Citations

3579 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 VEGF receptors. Based on FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) data, F was approved by the US FDA for previously treatedmetastatic colorectal cancer (mCRC). Efficacy and safety of F + best supportive care (BSC) vs placebo (P) + BSC were analyzed according to prior treatment (tx) sequence using FRESCO and FRESCO-2 data. Methods: In FRESCO and FRESCO-2, patients (pts) were randomized 2:1 to receive F 5 mg or matching P, PO daily x 21 days every 28 days. In FRESCO, eligible pts had received ≥2 prior chemotherapy regimens and were permitted to have received prior anti-VEGF and/or anti-EGFR therapies, whereas in FRESCO-2, in addition to standard chemotherapies, anti-VEGF, and anti-EGFR therapies if indicated, prior exposure to trifluridine/tipiracil (TAS) and/or regorafenib (rego) was required. FRESCO-2 pts must have also received a BRAF inhibitor and/or immunotherapy, if indicated and available in their country. Results: In FRESCO (F n=278 vs P n=138), no pts had received rego and 16/416 pts (4%) had received TAS. InFRESCO-2, prior therapies were balanced between F vs P arms; pts had received prior TAS or rego in these sequences: prior TAS only (n=240 vs n=121); prior rego only (n=40 vs n=18); prior rego then TAS (n=84 vs n=45); prior TAS then rego (n=95 vs n=44). Improvements in OS and PFS were seen with F vs P regardless of prior tx sequence (Table), with similar magnitudes of benefit for OS (HRs 0.53–0.77) and PFS (HRs 0.25–0.37). F safety profile was consistent regardless of prior tx sequence (Table). Conclusions: F is effective in mCRC with a manageable safety profile regardless of prior TAS or rego tx and sequence. Improvement with F was similar for OS and PFS despite the number and sequence of prior regimens. F provides a new tx option for pts with previously treated mCRC regardless of prior TAS or rego exposure. Clinical trial information: NCT04322539 . [Table: see text]

3523 Background: Evidence suggests neurotransmitter signaling may play a crucial role in tumorigenesis of gastrointestinal (GI) cancers, including migration, proliferation, and apoptosis, as well as angiogenesis and the microenvironment. We developed and applied a strategy to identify upstream regulators of neurotransmitters and their associations with patient outcomes. Methods: Prior literature yielded 85 neurotransmitter signaling genes mapped to RNA-seq gene expression in tumor tissue from 545 patients with mCRC enrolled in the phase III CALGB/SWOG 80405 trial. These samples were also sequenced by FoundationOne CDx for DNA damage. Using Cox proportional hazards regression, we identified a subset of CDx genes associated with overall survival (OS) or progression-free survival (PFS). We extended the Causal Inference Test (CIT) for time-to-event data and identified a subset of the 85 signaling genes consistent with mediation of DNA mutation effects on OS and PFS. Another CIT analysis identified potential upstream neurotransmitter regulators, gene expression mediators of mutation effects on the signaling genes. Top genes were then assessed in whole-transcriptome sequencing (WTS) expression data with Caris MI profile collected from 398 patients with advanced CRC enrolled in the MONSTAR-SCREEN-2 trial. Results: At the 0.05 alpha level, we identified 20 signaling genes with gene expression associated with PFS and/or OS, and 68 genes with evidence of DNA mutations associated with PFS and/or OS. False discovery rate (FDR) < 0.05 was applied to filter the 56,674 expression features on PFS and OS associations, yielding 173 unique genes as possible mediators. The CIT yielded 53 putative mediators at FDR < 0.05, suggesting upstream regulation of neurotransmitter signaling. Five genes were identified as targeting at least 8 signaling genes each, PIGU, ANO9, LY6G6D, and GPR160, and FSCN1, where the first 4 are favorable and only FSCN1 is a poorer prognostic. Following up on these 5 genes in MONSTAR-SCREEN-2 by dichotomizing at the median value of WTS expression, 3 were nominally associated with OS, PIGU ( P = 0.050; HR, 0.59; 95%CI, 0.34-1.00), ANO9( P = 0.029; HR, 0.55; 95%CI, 0.32-0.95), LY6G6D( P = 0.0024; HR, 0.44; 95%CI, 0.25-0.76), and FSCN1 was suggestive ( P = 0.079; HR, 1.62; 95%CI, 0.94-2.77), with direction of effects in agreement with 80405 results for all four. Conclusions: Our novel approach identified previously unknown upstream regulators of neurotransmitter signaling associated with treatment outcomes in mCRC. PIGU, FSCN1, and LY6G6D have been suggested in prior literature as targets for CRC and ANO9 has been suggested as a target for GI cancer. These results bolster the strategy of using mediation analysis with large-scale molecular data to identify new therapeutic targets in CRC. NCT00265850.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Background Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). Methods CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. Results From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3–4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. Conclusions The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. Trial registration number NCT03414983 .

538 Background: In biliary tract cancer (BTC), TP53 is the most commonly altered gene and may co-occur with KRAS alteration. The presence of a co-alterations in of TP53 and KRAS is associated with poor prognosis in many cancers. In patients (pts) with advanced BTC, the prognostic implications of such co-alterations have not been fully investigated. Methods: This is a pooled analysis of SCRUM-Japan GOZILA and MONSTAR-SCREEN-1 and -2 studies. Genomic profiling was conducted with Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Pts with advanced BTC receiving systemic therapy were included in this study. Results: Among 636 pts with advanced BTC, 85 had TP53/KRAS co-alteration, 293 had TP53, 44 had KRAS, and 214 had neither KRAS nor TP53 alteration (WT/WT). Tumors with TP53 alteration had significantly higher level of tumor mutation burden (TMB) compared to the other groups (3.8 mut/Mb for TP53/KRAS, 5.0 mut/Mb for TP53, 2.8 mut/Mb for KRAS, and 2.5 mut/Mb for WT/WT, respectively, P<0.001). In addition, the frequency of microsatellite instability-high (MSI-High) in the TP53/KRAS group (11.0%) was significantly higher compared to the TP53 group (3.1%, P<0.05), and the WT/WT group (0.6%, P<0.001), respectively. The objective response rate of first-line therapy in the TP53/KRAS group (8.2%) was significantly lower than in the other groups (20.8% for TP53, 23.3% for KRAS, and 19.7% for WT/WT groups, P=0.035). There was no pts treated with durvalumab plus gemcitabine and cisplatin. Two pts with TP53/KRAS alteration and MSI-High received pembrolizumab monotherapy, and partial response was achieved with a progression-free survival of 9.4 and 22.0 months. The median overall survival (OS) for pts treated with first-line therapy of the TP53/KRAS, KRAS, TP53, and WT/WT groups were 13.6 (95% confidence interval [CI], 11.5-15.5), 14.3 (95%CI, 9.7-25.9), 18.8 (95%CI, 16.9-20.6), and 22.7 months (95%CI, 20.4-25.9), respectively. Multivariate analysis identified TP53/KRAS alteration (hazard ratio [HR] 2.14, 95%CI 1.43-3.22, P<0.001), number of detected variants (≥2) (HR 1.50, 95%CI 1.04-2.16, P=0.029), locally advanced (HR 1.72, 95%CI 1.05-2.83, P=0.033), and metastatic status (HR 1.78, 95%CI 1.39-2.28, P<0.001) as independent prognostic factors for shorter OS. Conclusions: Patients with advanced BTC with co-occurring TP53/KRAS alterations have worse prognosis. Interestingly, the presence of these co-alterations was associated with a higher likelihood of MSI-High phenotype.

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]

544 Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.