.107). The benefit was highly pronounced, however, in stage IV pts (HR: 0.53, P = 0.012). In addition, after excluding pts with low ctDNA levels (<0.179 MTM/mL, threshold determined by ROC analysis) from both arms, significant benefit with FTD/TPI was observed in the primary population, resulting in an improved DFS (N=154, HR: 0.61 95% CI: 0.43-0.85; P = 0.003) with a median DFS of 8.12 months for FTD/TPI vs. 3.89 months for placebo; consistent with these findings, a trend toward higher ctDNA clearance rate was observed for the FTD/TPI group (8.33%), compared to placebo (4.05%).OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals. Conclusions: Although statistical significance was not reached in the primary population, FTD/TPI showed benefit in pts with high molecular tumor burden and/ or Stage IV disease, resulting in improved DFS. Citation Format: Hideaki Bando, Jun Watanabe, Masahito Kotaka, Nobuhisa Matsuhashi, Eiji Oki, Yoshito Komatsu, Manabu Shiozawa, Keiji Hirata, Yuji Miyamoto, Kun-Huei Yeh, Shruti Sharma, Vasily Aushev, Adham Jurdi, Minetta C. Liu, Alexey Aleshin, Ichiro Takemasa, Daisuke Kotani, Akihito Sato, Toshihiro Misumi, Yoshiaki Nakamura, Qian Shi, Hiroya Taniguchi, Takeshi Kato, Takayuki Yoshino. A randomized, double-blind, phase III study comparing trifluridine/tipiracil (FTD/TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): The ALTAIR Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT131.

LBA22 Background: Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain. Methods: Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml. Results: Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, but this difference did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05; P = 0.107). The FTD/TPI benefit was highly significant in resected oligometastatic stage IV pts as shown in Table. The baseline MTM/ml levels were significantly higher in resected oligometastatic Stage IV pts vs non-Stage IV (0.68 vs 0.32, P = 0.024). Overall, FTD/TPI benefit was significantly pronounced with higher MTM/mL, with linear benefit observed with increasing MTM/mL values at the enrollment time point. OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals. Conclusions: Although statistical significance was not reached in the primary population, FTD/TPI showed clinically meaningful DFS benefit in pts with resected oligometastatic disease and a trend towards increasing DFS benefits with increasing MTM/mL values. Clinical trial information: NCT04457297 . Number Baseline MTM/ml Median DFS FTD/TPI(months) Placebo (months) Primary population 243 0.40 9.30 5.55 HR, 0.79 P = 0.107 Stage IV 66 0.68 9.76 3.96 HR, 0.53 P = 0.012 Non-Stage IV 177 0.32 9.26 6.05 HR, 0.86 P = 0.378

115 Background: Randomized clinical trials provide the best evidence for the effects of a new treatment. However, the use of a placebo control arm may present practical and ethical concerns for enrolled patients and treating providers. The CRC ARCAD global database includes a total of 1,673 individual patient data (IPD) treated with placebo plus best supportive care in a salvage-line setting for refractory mCRC. By using placebo IPD, we have proposed to construct a synthetic control arm for clinical trials (Yoshino T. et al., Nature Medicine 2023). Methods: From 40,889 IPD from 59 studies in ARCAD mCRC database, 723 placebo pts were selected from 4 placebo-controlled randomized studies in a salvage-line setting (CORRECT, RECOURSE, CONCUR and TERRA). We analyzed the impact of baseline patient characteristics and various prognostic factors on outcome in the placebo control. Results: The adjusted hazard ratios (HRs) (95% confidence interval [CI]) were 0.52 (0.40-0.67) for the number of metastatic sites (1 vs 2+), 0.71 (0.59-0.84) for ECOG performance status (PS) (0 vs 1), 0.54 (0.45-0.66) for liver metastases (No vs Yes), 0.54 (0.40-0.71) for peritoneal metastases (No vs Yes), and 0.51 (0.38-0.70) for Royal Marsden Hospital (RMH) Score (consisting of albumin level, number of metastatic sites, and LDH level) (0-1 vs 2-3). Conclusions: Number of metastatic sites, ECOG PS, liver metastasis, peritoneal metastasis and RMH Score were significant prognostic factors in patients with mCRC receiving placebo in a salvage-line setting. Further prognostic factors should be investigated to increase the accuracy of the proposed synthetic control arm. [Table: see text]

107 Background: The "No Placebo Initiative" demonstrated that the survivals of patients (pts) receiving placebo in a salvage-line setting, exhibited no significant difference across trials (CORRECT, RECOURSE, CONCUR and TERRA). Therefore, we believe that a nomogram can be generated using the ARCAD database to predict survival of pts who completed standard therapy. Methods: Of 40,889 Individual patient data (IPD) from 59 studies, 723 pts received placebo from 4 randomized studies were pooled. The potential prognostic factors considered include BMI and Age. Imputed datasets were constructed by a multiple imputation method since the original dataset contains some missing values. Overall survival (OS) was defined as the time from randomization to death from any cause. Multivariate Cox proportional hazards models for OS were estimated based on the variables showing clinically and statistically significant by univariate analysis. Prediction performance of the final model was evaluated using the concordance index for survival data and calibration plots. Results: From univariate and multivariate analysis, ECOG performance status, Royal Marsden Hospital score (calculated by albumin level, LDH level, and number of metastatic site), primary site location, liver meta, peritoneal meta were selected as variables. We successfully developed a highly accurate nomogram to predict post-standard treatment prognosis for pts with mCRC. Concordance index for OS was 0.66. Conclusions: Although further validation in other cohorts is needed, this nomogram could be very useful to estimate the survival for clinical practice and enrolling in clinical trials. [Table: see text]

3588 Background: Although anti-EGFR antibody plus doublet chemotherapy has become the standard of first-line treatment for RAS wild-type (wt), left sided metastatic colorectal cancer (mCRC), the optimal molecular-targeted therapy for RAS wt, right-sided mCRC is not clear. Methods: To evaluate the efficacy between anti-EGFR antibody vs. bevacizumab combination therapy, from 40,889 Individual patient (pt) data from 59 studies in ARCAD mCRC database, 723 pts with RAS wt, right-sided mCRC who received a first-line molecular-targeted therapy with backbone chemotherapy (FOLFOX/FOLFIRI when anti-EGFR antibody combination, and FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI when bevacizumab combination) were selected from 10 randomized studies (FIRE-3, CALGB80495, CRYSTAL, PRIME, CAIRO2, OPUS, TRIBE, TRIBE2, ATOM, and CCOG1201). Primary objective was overall survival (OS), and secondary objectives were progression-free survival (PFS) and overall response rate (ORR); Hazard ratio (HR) and Odds ratio (OR) were adjusted for ECOG-PS, age, and gender. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) as sensitivity analysis were also performed. Secondary analyses were limited to BRAF wt pts. Results: Anti-EGFR antibody and bevacizumab were administrated in 329 and 394 pts, respectively, of whom 162 and 151 pts were BRAF wt, respectively. Baseline characteristics were as follows (anti-EGFR antibody/bevacizumab): median age, 63.0 years both; female, 47.1/46.4%; and ECOG-PS 0, 53.2/65.2%. The OS and PFS were significantly prolonged in pts receiving bevacizumab combination therapy compared to those receiving anti-EGFR antibody combination therapy (Table). These trends were more pronounced when limited to BRAF wt pts (Table). There were no significant differences in ORR for both overall and BRAF wt pts. These results were similar in the sensitivity analysis (Table). Conclusions: For patients with RAS wt or RAS/ BRAF wt, right-sided mCRC, bevacizumab combination therapy is preferred first-line treatment. [Table: see text]

3566 Background: According to the various types of clinical trials for metastatic colorectal cancer (mCRC), ETS and DpR are suggested as the surrogates of OS. Whereas associations between ETS/DpR and OS/PPS in the era of chemotherapy (chemo) +anti-EGFR antibody (ab)/bevacizumab (bev) in 1st line therapy have not been elucidated. Methods: From 40,889 Individual patient data (IPD) from 59 studies in ARCAD mCRC database, 2,138 treatment-naïve pts with RAS wild-type (wt) mCRC were selected from 7 randomized studies (PRIME, CAIRO2, CRYSTAL, OPUS, CALGB80495, WJOG4407G, ATOM) of chemo with/without anti-EGFR ab or bev. The ETS was defined as 20%≥ tumor shrinkage at 8 ± 2wks (ETS+: ≥20%, ETS-: <20%). Multivariate Cox regression models for OS/PPS were performed to investigate associations between ETS+ and ETS- by primary tumor location (overall/left-sided/right-sided), adjusting for potential confounders. DpR was defined as tumor shrinkage at nadir. OS/PPS were evaluated across quartile limits of DpR by multivariate Cox regression models. Results: In pts with overall or left-sided RAS wt mCRC, adjusted hazard ratios (HRs) of OS/PPS between ETS- and ETS+ for chemo +anti-EGFR ab, chemo +bev, and chemo alone showed great improvement, respectively (Table). In pts with overall or left-sided RAS wt mCRC, HRs of ETS for OS/PPS are higher in pts treated with chemo +anti-EGFR ab compared to those treated with chemo +bev or chemo alone. Compared to the pts with highest quartile (defined as ≥ 75th percentile (Q3)) of DpR, HRs of OS/PPS for lower quartile groups showed upward trends in pts with RAS wt & overall (Table). Conclusions: ETS/DpR in pts with RAS wt mCRC might be a potential prognostic marker of OS/PPS regardless of targeted therapy and primary tumor location. Superior prognostic values of ETS+ are expected in pts treated with anti-EGFR ab. [Table: see text]