Efficacy Of Molecular Targeted Agents Research Articles

The efficacy of molecular targeted therapy and nivolumab therapy for metastatic non-clear cell renal cell carcinoma: A retrospective analysis using the Michinoku Japan urological cancer study group database.

To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population. In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database. In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups. The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population.

Methylated SEPT9 assay-based liquid biopsy as a biomarker in molecular targeted agent-treated hepatocellular carcinoma.

The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs.

P413: THE POTENTIAL USE OF AN ORAL HYPOMETHYLATING AGENT, OR-2100, AS A COMBINATION THERAPY FOR MYELOID MALIGNANCIES

Background: The combination therapy of hypomethylating agents (HMAs), azacytidine (AZA) and decitabine (DAC), with venetoclax (VEN), a selective BCL-2 inhibitor, have revolutionized the outcome of elderly patients with acute myeloid leukemia (AML), which have demonstrated the potential effect of HMAs as a combination therapy with molecular targeting agents for myeloid malignancies. However, there are a few studies on the combined effect of HMAs with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) and the mechanism by which HMAs enhance the efficacy of molecular targeting agents remain poorly understood. We have developed OR-2100 (OR21), an oral HMA, a 5’-O-trialkylsilylated DAC. OR21 is as effective as DAC, but less myelosuppressive, in xenograft mouse models of solid and hematological malignancies (Hattori et al. Clin Epigenetics 2019, Watanabe et al. Blood 2020, Ureshino et al. Mol Cancer Ther 2021, Kamachi et al. Cancer Letters 2022). We investigated the efficacy and mechanism of OR21 in combination with VEN or TKIs for myeloid malignancies, AML, and CML. Aims: To investigate the efficacy and mechanism of the combination therapy of OR21 for myeloid malignancies. Methods: We investigated the efficacy and mechanism of OR21 in combination with VEN against AML and with TKIs against CML, in vitro and in vivo. Results: In AML, OR21 plus VEN synergistically inhibited cell growth, increased apoptosis in AML cell lines as similar to AZA and DAC, and significantly prolonged survival in a xenograft mouse model using HL60 cell line (p<0.05). Gene expression analysis using AML cell lines (HL60, KG1a) showed that OR21 plus VEN significantly downregulated VAMP7 which regulates mitophagy/autophagy to maintain mitochondrial homeostasis compared to VEN monotherapy. Consistently, OR21 plus VEN enhanced apoptosis by increasing ROS accumulation and attenuated mitophagy/autophagy response triggered by decreased mitochondrial membrane potential. The addition of mitophagy inducers, such as rapamycin and p62-mediated mitophagy inducer, to OR21 plus VEN decreased ROS accumulation and apoptosis, indicating OR21 enhanced ROS accumulation via attenuating VEN-induced mitophagy/autophagy pathway. In CML, OR21 plus TKIs (imatinib, dasatinib, ponatinib) synergistically inhibited cell growth, increased apoptosis in CML cell lines as similar to AZA and DAC, and significantly suppressed the colony-forming capacity of bone marrow CD34+ stem/progenitor cells in CML patients. OR21 plus imatinib significantly suppressed tumor growth compared to imatinib monotherapy in a xenograft mouse model using K562 cell line (p<0.05). In phosphoproteomic, transcriptome and methylome analysis (K562, KBM5), OR21 augmented imatinib-induced apoptosis by dephosphorylating of STAT and Src family proteins by upregulating several tumor suppressor genes, including PTPN6, through demethylation of their promoter CpG regions. Image:Summary/Conclusion: OR21 enhanced the anti-tumor effect in combination with the molecular agents for myeloid malignancies with different mechanisms: OR21 increased ROS accumulation in combination with VEN, and dephosphorylated BCR-ABL1 downstream protein kinases by demethylating effect in combination with TKIs. With its advantage as an oral HMA, OR21 is expected to have future clinical trials as a combination therapy for myeloid malignancies.

The Outcome of Conversion Liver Resection Surgery by Lenvatinib Treatment: A Single Center Experience.

The efficacy of molecular-targeted agents (MTAs) has been demonstrated in recent years. However, the results of multidisciplinary treatment including hepatic resection are still unclear. The present study evaluated the outcomes of MTA treatment for advanced, unresectable hepatocellular carcinoma (HCC), with the goal of achieving liver resection, in our department. Nine patients in whom Lenvatinib had been administered to achieve conversion surgery for unresectable HCC were included in this study. The patient characteristics were as following: median tumor size of 10 cm, vascular invasion in 5 cases, multiple tumors in 2 cases, median treatment duration of 8 weeks, dose reduction due to side effects in 4 patients, and discontinuation of treatment in 1 patient due to tumor growth. The efficacy by modified Response Evaluation Criteria in Solid Tumors (mRECIST) was partial response in 3, sustained disease in 5 and progressive disease in 1, while the liver resection rate was 88%. Four patients (50%) had recurrence after resection, and the median recurrence-free survival was 12.7 months; however, treatment for recurrence was successful and all patients are alive. Lenvatinib may improve the prognosis of HCC with vascular invasion and multiple lesions by achieving radical resection at the appropriate time for patients with tumor shrinkage.

Pediatric Hemispheric Glioma

About one-third of pediatric low-grade glioma and a half of pediatric high-grade glioma occur in the cerebrum. Pediatric hemispheric glioma may harbor diagnostic and therapeutically targetable genetic abnormalities, including BRAF V600E, H3.3 G34R/V, FGFR1 alternation, MYB or MYBL1 alternation, and NTRK/ALK/ROS1/MET fusion. In addition, the efficacy of molecular-targeted agents, such as BRAF inhibitors, MEK inhibitors, and NTRK inhibitors, against pediatric glioma with the relevant mutations has been demonstrated in several clinical trials. Furthermore, checkpoint inhibitors are considered a choice of treatment for hypermutated glioma, which is typically observed in patients with constitutional mismatch repair deficiency syndrome. Cancer gene panel testing, approved for insurance coverage in Japan in 2019, has been beneficial to pediatric cancer patients. However, to promote the clinical application of the recent molecular understanding of pediatric neuro-oncology, some issues have to be addressed. Herein, we review the genetic profiles of pediatric hemispheric glioma and introduce the current medical situation of precision medicine for pediatric patients with glioma in Japan.

Hsa-miR-4271 downregulates the expression of constitutive androstane receptor and enhances in vivo the sensitivity of non-small cell lung cancer to gefitinib

The efficacy of molecular targeting agents is dependent on the metabolism or nuclear receptor-mediated clearance of chemotherapy resistance-related factors such as cytochrome P450 (CYP) or ATP binding cassette subfamily B member 1 (ABCB1). In this study, we revealed the roles of the microRNA-4271/CAR (constitutive androstane receptor) axis in the regulation of the resistance to molecular anticancer targeting agents in non-small cell lung cancer (NSCLC) cells including two main categories of NSCLC: lung adenocarcinoma (AC) and large cell lung cancer (LCC). The expression of miR-4271 was negatively correlated with CAR expression in NSCLC tissues. MiR-4271 targeted CAR and inhibited the activation of the CAR signaling pathway. Overexpression of CAR in NSCLC enhanced the resistance of NSCLC cells to molecular targeting agents and miR-4271-infected NSCLC cells enhanced their sensitivity to molecular targeting agents such as Gefitinib. The mechanism-data showed that overexpression of miR-4271 decelerated the mechanism or the clearance of molecular targeting agents by targeting the 3′UTR (3′ un-translation region). These results suggest that miR-4271 may contribute to the development of more effective strategies for the treatment of advanced NSCLC.

97P - Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability

BackgroundSIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. MethodsAll SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test.All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. ResultsThe 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1mo in IIIA; 1.7mo in IIIB, and 3.2mo in IVA (p=0.13). Median OS was 11.7mo in tier II, 11.2mo in IIIA, 6.3mo in IIIB, and 12.1mo in IVA (p=0.002). ConclusionsThe majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway. Legal entity responsible for the studyInstitut Curie. FundingANR-10-EQPX-03 from the Agence Nationale de le Recherche (Investissements d’avenir) and SiRIC (Site de Recherche Intégré contre le Cancer). DisclosureAll authors have declared no conflicts of interest.

Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability.

e14750 Background: SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. Methods: All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. Results: The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002). Conclusions: The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.

Efficacy of Molecular Targeting Agents and Immune Checkpoint Inhibitors for Head and Neck Cancer

Efficacy of Molecular Targeting Agents and Immune Checkpoint Inhibitors for Head and Neck Cancer

Differences in EGFR and KRAS mutation spectra in lung adenocarcinoma of never and heavy smokers

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas of never smokers, while KRAS mutations are more frequent among heavy smokers. Different clinicopathological and biological characteristics may, therefore, exist in lung adenocarcinoma according to smoking status. In the present study, a retrospective review was performed using 521 patients with surgically resected lung adenocarcinomas. The clinicopathological factors of age, gender, pathological tumor size, nodal status, lymphatic permeation and blood vessel invasion and the EGFR and KRAS mutation spectra were compared between never and heavy smokers. EGFR mutations were detected in 233 (45%) patients, while KRAS mutations were detected in 56 (11%) patients. EGFR-mutated adenocarcinomas had a higher prevalence of females in the never smokers compared with the heavy smokers (P<0.001). KRAS-mutated adenocarcinomas had a higher prevalence of females (P<0.001) and showed less frequent vascular invasion (P=0.018) in the never smokers compared with the heavy smokers. Minor EGFR mutations, excluding exon 21 L858R and exon 19 deletions, were more common in heavy smokers than never smokers (P=0.055). KRAS G to A transition was more common in never smokers, while KRAS G to T and G to C transversions were more common in heavy smokers (P=0.036). The clinicopathological characteristics and the spectra of the EGFR and KRAS mutations in lung adenocarcinoma were different between the never and heavy smokers. Further large-scale studies are required to evaluate the efficacy of molecular targeting agents with consideration to specific EGFR and KRAS mutations.

Applicability of the BCLC staging system to patients with hepatocellular carcinoma in Korea: analysis at a single center with a liver transplant center

Background/AimsThe Barcelona Clinic Liver Cancer (BCLC) staging system is logical for the staging and treatment of hepatocellular carcinoma (HCC) because it was based on survival data. This study evaluated the applicability of the BCLC staging system and reasons for divergence from BCLC-recommended treatments in Korean HCC patients.MethodsOne hundred and sixty consecutive HCC patients were prospectively enrolled. Treatments were generally recommended according to the guideline of the American Association for the Study of Liver Diseases, but patients were also informed about alternative treatments. The final decision was made with patient agreement, and was based on the doctor's preferences when a patient was unable to reach a decision.ResultsThere were 2 (1%), 101 (64%), 20 (12.5%), 34 (21.5%), and 3 (1%) patients with very early-, early-, intermediate-, advanced-, and terminal-stage disease, respectively. Only 64 patients (40%) were treated according to BCLC recommendations. The treatment deviated from BCLC recommendations in 68% (69/101) and 79% (27/34) of patients with early and advanced stage, respectively. The main causes of deviation were refusal to undergo surgery, the presence of an indeterminate malignancy nodule, the absence of a suitable donor, or financial problems.ConclusionsDonor shortage, financial problems, the relatively limited efficacy of molecular targeting agents, and the presence of an indeterminate nodule were the main causes of deviation from BCLC recommendations. Even after excluding cases in which decisions were made by patient preference, only 66% of the HCC patients were treated according to BCLC recommendations. Treatment guidelines that reflect the Korean situation are mandatory for HCC patients.

Is response rate increment obtained by molecular targeted agents related to survival benefit in the phase III trials of advanced cancer?

BackgroundIt remains unclear whether response rate (RR) is related to survival benefit in phase III trials of advanced cancer treated with molecular targeted agents (MTA) in combination with standard therapies. Materials and methodsWe carried out a systematic search of PubMed for randomized phase III trials of four solid tumors examining the efficacy of MTA when added to a standard therapy. We examined whether there were any associations between RR increment obtained by the addition of targeted agents (ΔRR) and survival benefit in phase III trials. ResultsWe identified 26 phase III trials of MTA with a total of 21156 patients and 29 experimental arms of MTA. Studies which showed significant survival benefit had higher ΔRR compared with those which did not show significant benefit. In the receiver operating characteristic curve analysis, using a 7% gain as threshold value for ΔRR allowed assessment of survival benefit with high sensitivity and specificity. There were also significant relationships between ΔRR and hazard ratios for overall survival and progression-free survival in the linear regression analysis. ConclusionRR increment obtained by the addition of MTA to a standard therapy may be useful to predict survival benefit in clinical phase III trials of advanced cancer.

Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

BackgroundThe tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death.MethodsHuman colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed.ResultsIn addition to G2/M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G1 population of cells with functional p53 but accumulation of both G1 and G2/M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G2/M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified.ConclusionIn these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.