Showing papers by "Won Ki Kang published in 2023"
TL;DR: Jang et al. as mentioned in this paper found that the optimal value of tumor mutational burden (TMB) for predicting the overall response of immune checkpoint inhibitors was defined as 13.31 mutations/megabase (mt/mb), with 56% sensitivity and 95% specificity.
Abstract:
Background: The optimal value of tumor mutational burden (TMB) for predicting treatment response of immunotherapy in advanced gastric cancer (AGC) is still unclear. We aimed to establish the optimal cut-off value of TMB, and evaluate the efficacy of immunotherapy in AGC according to TMB and other markers.
Method: From October 1, 2020, to July 27, 2021, at Samsung medical center in Korea, patients with AGC, who received pembrolizumab or nivolumab were included. TMB was measured by next-generation sequencing (NGS)-based assays, and PD-L1 is tested using immune-histochemical assay 22C3 pharmDx. Based on receiver operating characteristic analysis, the cut-point value of TMB was determined as the point where the Youden’s index is maximum.
Result: A total of 53 patients were analyzed. The cut-off value of TMB for predicting the overall response of immune checkpoint inhibitors was defined as 13.31 mutations/megabase (mt/mb), with 56% of sensitivity and 95% of specificity. Under this definition of TMB, 7 patients were TMB-high group (≥13.31 mt/mb), while 46 patients were TMB-low group (<13.31 mt/mb). The overall response rate (ORR) had a statistically significant difference between TMB-low (8.7%, n=4/46) and TMB-high patients (71.4%, n=5/7; p=0.001). The progression-free survival (PFS) and overall survival (OS) for 53 patients were 1.93 months (95% CI, 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The OS was longer in the TMB-high group with the median of 20.8 months (95% CI, 2.292-39.281) compared to the TMB-low group with the median of 3.31 months (95% CI, 1.604-5.019; p=0.049). The ORR of the patients whose PD-L1 CPS was 1 or above was not different from the patients whose PD-L1 CPS was lower than 1.
Conclusion: In this study, the optimal value of TMB for predicting the objective response rate of immunotherapy in AGC was determined as 13.31 mt/mb. TMB-high (≥13.31 mt/mb) was associated with a better objective response rate, and TMB-high patients exhibited better overall survival. TMB has the potential for predicting therapeutic response to immunotherapy in advanced gastric cancer.
Citation Format: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Ye Ji Jung, Daeho Choi, Joohyun Hong, Jeeyun Lee, Won Ki Kang, Seung Tae Kim. Tumor mutational burden, as a potential predictive marker for the efficacy of immunotherapy in advanced gastric cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4405.
TL;DR: In this article , the maximum tolerated dose (MTD) of Minnelide monotherapy and the MTD of minnelide in combination with paclitaxel in refractory GC patients were determined.
Abstract: 414 Background: Minnelide is a prodrug that rapidly releases the active compound triptolide when exposed to phosphatases in the bloodstream. Triptolide is a diterpene that has been shown to inhibit tumor cell proliferation and induce apoptosis in various cancer types. The anti-tumor effect of triptolide is the result of inhibition of heat shock protein (HSP) 70 expression. In GC Minnelide inhibits Sp1 to decrease HSP70 and induce cell death in preclinical data. Methods: This phase 1 trial was designed to determine the maximum tolerated dose (MTD) of Minnelide monotherapy and the MTD of Minnelide in combination with paclitaxel in refractory GC patients. There were 6 cohorts tested in this trial: cohort A: Minnelide 1 mg qd D1-21, q 28 days; cohort B: Minnelide 1.25 mg qd D1-21, q 28 days; cohort C: 1.5 mg qd D1-21, q 28 days; cohort D: Minnelide 0.25 mg D1-21 + weekly paclitaxel 60 mg/m2 on D1, D8, D15; cohort E: Minnelide 0.5 mg qd D1-21+ weekly paclitaxel 80 mg/m2 on D1, D8, D15; cohort F: Minnelide 0.75 mg qd D1-21+ weekly paclitaxel 80 mg/m2 D1, D8, D15. Results: From Feb 2021 to Sep 2022, 23 GC patients were enrolled (cohort A – C, N=10; cohort D-F, N=12). All patients had metastatic disease at the time of study enrollment. 20 of 23 patients received the study treatment as >= 3rd-line (range, 2 – 6th line). In all, 3 patients had HER2 positive GC and 10 patients had PDL1 + tumor. In the monotherapy cohorts, there were no DLTs observed, and the regimen was tolerated well. One patient achieved confirmed PR which lasted for 6 months. For the combination arm (cohort D-F), there were no DLTs observed. Of the 11 patients who were evaluable for treatment response, there were 1 PR, 5 SDs and 5 PDs. Two of five patients who achieved stable disease had durable stable disease for > 6 months on study treatment. In the combination cohorts, the most common adverse events of any grade were neutropenia; however, there was no neutropenic fever or treatment related mortality. Conclusions: Minnelide in combination with weekly paclitaxel demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: Underreview .
TL;DR: For example, this paper showed that adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients.
Abstract: Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov: NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.
TL;DR: Jeon et al. as mentioned in this paper showed that ramucirumab plus paclitaxel as second-line therapy was not sufficient in advanced gastric cancer patients who previously treated with first-line nivolumab+ chemotherapy.
Abstract:
Background: For human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC), a combination of fluoropyrimidines and platinum agents was the standard first-line treatment. After the failure of the first-line therapy, ramucirumab plus paclitaxel was the standard second-line treatment. In the CheckMate 649 study, nivolumab plus chemotherapy has been considered a new standard first-line treatment in previously untreated AGC. However, the role of ramucirumab plus paclitaxel as 2nd line after the failure of nivolumab plus chemotherapy is not confirmed.
Methods: We analyzed AGC patients with ramucirumab plus paclitaxel as second-line therapy, who failed the nivolumab plus chemotherapy (capecitabine plus oxaliplatin (XELOX) or 5-fluorouracil plus oxaliplatin (FOLFOX)) as frontline therapy at Samsung Medical Center, South Korea.
Results: Under the routine clinical practice, 23 AGC patients, who progressed after first-line chemotherapy with nivolumab plus chemotherapy, were treated with ramucirumab plus paclitaxel between Dec 2021 to Sep 2022. The median age was 56 (range, 24-76), and 18 (78.3%) patients received nivolumab plus XELOX, while 5 (21.7%) patients received nivolumab plus FOLFOX. The overall response rate (ORR) to ramucirumab plus paclitaxel was 10.0% (2 of PR) and the disease control rate was 55.0%. At the median follow-up of 4.5 months, the median progression-free survival (PFS) from second-line ramucirumab plus paclitaxel commencement was 2.7 months (95% confidence interval (CI), 1.7-3.7); 6.9 months (95% CI, not calculated) in the first nivolumab plus chemotherapy responders(n=7), and 2.3 months (95% CI, 1.6-3.0) in non-responders(n=15) (p=0.232). At the time of data cutoff, 6 patients continued to receive ramucirumab plus paclitaxel and the median OS was 6.3 months (95% CI, 4.9-7.7).
Conclusions: This analysis showed that ramucirumab plus paclitaxel as 2nd line therapy was not sufficient in AGC patients after the failure for nivolumab plus chemotherapy. The new innovative 2nd line therapy might be needed in AGC patients after nivolumab plus chemotherapy.
Citation Format: Youngkyung Jeon, Sun Young Jeong, Jaeyeon Jang, Ye Ji Jung, Daeho Choi, Joohyun Hong, Seung Tae Kim, Won ki Kang, Jeeyun Lee. Ramucirumab plus paclitaxel as second-line treatment in patients with advanced gastric cancer who previously treated with first-line nivolumab plus chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6756.