Cox multivariate analysis of overall survival

Comparison of overall survival between patients receiving matched therapy vs. those not receiving matched therapy among patients with any targets recommended for matched therapy.

Design of the whole transcriptome sequencing–based clinical trial platform in MONSTAR-SCREEN-3

Conceptual framework for virtual sequencing using deep learning.

Summary of umbrella and basket trials evaluating the efficacy of targeted biomarker-driven therapies

List of regulatory approvals for targeted therapies and associated clinical trials in SCRUM-Japan MONSTAR-SCREEN project

List of regulatory approvals for companion diagnostic therapeutics in SCRUM-Japan MONSTAR-SCREEN project

169 Background: ACHIEVE-2 was conducted as one of four phase III trials for patients with high-risk stage II colon cancer (CC) investigating the duration of adjuvant (adj) oxaliplatin-based therapy in a prospective pooled analysis, IDEA collaboration. The results of the 7-year follow-up are presented here. Methods: From Feb 2014 to Jan 2017, 525 Asian patients with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation, or vascular invasion) were randomly assigned to 3- or 6-month mFOLFOX6/CAPOX treatment after curative surgery. The cutoff date for the data was Jan 2024. Results: Of the 525 randomized patients, 11 were not treated. Among the 514 participants (255 in the 3-month arm; 259 in the 6-montharm), 432 (84%) received CAPOX and 184 (36%) presented with T4 as a high-risk factor for recurrence. The baseline characteristics of the patients in each arm were well balanced between the treatment arms and two therapy regimens. The 7-year disease-free survival (DFS) rates were 83.4% and 81.8% in the 3- and 6-month arms, respectively (hazard ratio [HR]= 1.00 [95% CI, 0.66-1.53]). The 7-year overall survival (OS) rates were 88.4% and 88.8% in the 3- and 6-month arms, respectively (HR= 1.16 [95% CI, 0.70-1.93]). With CAPOX, the HR for DFS and OS of the 3-month arm compared with the 6-month arm were 0.97 (95% CI, 0.61-1.52) and 1.09 (95% CI, 0.64-1.89), respectively. Multivariate analysis of the six high-risk factors for recurrence showed that T4 and inadequate nodal harvest were independent risk factors for both DFS and OS. The rates of any grade of peripheral sensory neuropathy (PSN) lasting up to 96 months in the 3- vs. 6-month arms were 7.9% vs. 25.0% ( P= 0.0189 ). With CAPOX, the incidence of PSN lasting up to 96 months in the 3- vs. 6-month arms were 9.4% vs. 27.5%. Conclusions: The incidence of long-lasting PSN was significantly lower at 3 months than at 6 months of therapy. Three months of CAPOX therapy may be appropriate for high-risk stage II CC, as shorter treatment did not worsen the outcome, even after a long follow-up. Clinical trial information: UMIN000013036 .

HER2-positive or ERBB2 amplified (ERBB2 amp+) metastatic colorectal cancer (mCRC) is an important subgroup due to emerging HER2-targeted therapies. Although ERBB2 amplification is associated with anti-EGFR antibody resistance, optimal first-line treatment remains unclear. We analysed data from the Flatiron Health-Foundation Medicine CRC clinico-genomic database, including patients with stage IV or recurrent mCRC diagnosed between January 2012 and March 2022 who underwent tissue-based comprehensive genomic profiling. ERBB2 amp+ was defined as an ERBB2 copy number ≥+3 of the tumour base ploidy. Among 5545 patients, 144 (3.1

58 Background: Patients (pts) with HER2-positive (HER2+) metastatic colorectal cancer (mCRC) represent a small, but increasingly important subgroup due to emerging HER2-targeted therapies. Although HER2 positivity is associated with resistance to anti-EGFR therapy (EGFRi), it is unclear if EGFRi or bevacizumab (BEV) is preferable as first-line (1L) therapy. Here, we offer novel evidence on the genomic profiles of pts with HER2+ mCRC and examine differences in survival between key treatment groups. Methods: This study used the US-based deidentified Flatiron Health-Foundation Medicine mCRC clinico-genomic database. The deidentified data originated from approximately 280 US cancer clinics (~800 sites of care). Included pts were 18 years or older, had evidence of stage IV or recurrent mCRC diagnosed between 01 Jan 2012 and 31 Mar 2022, and underwent tissue-based Comprehensive Genomic Profiling testing. HER2+ was defined as an ERBB2 copy number of ≥5 for diploid tumors. A doublet regimen was defined as fluoropyrimidines plus oxaliplatin or irinotecan. Data cut-off was 31 Mar 2024. Kaplan-Meier methods were used to examine real-world overall survival (rwOS) and progression-free survival (rwPFS) overall, by 1L treatment class and across key subgroups defined by tumor sidedness and genomic profile, indexed to the start of 1L with pts censored at their last EHR-recorded activity. Results: Among a cohort of 5545 pts, HER2+ was detected in 171 (3.1%) pts. Median age (years) was 57 for HER2+ vs 61 for HER2-; 69.3% of HER2+ pts were White, compared to 72.1% in HER2-. Among pts with HER2+, 31 (18.1%) had RAS mutation (mt), BRAF V600E mt, or microsatellite instability-high. ERBB2 copy number was significantly lower in pts with RAS mt or BRAF V600E mt compared to those without these mutations (p < 0.01, p = 0.045, respectively). Among pts who received 1L treatment (n=4748), rwPFS significantly differed between HER2+ (n=144) and HER2-negative (HER2-; n=4604) groups (7.6 vs 8.7 months, unadjusted HR (uHR) 1.20, p=0.04). This difference was consistent in pts with left-sided RAS/BRAF V600E wild-type microsatellite stable (MSS) mCRC and treated with 1L doublet plus EGFRi (8.7 vs 12.5 months, uHR 2.18, p=0.02; n=10 HER2+,n=117 HER2-) or 1L doublet plus BEV (8.9 vs 10.5 months, uHR 1.65, p=0.04; n=20 HER2+, n=387 HER2-). No significant rwPFS difference was observed between EGFRi and BEV in the HER2+ subgroup. rwOS showed no significant difference between HER2+ and HER2- groups (overall: 26.1 vs 24.5 months, uHR 0.94, p=0.52; n=144 HER2+, n=4604 HER2-). Conclusions: Although about 80% of pts with HER2-positive mCRC are RAS/BRAF V600E wild-type and eligible for EGFRi, no survival benefit was observed in EGFRi relative to BEV as first-line combination. While the impact of potential confounders needs to be examined in further analyses, these findings highlight the need for specific treatments for pts with HER2+ mCRC.

36 Background: The incidence of eo CRC (age of onset: <50 years) is rising globally, although specific reasons remain unknown. In a prior study using the ARCAD database, the addition of EGFRi to chemotherapy (chemo) significantly improved progression-free survival (PFS) in late-onset (lo) KRAS wild-type (wt) left-sided mCRC patients (pts); however, no such effect was observed in eo mCRC pts (Jin Z et al., 2022). Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database of adult patients diagnosed with mCRC on/after January 1, 2013 with data cut-off on June 30, 2023. The cohort included pts with RAS/BRAF wt and left-sided primary tumors who were treated with first-line (1L) chemo+EGFRi, chemo+bevacizumab (bev), or chemo alone. Associations of disease onset and 1L therapy with real-world overall survival and time to next treatment (rwOS, rwTTNT) were assessed using Kaplan-Meier methods and hazard models adjusted for clinical confounders including year of metastatic diagnosis, group stage at initial diagnosis, site of disease, gender, race/ethnicity, and ECOG performance status. Results: Among 895 left-sided RAS/BRAF wt mCRC pts, 216 and 679 pts had eo and lo mCRC, respectively. In pts treated with chemo+EGFRi vs chemo alone, the adjusted hazard ratio (HR) (95% CI) of rwTTNT was 0.93 (0.56-1.53) and 0.77 (0.58-1.02) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.96 (0.51-1.83) and 0.78 (0.57-1.07) in eo and lo pts, respectively. In pts treated with chemo+bev vs chemo alone, the adjusted HR (95% CI) of rwTTNT was 1.00 (0.62-1.60) and 0.75 (0.58-0.97) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.97 (0.54-1.75) and 0.78 (0.58-1.03) in eo and lo pts, respectively. Conclusions: Adding EGFRi to chemotherapy suggested potential improvements in rwTTNT and rwOS in lo pts but not in eo pts, similar to findings from the prior ARCAD database study. Such differences in outcomes, similarly observed in pts treated with chemo+bev, underscore the need for tailored therapeutic strategies. Given the wide confidence intervals in this study, future research with larger patient cohorts or longer follow-up may yield more precise estimates of these differences. [Table: see text]

The extraction of data that contribute to regulatory approval from real-world data (RWD) is difficult because of the lack of a standardized data format and extraction methodology. Additionally, when real-world evidence (RWE) is used as an external control group, the similarity between internal and external control data is not evaluated. To investigate the data extraction methodology for the external control data of rare molecular subtypes, we have initiated the “REALISE” study. In this study, we aim to elucidate the “relevance” and “reliability” of RWD/RWE necessary for regulatory approval. As most databases are not designed for regulatory use in the creation phase, we will investigate retrospective methodologies to ensure RWD/RWE reliability.This study will compare the “relevance” and “reliability” of the ARCAD global database, SCRUM-Japan Registry, SCRUM-Japan observational study, and Flatiron Health RWD and statistically analyze the differences and similarities among the four databases. We will also examine the methodology for extracting sufficiently relevant data from the SCRUM-Japan observational study. Additionally, if the reliability of the RWD/RWE does not reach the required level for regulatory approval, we will examine the methodologies to ensure the “reliability” of the SCRUM-Japan observational study for regulatory approval. The obtained results will be submitted to the “Consultation for Development of Registry” in the Pharmaceuticals and Medical Devices Agency, and we will discuss the standard methodology. The procedures and findings identified in the REALISE study will be organized from the perspectives of “database construction,” “data analysis,” and “outcome evaluation” and will be issued as “the draft guidelines.”

Through the Clinical Innovation Network, Japan’s regulatory authorities have enhanced the development of registries that utilize real-world data (RWD). The Ministry of Health, Labour and Welfare has issued guidelines, whereas the Pharmaceuticals and Medical Devices Agency has conducted consultations to manage and verify the integrity of these registries, thus improving the framework for the effective use of RWD. The use of cancer registry data as an external control group has been promoted by regulatory bodies and academic institutions. Given the aforementioned background, several high-quality cancer registries, such as the ‘SCRUM-Japan Registry’, ‘MASTER KEY project’, and ‘GALAXY registry’, have been established. The SCRUM-Japan Registry has been instrumental in achieving the world’s first regulatory approval for human epidermal growth factor receptor 2 (HER2)-positive colorectal cancer, demonstrating the value of regulatory-grade registries in managing rare molecular subtypes. However, the broader adoption of registry data for regulatory use in Japan remains limited, primarily owing to the lack of clear standards for using RWD/real-world evidence (RWE) for drug approval. This uncertainty has made pharmaceutical companies hesitant to use such data for regulatory submissions. This review aimed to elucidate the perspectives and related guidelines of the regulatory authorities concerning cancer registries in Japan. In response, the ‘REALISE study’ was initiated to define the ‘relevancy’ and ‘reliability’ of data necessary for new drug approvals and to develop methodologies to ensure data reliability retrospectively. The findings of this study will inform the creation of draft guidelines aimed at broadening the application of RWD/RWE throughout Japan.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4-16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry-academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine.

TPS100 Background: The extraction of the data that contributes to regulatory approval from real-world data (RWD) are difficult due to the lack of standardized data format as well as the extraction methodology. In addition, when RWE is used as an external control group, the similarity between internal and external control data has not been evaluated. Methods: In our ‘REALISE’ study, we will investigate the data extraction methodology as external control data of rare molecular subtype. We also elucidate the 'quality' and 'reliability' of RWD/RWE necessary for regulatory submissions. In addition, as most databases are not designed for regulatory use in the creation phase, we will investigate the retrospective methodologies to ensure reliability of RWD/RWE. We compare ‘data quality’ and ‘data reliability’ of ARCAD global DB (N=45,224), SCRUM-Japan registry (N=546), SCRUM-Japan observational study (N=14,325), and the Flatiron health RWD in Japan (N=650) and statistically analyze the differences and similarities among 4 databases. All analyses will be summarized descriptively. Similarity of patient characteristics and efficacy endpoints such as response rate, progression-free survival, overall survival, and all available endpoints will be evaluated by cancer type, treatment line, and standard treatment. For colorectal cancer, data extracted from the SCRUM-Japan registry, SCRUM-Japan observational study, and the Flatiron health RWD will be compared with data extracted from randomized controlled trials in the ARCAD global DB to examine the availability as an external control of RWD. The Kaplan-Meier method will be applied to estimate the survival distribution of time-to-event data. No imputation method for missing data will be used, and the frequency of missing data will also be summarized. We will also examine the methodology for extracting data with sufficient quality from the SCRUM-Japan observational study. In addition, if the reliability of RWD/RWE does not reach the required level, we will also examine the methodologies to retrospectively assure the reliability of the SCRUM-Japan observational study for regulatory submissions. [Table: see text]

BACKGROUND:Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation.METHODS:HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis.RESULTS:The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.CONCLUSIONS:We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.

In the era of targeted therapy based on genomic alterations, the treatment strategy for metastatic colorectal cancer (mCRC) has been changing. Before systemic treatment initiation, determination of tumour genomic status for KRAS and NRAS , BRAF V600E mutations, ERBB2 , and microsatellite instability and/or mismatch repair (MMR) status is recommended. In patients with deficient MMR and BRAF V600E mCRC, randomized phase III trials have established the efficacy of pembrolizumab as first-line therapy and the combination of encorafenib and cetuximab as second-line or third-line therapy. In addition, new agents have been actively developed in other rare molecular fractions such as ERBB2 alterations and KRAS G12C mutations. In March 2022, the combination of pertuzumab and trastuzumab for ERBB2-positive mCRC was approved in Japan, thereby combining real-world evidence from the SCRUM-Japan Registry. As the populations are highly fragmented owing to rare genomic alterations, various strategies in clinical development are expected. Clinical development of a tumour-agnostic approach, such as NTRK fusion and tumour mutational burden, has successfully introduced corresponding drugs to clinical practice. Considering the difficulty of randomized trials owing to cost–benefit and rarity, a promising solution could be real-world evidence utilized as an external control from the molecular-based disease registry.

PURPOSE Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.