Molecular-targeted Agents Research Articles

Phase II study of FOLFIRI with low-dose irinotecan plus ramucirumab as second-line treatment in Japanese patients with metastatic colorectal cancer (RINDO study).

124 Background: Phase III trials (ML18147, VELOUR, and RAISE trials) of second-line combination therapy with molecular-targeted agents after first-line treatment with bevacizumab (BEV) for metastatic colorectal cancer (mCRC) demonstrated significant improvements in overall survival (OS). In the RAISE trial (irinotecan (IRI) dose: 180 mg/m²), the relative dose intensity (RDI) of IRI was lower (63.8%) and the incidence rates of adverse events leading to discontinuation of cytotoxic agents was higher (48.6%) in the Japanese population compared to all patients. Based on these results, we conducted a prospective trial to evaluate the efficacy and safety of fluorouracil, levofolinate, and IRI (150 mg/m², standard dose in Japan) (FOLFIRI) plus ramucirumab (RAM) as second-line treatment for mCRC in Japanese patients. Methods: On day 1 of each 2-week cycle, patients with unresectable mCRC who were refractory to oxaliplatin and fluoropyrimidine in combination with BEV or anti-epidermal growth factor receptor (EGFR) antibodies as first-line treatment received 8 mg/kg RAM, followed by the FOLFIRI regimen with low-dose IRI (150 mg/m²). The primary endpoint was progression-free survival (PFS), and secondary endpoints were OS, treatment compliance, and safety. We hypothesized an RFS threshold of 4.3 months and expected RFS of 5.7 months based on data from a Japanese subgroup of the RAISE trial. The protocol treatment was considered to be effective if the lower limit of the 95% confidence interval (CI) exceeded the 4.3-month threshold. Results: A total of 62 patients were enrolled from 15 institutions between January 2018 and August 2021. The intent-to-treat and safety populations included 61 and 58 patients, respectively. The cutoff date for the primary analysis was December 2023. Median PFS and OS were 5.9 months (95% CI, 4.8-6.9 months) and 17.0 months (95%CI, 12.0-21.0 months), respectively. Median PFS was 5.7 months (95% CI, 4.4-6.8 months) in patients treated with first-line chemotherapy with BEV and 7.4 months (95% CI, 4.6-11.0 months) in those treated with first-line chemotherapy with anti-EGFR antibodies (hazard ratio [HR], 1.17; 95% CI, 0.64-2.12; p = 0.60), and median OS was 19.8 months (95% CI, 10.4-22.4 months) and 17.5 months (95% CI, 11.5-26.1 months), respectively (HR, 0.96; 95% CI, 0.52-1.78; p = 0.91). The objective response rate and disease control rate were 8.2% and 74%, respectively. Median RDI of IRI, 5-fluorouracil, and RAM were 73.8% (range, 40.3-102.4%), 58.5% (range, 22.8-102.4%), and 80.8% (range, 36.1-102.4%), respectively. The observed Grade ≥3 adverse events included neutropenia (40%), anemia (1.7%), diarrhea (8.6%), fatigue (6.9%), decreased appetite (10%), hypertension (6.9%), and proteinuria (3.4%). Conclusions: FOLFIRI with low-dose IRI plus RAM is a feasible second-line treatment in Japanese patients with mCRC. Clinical trial information: jRCTs041180074 .

The Prognostic Value of CRP/Alb Ratio in Predicting Overall Survival for Hepatocellular Carcinoma Treated with Transcatheter Intra-Arterial Therapy Combined with Molecular-Targeted Agents and PD-1/PD-L1 Inhibitors.

This study aimed to evaluate the prognostic value of C-reactive protein to albumin (CRP/Alb) ratio in hepatocellular carcinoma (HCC) treated with transcatheter intra-arterial therapy combined with molecular targeted agents (MTAs) and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. Medical records of 271 consecutive patients with HCC receiving this combination therapy in China between 2019 and 2023 were retrospectively analyzed. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were identified using univariate and multivariate Cox regression analyses. The discriminatory capability of inflammation-based prognostic scores-including the CRP/Alb ratio, C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) score, modified Glasgow prognostic score (mGPS), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)-was assessed using the area under the curve (AUC). A total of 133 patients met the inclusion criteria. The optimal cutoff value for the binary classification of CRP/Alb ratio in predicting OS, as determined using X-tile software, was 0.02. Multivariate analysis identified the CRP/Alb ratio (hazard ratio [HR] = 2.61, p < 0.001), tumor size (HR = 2.45, p = 0.018), and extrahepatic metastases (HR = 1.93, p = 0.015) as independent predictors of OS. For PFS, significant factors included Eastern Cooperative Oncology Group Performance Status (HR = 1.55, p = 0.033) and macrovascular invasion (HR = 1.48, p = 0.046). Patients with higher CRP/Alb ratios were more likely to experience fever and fatigue. The CRP/Alb ratio demonstrated significantly higher AUCs than PLR and SII at 24 months (all p < 0.05) and showed comparable AUCs to CRAFITY score and mGPS at 12, 24, and 36 months. The CRP/Alb ratio is a valuable prognostic marker for predicting OS and treatment-related adverse events in HCC patients receiving transcatheter intra-arterial therapy combined with MTAs and PD-1/PD-L1 inhibitors. This ratio can be used as a simple and reliable biomarker for assessing prognosis and guiding patient selection in clinical practice.

Molecular and immune landscape of hepatocellular carcinoma for therapeutic development.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents (MTAs) and immune checkpoint inhibitors (ICIs) and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein (AFP), glypican-3 (GPC3), and epithelial cell adhesion molecule (EpCAM) have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

Fibrocytes in tumor microenvironment: Identification of their fraction and novel therapeutic strategy.

Fibrocytes were identified as bone marrow-derived myeloid cells that also have fibroblast-like phenotypes, such as ECM production and differentiation to myofibroblasts. Although fibrocytes are known to contribute to various types of tissue fibrosis, their functions in the tumor microenvironment are unclear. We focused on fibrocytes as pivotal regulators of tumor progression. Our previous studies have indicated that fibrocytes induce angiogenesis and cancer stem cell-like phenotypes by secreting various growth factors. In contrast, immune checkpoint inhibitor (ICI)-treated fibrocytes demonstrated antigen-presenting capacity and enhanced antitumor T cell proliferation. Taken together, these findings indicate that fibrocytes have multiple effects on tumor progression. However, the detailed phenotypes of fibrocytes have not been fully elucidated because the isolation of distinct fibrocyte clusters has not been achieved without culturing in ECM-coated conditions or intracellular staining of ECM. The development of single-cell analyses partially resolves these problems. Single-cell RNA sequences in CD45+ immune cells from tumor tissue identified ECM-expressing myeloid-like cells as distinct fibrocyte clusters. In addition, these findings enabled the isolation of tumor-infiltrating fibrocytes as CD45+CD34+ cells. These tumor-infiltrating fibrocytes demonstrated both antigen-presenting ability and differentiation into myofibroblast-like cancer-associated fibroblasts. Considering these functions of fibrocytes in tumor progression, molecular-targeting agents for the migration, activity, and differentiation of fibrocytes are promising therapeutic strategies. Furthermore, identification of specific cell surface markers and master regulators of fibrocytes will advance novel fibrocyte-targeting therapies. In this review, we discuss the multiple roles of tumor-infiltrating fibrocytes and novel cancer therapeutic strategies.

Transarterial chemoembolization combined with molecular targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma beyond the up-to-seven criteria: a propensity score-matching analysis

Purpose Not all patients benefit from transarterial chemoembolization (TACE) due to the heterogeneity of the tumour burden in intermediate-stage hepatocellular carcinoma (HCC). To compare the outcomes of transarterial chemoembolization (TACE) combined with molecular-targeted agents plus immune checkpoint inhibitors (TACE-MTAs-ICIs) with those of TACE for patients with unresectable hepatocellular carcinoma (uHCC) that were beyond the up-to-seven criteria. Patients and methods Between January 2019 and July 2022, 130 patients diagnosed with uHCC beyond the up-to-seven criteria were retrospectively identified, including 47 patients who received TACE-MTAs-ICIs and 83 patients who received TACE alone. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included tumour response and adverse events (AEs). Results There were 43 matched patients. The median OS and PFS times in the TACE-MTAs-ICIs group were significantly longer than those in the TACE group (OS: 27.2 vs. 15.9 months, p = 0.007; PFS: 15.4 months vs. 4.8 months, p < 0.001). The objective response rate (ORR) in the TACE-MTAs-ICIs group was higher than that in the TACE group (65.1% vs. 37.2%, p = 0.010). Reversible AEs (grade 3 or 4) occurred differently in TACE-MTAs-ICIs and TACE groups (83.7% vs. 51.2%, p = 0.001). Univariate and multivariate analyses revealed that TACE-MTAs-ICIs treatment was an independent favourable prognostic factor for both PFS and OS (p < 0.001). Conclusion For uHCC patients beyond the up-to-seven criteria, TACE-MTAs-ICIs provided superior ORR and OS. Early combined TACE and systemic treatment should shift for patients who are beyond these criteria.

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database.

Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in KIT (78%), CDKN2A (37%), CDKN2B (29%), RB1 (11%), STK11 (10%), TP53 (9%), PDGFRA (6%), and SDHB (6%). Loss of CDKN2A/CDKN2B was only observed in KIT/PDGFRA-mutated GISTs, while alterations in SDHA/SDHB were only detected in KIT/PDGFRA wild-type GISTs. Among 119 KIT/PDGFRA-mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding KIT and PDGFRA. However, among 25 KIT/PDGFRA wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in KIT/PDGFRA-mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for ETV6-NTRK3 fusion in one with KIT/PDGFRA wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with KIT/PDGFRA-mutated GIST. This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

Targeted regulation of autophagy using sorafenib-loaded biomineralization nanoenzyme for enhanced photodynamic therapy of hepatoma

Sorafenib (SF), a multi-targeted tyrosine kinase inhibitor, serves as a primary therapeutic modality for advanced liver cancer. Nonetheless, its clinical efficacy is hindered by various obstacles, such as limited bioavailability and inadequate accumulation. This study introduces a novel biomimetic mineralization enzyme, known as BSA@Pt/Ce6/SF@M (PCFM). The PCFM incorporates platinum (Pt) as a catalytic agent, SF as a molecular-targeted therapeutic agent, and Ce6 as a photosensitizer within liver cancer cell membranes. This strategy enables the combination of various anti-tumor treatments, such as photodynamic therapy (PDT) and autophagy induction, leading to increased bioavailability of SF and achieving a multidimensional synergistic anticancer effect. The PDT effect produced by Ce6 in PCFM greatly enhances SF-induced autophagy, effectively promoting autophagic cell death. Furthermore, Pt dissociates from the biomineralization process, acquiring peroxidase properties through chemokinetic reactions. This facilitates the catalysis of significant oxygen generation, addressing the challenge of hypoxia in the tumor microenvironment and improving the efficacy of PDT. Moreover, the SF further enhances therapeutic efficacy by inducing autophagy in response to energy deprivation, as indicated by the reduced levels of HIF-1α, p62, along with increased levels of ROS and LC3-Ⅱ/Ι. This biomineralization-based nanoenzyme exhibits strong anti-tumor characteristics, offering a novel strategy for overcoming challenges in liver cancer treatment.

The effectiveness of targeted therapy for recurrence or metastasis adenoid cystic carcinoma: a systematic review and meta-analysis

Background and purpose Several clinical studies have demonstrated the potential of molecular-targeted agents for the treatment of recurrent or metastatic adenoid cystic carcinoma (R/M ACC). However, there is currently no consensus regarding the efficacy of molecular-targeted agents for patients with R/M ACC. This study aimed to evaluate the therapeutic efficacy and safety of molecular-targeted agents in patients with R/M ACC and provide insights to guide clinical decision-making. Materials and methods Five databases (PubMed, Embase, Cochrane, ProQuest, and Scopus) were searched based on the search strategy and selection criteria. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS), metastatic sites, and adverse events (AE). Pooled estimates were calculated using a random-effects meta-analysis. Results Finally, 28 studies, involving 849 patients, were included. The most common metastatic sites were the lungs, bones, liver, lymph nodes, and kidneys. The pooled ORR was 4.0% (95% CI, 0.7–8.8%), the pooled DCR was 80.5% (95% CI, 72.2%–87.7%). Compared with other-target drugs, multiple kinase inhibitors (MKIs) improved the ORR (pooled ORR for single-target drugs vs. MKIs: 5.9% vs. 0%). The combination of MKIs and immune checkpoint inhibitors (ICIs) had a significantly higher ORR (17.9% in the axitinib + avelumab group). The pooled median PFS and OS were 8.35 and 25.62 months, respectively. MKIs improved the median PFS compared to other-target drugs (9.43 months vs 5.06 months). In addition, the most common adverse events (AEs) were fatigue (51.6%), hypertension (44.2%), and nausea (40.0%), followed by hand-foot skin syndrome (36.8%), diarrhoea (34.4%), weight loss (34.2%), anorexia (31.8%), rash (31.7%), and headache (29.0%). Conclusion The findings of this study suggest that MKIs have a better therapeutic efficacy than single-target drugs in patients with R/M ACC. Future studies are warranted to verify the synergistic role of the combination strategy of MKIs plus ICIs, given the limited number of studies on this topic conducted and published to date.

A New Self-Expandable Metallic Stent with Low Axial Force and a High Axial Force Zero-Border Shows a Very Low Perforation Rate in Malignant Colorectal Obstruction: A Japanese Multicenter Prospective Study.

Background: Recently, there has been a significant increase in the utilization of self-expandable metallic stents (SEMSs) for treating malignant colorectal obstructions through colorectal stenting. The mechanical properties of SEMSs are usually considered to affect clinical outcomes of patients with malignant colorectal obstructions. Methods: This single-arm, prospective, multicenter study of SEMS with a lower axial force and high axial force zero-border included 200 patients with malignant colorectal obstruction. Technical and clinical success, stent patency, and adverse events associated with SEMS placement were evaluated. Results: One patient was excluded, and 199 patients were evaluated. The treatment intent was bridge-to-surgery in 129 and palliation in 70 patients. Technical and clinical success rates were 99.5% and 97.0%, respectively. The percentage of the ColoRectal Obstruction Scoring System scores of 3 or higher improved significantly from 19.2% before placement to 93.9% after placement. Clinical success was not achieved in five patients due to insufficient stent expansion in four patients and stent occlusion in one patient. Only one patient underwent emergency surgery for perforation of the proximal colon, far from where the stent was placed; the rescue procedure was not performed, despite no improvement in proximal dilatation due to insufficient stent expansion. Among the palliation cohort, 15 patients received chemotherapy, including molecular-targeted agents such as bevacizumab. There were no fatal cases related to stent placement. Conclusions: For management of malignant colorectal obstruction, this newly developed SEMS with low axial force and a high axial force zero-border showed high technical and clinical success rates, and an extremely low perforation rate (0.5%).

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

BackgroundIntegrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.MethodsWe screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.ResultsOur combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib’s off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.ConclusionIn the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

Targeted HER2-positive cancer therapy using ADAPT6 fused to horseradish peroxidase

Targeted cancer therapy is a promising alternative to the currently established cancer treatments, aiming to selectively kill cancer cells while sparing healthy tissues. Hereby, molecular targeting agents, such as monoclonal antibodies, are used to bind to cancer cell surface markers specifically. Although these agents have shown great clinical success, limitations still remain such as low tumor penetration and off-target effects. To overcome this limitation, novel fusion proteins comprised of the two proteins ADAPT6 and Horseradish Peroxidase (HRP) were engineered. Cancer cell targeting is hereby enabled by the small scaffold protein ADAPT6, engineered to specifically bind to human epidermal growth factor receptor 2 (HER2), a cell surface marker overexpressed in various cancer types, while the enzyme HRP oxidizes the nontoxic prodrug indole-3-acetic acid (IAA) which leads to the formation of free radicals and thereby to cytotoxic effects on cancer cells. The high affinity to HER2, as well as the enzymatic activity of HRP, were still present for the ADAPT6-HRP fusion proteins. Further, in vitro cytotoxicity assay using HER2-positive SKOV-3 cells revealed a clear advantage of the fusion proteins over free HRP by association of the fusion proteins directly to the cancer cells and therefore sustained cell killing. This novel strategy of combining ADAPT6 and HRP represents a promising approach and a viable alternative to antibody conjugation for targeted cancer therapy.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs’ half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. Statement of significanceTreatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Real-world performance of the digital drug-assignment system for precision oncology in lung cancer.

e13590 Background: Precision medicine has profoundly transformed lung cancer treatment, an array of molecularly targeted agents (MTAs) are approved and used in clinical practice. Comprehensive molecular testing is key in treatment decisions, nevertheless, interpretation of complex molecular profiles can be challenging and subjective. Previously we demonstrated that digital drug assignment (DDA), an algorithmic computational reasoning model that ranks associated targeted therapies based on the totality of individual tumor genomic data, rather than matching one drug to one biomarker, was predictive of relative benefit of the agents as used in the SHIVA01 trial (1). Here, we collected real-world clinical outcome data from lung cancer patients who received decision support where DDA was integrated to aid a molecular tumor board (MTB) and investigated the effectiveness of administered therapies. Methods: Between 2018 and 2022, 111 lung cancer patients were involved in our precision oncology program. Following molecular diagnostic tests, analysis of the individual molecular profiles and scoring of associated drugs (DDA score) was performed by the DDA system as previously described. The output was assessed by the MTB that provided a strategy to the clinicians who made the final therapy decisions. Treatment courses and outcomes were collected from hospital health records and analyzed. Treatment lines were categorized as the following: high-score MTA (1000≤DDA score), low-score MTA (DDA score&lt;1000), and standard of care (SOC). Results: Overall response rate (ORR) of high-score MTA lines administered following DDA-based decision support (n=13) was 69%, whereas of other treatment lines (low-score MTAs and SOC; n=55) it was 16% (p&lt;0.001); and 26% in low-score MTA lines (n=34; p=0.017). Median progression-free survival (mPFS) of high-score MTA lines administered following DDA-based decision support (n=13) was 63 months (95% CI: 12.0 – 66.0), whereas it was 9 months both for any other treatment lines (low-score MTAs and SOC; n=44; 95% CI: 5.0 – 66.0; p&lt;0.001) and for low-score MTA lines only (n=27; 95% CI: 5.0 – 66.0; p&lt;0.001). Median overall survival (mOS) of patients who received at least one line of high-score MTA after decision support (n=13) was significantly longer than of those who only received non-high score treatments after decision support (patients only treated with low-score MTAs and/or SOC, n=34): not reached vs. 32 months (95% CI 24.0 – not reached), respectively (p=0.012). Conclusions: This study revealed that the DDA system is predictive of relative benefit of the various agents as used in lung cancer care, in line with our previous clinical validation. Validated algorithmic AI-guided drug assignment methods represent a new class of tools that can potentially address challenges in utilizing the results of complex molecular profiles in routine clinical setting. 1. Petak et al., 2021, npj Precis. Onc. 5, 59.

Combining immune checkpoint inhibitors and molecular-targeted agents with hepatic arterial infusion chemotherapy for hepatocellular carcinoma with inferior vena cava and/or right atrium tumor thrombus.

e16177 Background: Patients with hepatocellular carcinoma and inferior vena cava and/or right atrium tumor thrombus (HCC-IVC/RATT) have a poor prognosis and lack evidence for standard first-line systemic treatment due to its low incidence. This study aims to evaluate the effectiveness and safety of three treatments in HCC-IVC/RATT patients: immune checkpoint inhibitors plus molecular-targeted agents (ICI-MTA), hepatic arterial infusion chemotherapy (HAIC), and their combination (ICI-MTA-HAIC). Methods: This multicenter retrospective cohort study included consecutive HCC-IVC/RATT patients who received ICI-MTA, HAIC, or ICI-MTA-HAIC from June 1, 2014, to December 31, 2022. The propensity score matching (PSM) was used to balance baseline characteristics. Survival analysis was conducted using Kaplan-Meier curves and compared using the log-rank test. Results: A total of 243 HCC-IVC/RATT patients were included, with 144 receiving ICI-MTA-HAIC, 29 receiving ICI-MTA, and 70 receiving HAIC. Before PSM, the ICI-MTA-HAIC group had significantly superior median overall survival (OS) of 16.5 months, progression-free survival (PFS) of 8.0 months, and objective response rate (ORR) of 47.9%, in comparison to both the ICI-MTA (OS: 7.7 months, P &lt; 0.001; PFS: 3.5 months, P = 0.001; ORR: 24.1%, P = 0.019) and HAIC groups (OS: 9.1 months, P = 0.003; PFS: 4.9 months, P = 0.007; ORR: 25.7%, P = 0.002) among HCC-IVC/RATT patients based on RECIST v1.1 criteria. The ICI-MTA and HAIC groups didn’t exhibit significant differences in OS, PFS, or ORR ( P = 0.061, 0.043, 0.869, respectively). After PSM, similar results were obtained across the three groups. All adverse reactions were manageable, and no unexpected adverse reactions or treatment-related deaths were observed among the three groups. Conclusions: ICI-MTA-HAIC was a safe and effective therapy that prolonged the survival of HCC-IVC/RATT patients compared to ICI-MTA or HAIC.

Insights from C-CAT repository: A novel approach to identifying appropriate patient populations for anticancer drug development using the clinicogenomic nationwide database in Japan.

11159 Background: The integration of Comprehensive Genomic Profiling (CGP) with real-world data (RWD) provides crucial insights for anticancer drug development to achieve precision oncology, therefore, the current global trend to construct as the national projects, yet its clinical impact remains underexplored. The therapeutic efficacy of each line of anti-cancer drug in various cancer types and the relationship between genetic alterations and the effect of anticancer drugs is needed to guide the direction of future drug development promptly and precisely. Methods: A comprehensive analysis was conducted on data from Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository between June 2019 and December 2023. Five genomic profiling assays for CGP testing were reimbursed by nation-wide insurance in Japan. Utilizing the clinicogenomic repository of C-CAT, registered data of therapeutic efficacy of anticancer drug including cytotoxic agents, molecular-targeted agents, and immune checkpoint inhibitors were evaluated in association with genetic alterations. Data on anticancer drug of patients (pts) with recurrent or metastatic disease were included in the analysis. Results: The C-CAT registry data encompassed 60,256 pts across 32 tumor organ sites, classified ontology by the OncoTree over 4.5 years. Of these patients, 30,234 were male, and 30,017 were female, with 5 classified as unknown. In terms of age, 31,919 pts were &lt; 65. The most registered origins were colorectal (n=10,110), pancreas (n=8,069), biliary tract (n=5,030), breast (n=3,744), esophagus/stomach (n=3,734), prostate (n=3,701), ovarian/fallopian tube (n=3,521), lung (n=3,427), and soft tissue (n=2,568). TP53mutations (58.3%, n=35,102) were most prevalent, followed by KRAS (25.8%, n=15,521), APC (19.9%, n=11,919), NOTCH3 (14.1%, n=8,502), and PIK3CA (13.0%, n=7,861). The frequency of BRCA1/2mutation was 4.1% (n=2,479). Overall response rate (ORR) for the first-, second-, third-, and fourth-lines treatment were 35.7%, 23.3%, 19.4%, and 19.2%, respectively. Pts treated with cisplatin or carboplatin in the first-line treatment, who had TP53 mutations, showed a better ORR than those without (44.0% vs. 38.9%, p &lt; 0.001). Similarly, pts with BRCA1/2mutation showed a better ORR than those without (53.9% vs. 41.4%, p &lt; 0.001) in the first-line treatment. Conclusions: This study was the first to report the relationship between genetic alterations and the therapeutic effect of anticancer drugs in each line. This approach based on big data analysis potentially accelerates drug development in the appropriate patient population by identifying significant associations between specific genetic mutations and improved outcomes with certain chemotherapy regimens in various cancers.

Clinical landscape of precision oncology for rare cancers among diverse Asian populations: Insights from the MASTER KEY registry.

3024 Background: Despite considerable strides in novel cancer treatments, disparities in access and care persist globally. This is particularly pronounced for rare cancers and among Asian patient cohorts, presenting a dual challenge. Methods: We conducted an analysis on clinical and biomarker data from the MASTER KEY Study, a multi-regional, prospective, observational precision oncology initiative encompassing 3,764 rare cancer patients across Asia. Clinical treatment and biomarker data, inclusive of DNA/RNA sequencing, were scrutinized to compare precision oncology adoption across various countries. Results: Within the Japanese cohort (3,268 patients), predominant rare cancer types included soft tissue sarcomas (22.0%), CNS/brain tumors (12.8%), and head and neck tumors (9.2%). The broader Asian cohort (496 patients) included soft tissue sarcomas (14.6%), liver/biliary tract tumors (14.4%), and head and neck tumors (13.8%), drawing patients from Malaysia, Korea, Taiwan, Philippines, Thailand, and Vietnam. Clinical trial participation for these rare cancers was notably higher in Taiwan (8.2%), followed by Japan (6.5%) and Malaysia (2.0%). The utilization of molecular target agents and/or immune checkpoint inhibitors was highest in Japan (20.3%), trailed by Taiwan (18.9%) and Korea (12.8%). DNA/RNA targeted sequencing data was available for 1,852 patients in Japan (56.7%) and 321 patients (64.7%) across the rest of Asia. 19.5% and 7.0% received on-target therapy in Japan and the rest of Asia, respectively. Notably, in Japan, patients harboring detectable targetable genes like BRAF V600E, BRCA1, and BRCA2 received BRAF/MEK inhibitors and PARP inhibitors at rates of 78.3%, 37.8%, and 25.0%, respectively, with varying response rates of 33.3%, 18.2%, and 20.2% each. Intriguingly, TP53 mutation acted as a negative predictor for response to BRAF/MEK inhibitors. Notably, no patients in the Asian cohort received BRAF/MEK inhibitors or PARP inhibitors despite the detection of these genes. Conclusions: The MASTER KEY Study demonstrates the feasibility of a prospective precision oncology platform, spotlighting rare cancers and enabling on-label targeted therapy as well as off-label targeted therapy for a subset of patients through trials. However, the broader Asian population outside Japan encounters heightened limitations in accessing precision oncology. Urgent expansion of clinical trials throughout Asia is crucial to effectively address the disparity that lies within Asian rare cancer patients.

Abstract PO2-06-06: Effectiveness and prognostic predictors of primary systemic therapy for de-novo Stage IV breast cancer - Supplementary analysis of JCOG1017 PRIM-BC

Abstract Background The optimal choice of drug is important in treating metastatic breast cancer, and the efficacy of the drug should be determined early, especially in cases of progression. On the other hand, untreated de novo Stage IV (dnST-IV) patients are expected to be more sensitive to drugs, but no detailed data are available. In JCOG1017 (Randomized trial of primary tumor resection in dnST-IV), dnST-IV patients were treated with primary systemic therapy for 3 months according to breast cancer subtypes before randomization. We already presented the results of primary endpoint. Primary tumor resection (PTR) could not significantly prolong the overall survival of de-novo stage IV breast cancer patients with sensitivity to primary systemic therapy. We conducted the supplementary analysis of JCOG1017 to clarify the efficacy of primary systemic therapy for dnST-IV and develop optimal treatment strategies for dnST-IV breast cancer. Methods In JCOG1017, systemic therapy was performed for each subtype/metastatic status as follows; 1) hormone therapy: ER+ HER2- and no life-threatening metastases, 2) weekly PTX therapy: life-threatening metastases, or ER-HER2-, 3) trastuzumab + pertuzumab + docetaxel (HPD) therapy OR trastuzumab + paclitaxel (HPTX) therapy: ER-HER2+. 4) hormone therapy: ER+HER2+ and no life-threatening metastases. The non-PD rate (no increase of more than 10% of the sum of the diameters of the target lesions compared before systemic therapy), the responses rate (cCR or cPR), and overall survival (OS) of responder (cCR or cPR)/non-responder (cSD or cPD) and PD/non-PD were examined. Results Among 569 patients who received primary systemic therapy in JCOG 1017, the non-PD rate was 77.2% and the response rate was 29.0% after 3 months of systemic therapy. By subtype, the non-PD rate was 78.2% for ER-HER2-, 75.4% for ER+HER2-, 92.9% for ER-HER2+, and 66.7% for ER+HER2+. The response rate was 36.4% for ER-HER2-, 13.4% for ER+HER2-, 81.0% for ER-HER2+, and 40.3% for ER+HER2+. In multivariable analysis, the non-PD rate was higher in postmenopausal (odds ratio [OR] 1.673, p=0.0240) and PgR-positive (OR 2.391, p= 0.0019) patients besides subtypes. Analysis results by drug were as follows; 1) hormone therapy (non-PD rate: 72.9%) was more effective for PgR-positive (OR 3.258, p&amp;lt; 0.0001), less effective for patients with visceral metastasis (OR 0.605, p=0.0334) and HER2-positive (OR 0.365, p=0.0016), 2) wPTX (non-PD rate: 76.1%) was no significant predictors of efficacy, 3) HPD/HPTX (non-PD rate: 92.7%) was more effective in patients with visceral metastasis (OR 15.818, p=0.0030). PD patients had much worse OS (hazard ratio [HR] 0.501, p&amp;lt; 0.0001) compared to non-PD, whereas responders had a little worse OS (HR 0.788, p=0.0538) compared to non-responders. Similar tendency was observed in any drug. Discussion Predictors of response to primary systemic therapy differed by subtype, with the need for treatment strategies tailored to PgR, HER2 expression, and the status of visceral metastasis. In the ER+HER2+ group, the efficacy of hormonal therapy alone was low, and combination therapy with molecular-targeted agents was considered necessary. The non-PD rate reflected prognosis in determining the efficacy of primary systemic therapy for dnST-IV. Citation Format: Tadahiko Shien, Akihiko Shimomura, Makoto Ishitobi, Kiyo Tanaka, Takahiro Tsukioki, Takashi Yamanaka, Fumitaka Hara, Kenjiro Aogi, Yasuhiro Yanagita, Michiko Tsuneizumi, Naohito Yamamoto, Hiroshi Matsumoto, Akihiko Suto, Ken-ichi Watanabe, Michiko Harao, Chizuko Kanbayashi, Mitsuya Ito, Keisei Anan, Shigeto Maeda, Keita Sasaki, Gakuto Ogawa, Haruhiko Fukuda, Hiroji Iwata. Effectiveness and prognostic predictors of primary systemic therapy for de-novo Stage IV breast cancer - Supplementary analysis of JCOG1017 PRIM-BC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-06.

Usefulness of atezolizumab plus bevacizumab as second-line therapy for patients with unresectable hepatocellular carcinoma.

To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

Prognostic and Immunotherapeutic Predictive Value of CAD Gene in Hepatocellular Carcinoma: Integrated Bioinformatics and Experimental Analysis.

Hepatocellular carcinoma (HCC) is a common type of cancer that ranks first in cancer-associated death worldwide. Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key components of the pyrimidine pathway, which promotes cancer development. However, the function of CAD in HCC needs to be clarified. In this study, the clinical and transcriptome data of 424 TCGA-derived HCC cases were analyzed. The results demonstrated that high CAD expression was associated with poor prognosis in HCC patients. The effect of CAD on HCC was then investigated comprehensively using GO annotation analysis, KEGG enrichment analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT algorithm. The results showed that CAD expression was correlated with immune checkpoint inhibitors and immune cell infiltration. In addition, low CAD levels in HCC patients predicted increased sensitivity to anti-CTLA4 and PD1, while HCC patients with high CAD expression exhibited high sensitivity to chemotherapeutic and molecular-targeted agents, including gemcitabine, paclitaxel, and sorafenib. Finally, the results from clinical sample suggested that CAD expression increased remarkably in HCC compared with non-cancerous tissues. Loss of function experiments demonstrated that CAD knockdown could significantly inhibit HCC cell growth and migration both in vitro and in vivo. Collectively, the results indicated that CAD is a potential oncogene during HCC metastasis and progression. Therefore, CAD is recommended as a candidate marker and target for HCC prediction and treatment.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P=0.032) as the only significant independent favorable predictive factor. The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.