Gemcitabine Therapy Research Articles

Real-world epidemiology and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma: Retrospective analysis of Diagnosis Procedure Combination claims data in Japan.

Evaluate real-world epidemiologic trends and treatment patterns in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in Japan. This retrospective analysis included adults with newly diagnosed la/mUC in Japan (January 2015-December 2019) from a nationwide-linked electronic medical record Diagnostic Procedure Combination claims dataset. Outcomes included epidemiologic trends (incidence and prevalence), baseline demographics, clinical characteristics, and treatment patterns in newly diagnosed patients with la/mUC before (2015-2017) and after (2018-2019) approval of pembrolizumab in Japan. Of 975 patients included, 76.4% were men; 71.6% were aged 70 years or older. Most cases (70.5%) were of the bladder. Between 2015 and 2019, the annual age-adjusted incidence increased from 6.8 to 12.4 per 100 000; the annual age-adjusted period prevalence increased from 13.0 to 25.2 per 100 000; and 307 (31.5%) and 668 (68.5%) patients were diagnosed from 2015 to 2017 and 2018 to 2019, respectively. Overall, 731 (75%) patients received systemic anticancer therapy; all received 1 line and 50.2% received 2 lines of therapy; 78.3% of patients received gemcitabine plus platinum-based therapy and 2.2% received pembrolizumab as first-line treatment. First-line treatment rates increased from 69.4% to 77.5% after pembrolizumab approval. Of 367 patients who received second-line treatment, 22.3% received gemcitabine plus platinum-based therapy; 14.7% received pembrolizumab. In the Japanese regions considered, incidence and prevalence of newly diagnosed la/mUC increased over time and first-line treatment with pembrolizumab increased after approval.

Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer

Colorectal cancer (CRC) is the third most common cancer associated with a poor prognosis. Effective targeted therapy alone or in combination for treating advanced CRC remains to be a major clinical challenge. Here, we propose the therapeutic efficacy and molecular mechanism underlying RC48, a FDA-approved anti-HER2 antibody conjugate via a cleavable linker to the microtubule inhibitor monomethyl auristatin E (MMAE), either alone or in combination with gemcitabine (GEM) in various models of HER2-positive advanced CRC. Our findings demonstrated that HER2 was widely expressed and located on the plasma membrane of CRC patient specimens, PDX xenograft tumors and cell lines. It confirmed that RC48 alone significantly targeted and eradicated HER2 positive CRC tumor in these models. Moreover, we screened a panel of FDA-approved first-line chemotherapy drugs in vitro. We found that GEM exhibited stronger antiproliferative activity compared to the other first-line anti-cancer agents. Furthermore, combination therapy of RC48 and GEM significantly showed synergetic antitumor activity in vitro and in vivo. To gain further mechanistic insights into the combination therapy, we performed RNA-seq analysis. The results revealed that combination treatment of RC48 and GEM regulated multiple signaling pathways, such as PI3K-AKT, MAPK, p53, Foxo, apoptosis, cell cycle and cell senescence, etc., to exert its antitumor activity in CRC cells. Collectively, these preclinical findings demonstrated that RC48 alone or combinational therapy exerted promising antitumor activity, and meriting the preclinical framework for combinational therapy of anti-HER2 drug conjugate drug and chemotherapy drugs for HER2-positive patients with advanced CRC.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201)

BackgroundAdvanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.MethodsThis multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.DiscussionGEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+–CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.

Abstract C068: Construction of preclinical study model for optimal anticancer drug selection using PDX model in pancreatic cancer

Abstract Background: Translational research using the patient-derived xenograft (PDX) model is progressing rapidly and is also becoming widespread in pancreatic cancer research. Since PDX models retain the characteristics and the heterogeneity of the primary tumor, PDX models can be reflected in the effectiveness of the anticancer drug in human. The purpose of this study was to establish the PDX library of pancreatic cancer for preclinical study. Methods: The tissues of the pancreatic cancer were obtained from patients who underwent surgery at our hospital. Two PDX models were established using immunodeficient rats. One case was effective in gemcitabine plus nab-paclitaxel (GnP) therapy, and the other was ineffective in GnP therapy in preoperative treatment. 5-FU, CPT-11, L-OHP, GEM, and CDDP were administered to these PDX models once a week for 3 weeks. The primary endpoint was tumor shrinkage. Results: GEM was effective in PDX model in a case in which GnP therapy was effective in the clinical setting, in contrast, GEM was ineffective in PDX model in a case in which GnP was ineffective in the clinical setting. This result was correlated with actual clinical practice. Conclusions: In this study, single anticancer drug tests were performed on PDX models using immunodeficient rats. The efficacy of anticancer drugs was correlated with the clinical setting, indicating that our PDX models might be useful as a preclinical study model. We are currently conducting multi anticancer drug studies. Citation Format: Ryota Tanaka, Kenjiro Kimura, Naoki Tani, Shimpei Eguchi, Ken Kageyama, Shuhei Kushiyama, Shigeaki Kurihara, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, Go Ohira, Akira Yamamoto, Takeaki Ishizawa. Construction of preclinical study model for optimal anticancer drug selection using PDX model in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C068.

Impaired Consciousness Due to Hyperammonemia During S-1 Administration for Unresectable Pancreatic Cancer.

A 71-year-old woman diagnosed with unresectable locally advanced pancreatic cancer was initially treated with gemcitabine and nab-paclitaxel as first-line therapy. The tumor exhibited no significant progression; however, after 12 cycles, the patient developed drug-induced interstitial pneumonia, leading to the discontinuation of gemcitabine and nab-paclitaxel therapy. Following recovery from pneumonia, S-1 therapy was initiated as second-line treatment. During S-1 treatment, she was hospitalized because of impaired consciousness and was subsequently diagnosed with hyperammonemia induced by S-1. Although rarely reported, S-1-induced hyperammonemia is potentially a significant adverse effect. Here, we herein report the case of a patient with pancreatic cancer.

Comparative analysis of recurrence rates between intravesical gemcitabine and bacillus Calmette-Guérin induction therapy following transurethral resection of bladder tumors in patients with intermediate- and high-risk bladder cancer: A retrospective multicenter study.

This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette-Guérin (BCG) therapy. Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p<0.001). There were no consistent significant differences observed between the two groups in the 3-month (gemcitabine, 98.4% vs. BCG, 95.3%; p=0.848), 6-month (94.9% vs. 90.0%, respectively; p=0.793) and 1-year CR rates (84.2% vs. 83.3%, respectively; p=0.950). Also, there was no significant statistical difference in progression-free survival between the two groups (p=0.953). The occurrence rates of adverse events were similar between the groups (22.2% vs. 22.1%; p=0.989); however, the rate of Clavien-Dindo grade 2 or higher was significantly higher in the BCG group (1.6% vs. 16.3%, respectively; p<0.001). Intravesical gemcitabine demonstrated efficacy comparable to BCG therapy for the first year in patients with intermediate- and high-risk NMIBC. However, long-term follow-up studies are warranted.

Genomic profile and clinical features of MSI-H and TMB-high pancreatic cancers: real-world data from C-CAT database.

Microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-high) pancreatic cancer are rare, and information is lacking. Based on the C-CAT database, we analyzed the clinical and genomic characteristics of patients with these subtypes. We retrospectively reviewed data on 2206 patients with unresectable pancreatic adenocarcinoma enrolled in C-CAT between July 2019 and January 2022. The clinical features, proportion of genomic variants classified as oncogenic/pathogenic in C-CAT, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) of chemotherapy as first-line treatment were evaluated. Numbers of patients with MSI-H and TMB-high were 7 (0.3%) and 39 (1.8%), respectively. All MSI-H patients were TMB-high. MSI-H and TMB-high patients harbored more mismatch repair genes, such as MSH2, homologous recombination-related genes, such as ATR and BRCA2, and other genes including BRAF, KMT2D, and SMARCA4. None of the 6 MSI-H patients who received chemotherapy achieved a clinical response, including 4 patients treated with gemcitabine plus nab-paclitaxel (GnP) therapy, whose DCR was significantly lower than that of microsatellite stable (MSS) patients (0 vs. 67.0%, respectively, p = 0.01). Among the TMB-high and TMB-low groups, no significant differences were shown in ORR, DCR (17.1 vs. 23.1% and 57.1 vs. 63.1%, respectively), or median TTF (25.9 vs. 28.0weeks, respectively) of overall first-line chemotherapy. MSI-H and TMB-high pancreatic cancers showed some distinct genomic and clinical features from our real-world data. These results suggest the importance of adapting optimal treatment strategies according to the genomic alterations.

CASP1 is a target for combination therapy in pancreatic cancer

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.

Combination therapy of niclosamide with gemcitabine inhibited cell proliferation and apoptosis via Wnt/β-catenin/c-Myc signaling pathway by inducing β-catenin ubiquitination in pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with high morbidity and mortality rates worldwide. Owing to a lack of therapeutic options, the overall survival rate of patients with pancreatic cancer is low. Gemcitabine has been mainly used to treat patients with pancreatic cancer, but its efficacy is limited by chemoresistance. Therefore, a novel therapeutic agent for PDAC therapy is urgently needed. An anthelminthic drug, niclosamide, has already been researched in breast, lung, colon, and pancreatic cancer as an anti-cancer purpose by re-positioning its original purpose. However, combination therapy of gemcitabine and niclosamide was not informed yet. Here, we found that niclosamide co-administered with gemcitabine significantly inhibited tumorigenesis of pancreatic cancer compared to gemcitabine alone. Further, combining niclosamide and gemcitabine inhibited cell proliferation and induced apoptosis. Niclosamide induced cell cycle arrest at the G1 phase, and the levels of CDK4/6 and cyclin D1 were lowered after gemcitabine treatment. In addition, the combination of these chemical compounds more effectively increased the binding level of activated β-catenin destruction complex and β-catenin to enable phosphorylation, compared to gemcitabine alone. After phosphorylation, niclosamide – gemcitabine upregulated the ubiquitin level, which caused phosphorylated β-catenin to undergo proteasomal degradation; the combination was more potent than gemcitabine alone. Finally, the combination more effectively suppressed tumor growth in vivo, compared to gemcitabine alone. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect of gemcitabine in pancreatic cancer, by inducing the degradation of β-catenin with ubiquitination. Therefore, this drug combination can potentially be used in PDAC therapy.

Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway.

The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC-MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.

PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways

Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most difficult to treat cancers. Gemcitabine is still the standard of care treatment for PDAC but with modest survival benefit and well reported resistance. Here we explored potential of inhibiting p21 activated kinase 4 (PAK4), a downstream protein of KRAS oncogenic pathway, in combination with Gemcitabine in PDAC cells. PAK4 inhibition by KPT-9274 led to significant potentiation of Gemcitabine activity in PDAC cells, with an increase in apoptosis, DNA damage and cell cycle arrest. At molecular level, PAK4 inhibition dose dependently inhibited Gemcitabine-induced β-catenin, c-JUN and Ribonucleotide Reductase subunit 2 (RRM2) levels. PAK4 inhibition further inhibited levels of phosphorylated ERK (p-ERK); Gemcitabine-induced phosphorylated AKT (p-AKT), phosphorylated and total c-Myc. These results suggest possible role of β-catenin, p-ERK and p-AKT, key effector proteins of Wnt/β-catenin, MAPK and PI3K pathways respectively, in sensitisation of Gemcitabine activity with PAK4 inhibition. Our data unravel probable molecular mechanisms behind combination of PAK4 inhibition with Gemcitabine to counter PDAC, which may be unequivocally proved further with knock down of PAK4. Our findings provide a strong rationale to exploit the combination therapy of Gemcitabine and PAK4 inhibitor for PDAC at pre-clinical and clinical levels.

Retrospective evaluation of our patients diagnosed with advanced pancreatic cancer

Aims: Pancreatic cancer attracts attention with its increasing frequency among gastrointestinal cancers. It has the worst prognosis of all cancer types. In this study, we aimed to retrospectively evaluate the clinical features and treatment results of our patients with advanced pancreatic cancer. Methods: In this study, 131 patients diagnosed with advanced pancreatic cancer and admitted to the Ankara Numune Training and Research Hospital Medical Oncology Polyclinic between November 2002 and January 2014 were retrospectively analyzed. Demographic characteristics of the patients, smoking, family history, basal CEA and basal CA 19-9 levels, treatment modalities, metastasis sites, progression-free survival, and overall survival times were evaluated. Results: The study population consisted of 131 patients, including 94 males and 37 females. Twenty of the patients were in the locally advanced stage, and 111 were in the metastatic stage. The median age of the patients was 60 years. 53.4% of the patients were smokers, and the median amount of smoking was 30 packs/year. Adenocancer was the most common histopathological subtype. The median basal CEA and Ca 19-9 levels were high at the time of diagnosis. Neoadjuvant chemotherapy was given to all locally advanced patients. The most commonly used chemotherapy regimens were single-agent gemcitabine and gemcitabine-cisplatin combination therapies. While 10 of the locally advanced patients received local treatment (chemotherapy or surgery) after neoadjuvant chemotherapy, the remaining 10 patients could not receive local treatment. The median overall and progression-free survival times were found to be significantly longer in patients with locally advanced disease who received local treatment after neoadjuvant chemotherapy [(18 months vs. 6.5 months; p=0.008), (11.3 months vs. 6.4 months; p=0.05)]. The most common site of metastasis in our patients with metastatic pancreatic cancer was the liver (80%). Cisplatin-gemcitabine was preferred as a KT regimen in 63.4% of metastatic cases. The median overall survival time of the patients in the metastatic stage was 8.1 months, and the median progression-free survival time was 5.7 months. The median progression-free survival of all patients included in the study was 6.2 months, while the median overall survival was 8.8 months. Conclusion: The median overall survival of patients with locally advanced pancreatic cancer was significantly longer compared to metastatic patients (18 months vs. 8.1 months; p=0.028). Progression-free survival and overall survival of patients with locally advanced disease who received or did not receive local treatment after neoadjuvant chemotherapy were found to be significantly longer in patients who received local treatment. (11.3 months vs. 6.4 months; p=0.05) (18 months vs. 6.5 months; p=0.008). Response rates of patients with metastatic pancreatic cancer; It was 49% in the gemcitabine-cisplatin combination arm and 30% in the single-agent gemcitabine arm.

CPC11 Immune checkpoint inhibitor-associated eosinophilic fasciitis: a case report

Abstract A 67-year-old man presented with a 3-month history of skin tightness associated with shooting, burning pains and numbness on both his upper and lower limbs. The patient had a background of metastatic bladder cancer, treated with six cycles of gemcitabine and cisplatin therapy from September 2019 to January 2020. Following this, he also had radical radiotherapy to the bladder, and in August 2020, he started pembrolizumab therapy. Pembrolizumab was paused in February 2022 due to the development of immunotherapy-related myositis. On examination, the patient had visibly shiny and thickened skin bilaterally involving the upper and lower limbs. Symptoms significantly limited the patient’s mobility and daily activities. A skin biopsy showed marked reduction in elastin fibres and mild fibromuscular thickening around the blood vessels, suggestive of scleroderma. Following a joint rheumatology and dermatology multidisciplinary meeting, a diagnosis of eosinophilic fasciitis (EF) secondary to the checkpoint inhibitor pembrolizumab was made. This was further supported by lower limb magnetic resonance imaging, which demonstrated evidence of bilateral oedema of the soleus muscle tendinous junction. Eosinophilic fasciitis is characterized by inflammatory infiltration, thickening and fibrosis involving the fascia. Unlike scleroderma, patients, such as in our case, with EF do not have sclerodactyly, Raynaud phenomenon, telangiectasias or nailfold capillary changes. Clinical manifestations of EF involve sudden onset, and pain and erythema (usually bilaterally) of the affected extremities. Patients have also been known to develop joint contractures, morphoea-like lesions and inflammatory polyarthritis. The reported triggers and causative agents of EF include trauma, autoimmune disorders and drugs. Only 13 cases have been reported secondary to pembrolizumab therapy, and the median time of symptom onset is 12 months following the commencement of checkpoint inhibitor treatment. According to the literature, there may be an underlying diagnosis of a solid tumour, haematological disorder or autoimmune disease. High-dose prednisolone is the primary treatment of choice, followed by methotrexate. However, some patients have shown spontaneous recovery. Our patient has now started a treatment course of high-dose intravenous methylprednisolone and methotrexate. While the therapeutic outcome is too early to report, he has already noticed improvements in skin tightening of the lower limbs.

A multi-cohort phase I/IIa clinical trial to evaluate the safety, tolerability, and pharmacokinetics of TST001 administered as a monotherapy, with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors: TransStar101.

TPS4176 Background: Gastric cancer (GC) remains the 4th leading cause of cancer death worldwide, accounting for about 7.7% of all cancer related mortality. Despite recent approval of nivolumab in combination with chemotherapy, the median survival of treatment naïve Gastric Cancer/gastroesophageal junction cancer (G/GEJ) cancer is only approximately 14 months, even in patients with high CPS PD-L1. Targeting claudin 18.2 (CLDN18.2) in combination with chemotherapy is a clinically validated approach for patients with CLDN18.2 expressing advanced G/GEJ cancer. TST001 is a humanized monoclonal antibody with improved affinity to human CLDN18.2 and enhanced antibody-dependent cellular cytotoxicity (ADCC). In pre-clinical studies, TST001 treatment upregulates PD-L1 expression on CLDN18.2-positive tumor cells. The in vivo analysis showed anti-tumor efficacy of TST001 combined with anti-PD-1 antibody and chemotherapy was superior to combination of anti-PD-1 antibody with chemotherapy or combination of TST001 with chemotherapy. Promising anti-tumor activities have been observed in patients with advanced G/GEJ cancer who have been treated with TST001 alone or in combination with chemotherapy, making the combination of TST001, nivolumab and chemotherapy attractive. Methods: This is a multi-cohort, open-label, multi-center phase I/II first in human (FIH) study of TST001 administered as single agent, in combination with nivolumab or standard of care in the treatment of patients with locally advanced or metastatic solid tumors. Primary endpoints include characterization of TST001 safety profile and the maximum tolerated dose / recommended phase 2 dose. Secondary endpoints include pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. The study includes two parts. Part A (completed) is a dose escalation of TST001 as a monotherapy. Part B (ongoing) consists of three independent cohorts: cohort A includes combination TST001 + nivolumab+ leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) as 1st line treatment for G/GEJ cancer; cohort B includes TST001 in combination with nivolumab in advanced pre-treated G/GEJ cancer; cohort C includes combination therapy of TST001, gemcitabine, and nanoparticle albumin-bound paclitaxel as 1st line treatment for advanced/metastatic pancreatic cancer. Multiple doses and schedules will be assessed during Part B. Conclusions: Combination of TST001 with nivolumab and chemotherapy has the potential to improve the outcomes of patients with advanced or metastatic CLDN18.2 expressing G/GEJ cancer. Data from this trial will support the selection of the optimal dose and dose regimen of TST001 in these combinations. Enrollment in the trial is ongoing. Clinical trial information: NCT04396821 .

Long-term outcomes of pembrolizumab (pembro) in combination with gemcitabine (gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIUC): A multicenter phase 2 trial.

4509 Background: Trimodality therapy (TMT) is a standard treatment option for MIUC. We previously reported an early analysis of a phase II study of pembro added to standard TMT with maximal transurethral resection of bladder tumor (TURBT), hypofractionated RT and twice weekly gem (ASCO 2021). Herein we present updated follow up safety and efficacy results. Methods: In this multicenter phase 2 trial, patients (pts) with clinical T2-T4aN0M0 MIUC who were ineligible fpr or declined radical cystectomy, had ECOG PS 0/1 and eGFR≥30 cc/min were enrolled. Pts received pembro 200 mg IV x 1 followed by maximal TURBT and then whole bladder RT (52 Gy/20 fx) with twice weekly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. Response was assessed every 12 weeks post-RT with CT/MRI, tumor bed biopsy and cytology. The primary endpoint was 2-yr bladder-intact disease-free survival (BIDFS; first of MIUC, regional or distant metastases, cystectomy or death). Our study had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (Mak JCO 2014). Key secondary endpoints included safety, 12-week pathologic complete response (CR) rate, metastases-free survival (MFS) and overall survival (OS). Results: Between 5/2016 and 6/2022, 54 pts (median age 74 years, 72% male, 83% Caucasian; clinical stage: 74% T2, 22% T3 and 4% T4) were enrolled at 5 institutions. PD-L1 status was available in 43 pts, and 21 pts (49%) had modified proportion score≥10. Forty-six (88%) pts completed all therapy. 1/54 (2%), 3/54 (6%), and 4/54 (7%) discontinued RT/Gem, Gem or Pembro, respectively, most commonly due to toxicity. 6 pts (11%) underwent salvage cystectomies. As of 6/2022, with a median FU of 23 months (1.6- 62.7) there were 12 (22%) tumor recurrences (3 MIUC, 5 locoregional, 4 distant). 4 pts (7%) had non-muscle invasive only recurrences. The efficacy outcomes are shown. 10 pts died during the study period (18%; 3 from disease progression, 1 from treatment toxicity and 6 from unrelated/unknown causes). There were no new safety signals in our updated analysis: 13 pts (24%) experienced 17 AEs that were Grade 3 or greater (cytopenias [n=7], colitis [n=5], cystitis [n=2], polyneuropathy, fatigue, hypokalemia [n=1, each]). Grade 3 or greater immune-related AEs included 2 pts with colitis, 1 pt with polyneuropathy and 1 pt with Grade 5 colonic perforation. Conclusions: TMT combined with pembro was well tolerated and continues to show promising early outcomes data. A large phase 3 trial is underway to further explore this treatment. Clinical trial information: NCT02621151 . [Table: see text]

Betulinic acid, a major therapeutic triterpene of Celastrus orbiculatus Thunb., acts as a chemosensitizer of gemcitabine by promoting Chk1 degradation.

Celastrus orbiculatus Thunb., also called as oriental bittersweet vine or climbing spindle berry, a traditional Chinese herbal medicine has been used to treat a spectrum of painful and inflammatory diseases for centuries. Explored for their unique medicinal properties, C.orbiculatus offers additional therapeutic effects on cancerous diseases. The effect of single-agent gemcitabine on survival has not long been encouraging, combination therapies provide patients multiple chances of benefit for improved clinical response. This study aims at expounding the chemopotentiating effects and underlying mechanisms of betulinic acid, a primary therapeutic triterpene of C. orbiculatus in combination with gemcitabine chemotherapy. The preparation of betulinic acid was optimized using ultrasonic-assisted extraction method. Gemcitabine-resistant cell model was established by induction of the cytidine deaminase. MTT, colony formation, EdU incorporation and Annexin V/PI staining assays were used to evaluate cytotoxicity, cell proliferation and apoptosis in BxPC-3 pancreatic cancer cell line and H1299 non-small cell lung carcinoma cell line. Comet assay, metaphase chromosome spread and γH2AX immunostaining were applied for DNA damage assessment. Western blot and co-immunoprecipitation was used to detect the phosphorylation and ubiquitination of Chk1. Mode of action of gemcitabine in combination with betulinic acid was further captured in BxPC-3-derived mouse xenograft model. We noticed that the extraction method had an impact on the thermal stability of C. orbiculatus. Ultrasound-assisted extraction at room temperature in shorter processing time could maximize the overall yields and biological activities of C. orbiculatus. The major constituent was identified as betulinic acid, and the pentacyclic triterpene represented the prominent anticancer activity of C. orbiculatus. Forced expression of cytidine deaminase conferred acquired resistance to gemcitabine, while betulinic acid displayed equivalent cytotoxicity toward gemcitabine-resistant and sensitive cells. A combination therapy of gemcitabine with betulinic acid produced synergistic pharmacologic interaction on cell viability, apoptosis and DNA double-strand breaks. Moreover, betulinic acid abrogated gemcitabine-triggered Chk1 activation by destabilizing Chk1 loading via proteasomal degradation. The combination of gemcitabine and betulinic acid significantly retarded BxPC-3 tumor growth in vivo compared to single-agent gemcitabine treatment alone, accompanied with reduced Chk1 expression. These data provide evidence that betulinic acid is a potential candidate for chemosensitization as a naturally occurring Chk1 inhibitor and warrants further preclinical evaluation.

Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer

To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

MP08-09 Down-STAGING IN AUA RISK STRATIFICATION AFTER INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY HAS FAVORABLE EFFECT ON RECURRENCE FREE SURVIVAL AFTER 2ND LINE INTRAVESICAL GEMCITABINE CHEMOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP08-09 Down-STAGING IN AUA RISK STRATIFICATION AFTER INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY HAS FAVORABLE EFFECT ON RECURRENCE FREE SURVIVAL AFTER 2ND LINE INTRAVESICAL GEMCITABINE CHEMOTHERAPY Kyung Hwan Kim, Byeong Jin Kang, Gwon Kyeong Lee, Wooseop Seong, Kyoungha Jang, Ja Yoon Ku, and Hong Koo Ha Kyung Hwan KimKyung Hwan Kim More articles by this author , Byeong Jin KangByeong Jin Kang More articles by this author , Gwon Kyeong LeeGwon Kyeong Lee More articles by this author , Wooseop SeongWooseop Seong More articles by this author , Kyoungha JangKyoungha Jang More articles by this author , Ja Yoon KuJa Yoon Ku More articles by this author , and Hong Koo HaHong Koo Ha More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite intravesical bacillus Calmette-Guerin (BCG) therapy, 40% of non-muscle invasive bladder cancer (NMIBC) patients experience tumor recurrence within 2 years. Subsequent intravesical chemotherapy is an alternative option. We evaluated the effect of down-staging in American Urological Association (AUA) risk stratification after intravesical BCG therapy on recurrence free survival (RFS) after 2nd line intravesical gemcitabine chemotherapy. METHODS: Out of 78 patients who received intravesical gemcitabine therapy from 2019 to 2022, 50 patients who received intravesical BCG (1st line) and gemcitabine (2nd line) therapy were identified. We determined the AUA risk group at the initial diagnosis of NMIBC and after the surgical treatment for tumor recurrence despite intravesical BCG therapy. The risk group migration after intravesical BCG therapy were analyzed. Kaplan-Meier analysis was performed to estimate RFS after intravesical gemcitabine therapy. RESULTS: Median number of intravesical BCG and gemcitabine therapy were 9 and 10, respectively. At initial diagnosis, 5 (10.0%), 12 (24.0%) and 33 (66.0%) cases were classified as low, intermediate and high risk group, respectively. After intravesical BCG therapy, 11 of up-staging and 8 of down-staging events occurred leading to 7 (14.0%), 6 (12.0%) and 37 (74.0%) patients stratified as low, intermediate and high risk group, respectively. RFS rate after 2nd line intravesical gemcitabine was significantly higher in the down-staging cases than the other cases (Log rank p=0.039). Median time to recurrence in the down-staging group and the other group were not reached and 13 months, respectively. CONCLUSIONS: Recurrence free survival rate after 2nd line intravesical gemcitabine therapy was higher in the patients who experienced risk group down-staging after 1st line intravesical BCG therapy. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e96 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyung Hwan Kim More articles by this author Byeong Jin Kang More articles by this author Gwon Kyeong Lee More articles by this author Wooseop Seong More articles by this author Kyoungha Jang More articles by this author Ja Yoon Ku More articles by this author Hong Koo Ha More articles by this author Expand All Advertisement PDF downloadLoading ...