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Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in patients with advanced gastric or gastroesophageal junction ...adenocarcinoma with tumor progression after first-line therapy (N =592). We explored the association of tissue tumor mutational burden (tTMB) status and clinical outcomes in patients with GC enrolled in KEYNOTE-061, including the relationship with PD-L1 combined positive score (CPS) and microsatellite instability-high (MSI-H) status. Methods: In patients from KEYNOTE-061 with evaluable tumor and matched normal whole exome sequencing (WES) data (N = 420; pembrolizumab, 218; paclitaxel, 202), the association of tTMB (continuous log
10
scale) with confirmed ORR and PFS by blinded central radiology review per RECIST v1.1, and OS was evaluated within each treatment arm using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS). The clinical utility of tTMB was assessed using the prespecified cutoff of 175 mut/exome. Clinical data cutoff: October 26, 2017. Results: tTMB was significantly associated (α=0.05) with ORR, PFS, and OS in patients treated with pembrolizumab (one-sided P<0.001) but not paclitaxel (two-sided P>0.600). The area under the receiver operating characteristics curve for tTMB and response (pembrolizumab vs paclitaxel) was 0.68 (95% CI, 0.56-0.81) vs 0.51 (95% CI, 0.39-0.63). Patient outcomes by tTMB cutoff are reported in Table. There was low correlation between tTMB and PD-L1 CPS in both treatment arms (r<0.18). tTMB remained significantly associated with all clinical end points with pembrolizumab after adjusting for PD-L1 CPS and with PFS and OS after excluding MSI-H patients. Conclusions: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and response to pembrolizumab in patients with GC. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. Clinical trial information: NCT02370498 . Table: see text
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4503
Background: KEYNOTE-061 ( NCT02370498) is a global phase 3 study of pembrolizumab vs paclitaxel as second-line therapy for GC. At the time of primary analysis (data cutoff: Oct 26, ...2017), in patients with PD-L1–positive status (combined positive score CPS ≥1), pembrolizumab did not significantly prolong overall survival (OS) vs paclitaxel (9.1 months vs 8.3 months) but did elicit a longer duration of response (DOR) and a favorable safety profile vs paclitaxel. We present results of KEYNOTE-061 in patients with CPS ≥1, ≥5, and ≥10 after 2 additional years of follow-up (cutoff: Oct 7, 2019). Methods: Adult patients with GC that progressed after platinum + fluoropyrimidine chemotherapy were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for up to 35 cycles (~2 y) or standard-dose paclitaxel. OS and progression-free survival (PFS) in the CPS ≥1 population were the primary end points. Comparisons were made using stratified log-rank tests. Results: At the time of this analysis, 366/395 patients with CPS ≥1 had died (92.6%). Pembrolizumab prolonged OS vs paclitaxel in PD-L1–positive patients (Table). No significant differences appeared between groups in PFS (Table). Objective response rate (ORR) was higher for pembrolizumab in the CPS ≥10 group, and DOR was longer with pembrolizumab using all CPS cutoffs (Table). There were fewer drug-related adverse events (AEs) with pembrolizumab than paclitaxel in the overall population (53% vs 84%). Conclusions: This long-term analysis found that second-line pembrolizumab prolonged OS among patients with PD-L1–positive GC and led to fewer drug-related AEs vs paclitaxel. Clinical trial information: NCT02370498 . Table: see text
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4537
Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in pts with advanced gastric or gastroesophageal junction (GEJ) ...adenocarcinoma with tumor progression after first-line therapy (N = 592). In this analysis, we evaluated tTMB using FoundationOne CDx (F1CDx; Foundation Medicine) in pts with gastric or GEJ cancer in KEYNOTE-061. Methods: In pts with evaluable F1CDx tTMB data (n = 204), we analyzed the association of tTMB with confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) within each treatment arm using one-sided (pembrolizumab) and two-sided (paclitaxel) Wald test nominal P for logistic regression (ORR) and Cox proportional hazards regression (PFS; OS) adjusted for ECOG performance status; significance was prespecified at 0.05. The clinical utility of tTMB was assessed using the prespecified cutoff of 10 mut/Mb for F1CDx. Clinical data cutoff: Oct 26, 2017. Results: tTMB was positively associated with ORR ( P < 0.001; AUROC, 0.68), PFS ( P < 0.001), and OS ( P = 0.003) with pembrolizumab but not paclitaxel (ORR, P = 0.047; AUROC, 0.30; PFS, P = 0.605; OS, P = 0.084). Pt outcomes by tTMB cutoff are reported in the Table; prevalence of TMB ≥10 mut/Mb was 17%. In pts with microsatellite stable disease-only, HRs (95% CI) by treatment arm for OS by F1CDx cutoff were 0.40 (0.14-1.17) for tTMB ≥10 mut/Mb (n = 21) vs 0.97 (0.70-1.34) for tTMB <10 mut/Mb (n = 168). Conclusions: In this exploratory analysis from KEYNOTE-061, tTMB as determined by F1CDx demonstrated a positive association with clinical outcomes with pembrolizumab, but not paclitaxel, in pts with GC; these findings are consistent with those reported with whole exome sequencing. Pembrolizumab demonstrated an OS benefit vs paclitaxel in the subgroup with tTMB ≥10 mut/Mb, which remained when pts with microsatellite instability-high disease were excluded. Clinical trial information: NCT02370498 . Table: see text
Background
Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-β (TGFβ), which can be overexpressed in these tumors, may enhance ...responses to programmed cell death protein 1/programmed death-ligand 1 PD-(L)1 inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβ receptor II (TGFβRII) (a TGFβ “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1.
Objective
The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1–unselected esophageal SCC.
Patients and Methods
In a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity.
Results
By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval CI 2.1–26.5); responses lasted 2.8–8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7–38.6). Median overall survival was 11.9 months (95% CI 5.7–not reached).
Conclusions
Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC.
Clinical Trials Registration
NCT02699515.
Abstract Objective Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the ...association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer. Methods Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles. Results Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes. Conclusion The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer.
Due to improved survival rate, gastric cancer (GC) patients have an increased risk of developing multiple primary cancer (MPC). The purpose of this study is to evaluate the clinicopathological ...features of MPC and to generate useful tools for the prediction of metachronous MPC following gastrectomy.
3066 patients who underwent curative resection of GC were reviewed retrospectively, based on the clinical information and the medical record.
The 5-year incidence of MPC was 2.5%. Of these, 54.3% had a metachronous MPC, while 45.7% had a synchronous MPC. The most prevalent site of metachronous MPC was the colorectum (26.3%), followed by lung (23.7%) and liver (18.4%). Multivariate logistic regression analysis revealed that old age at the time of GC diagnosis (≥60 years), early stage of GC (stage I and II), and multiplicity of GC at the time of gastrectomy were independent predictive factors for metachronous MPC. GC patients with either metachronous or synchronous MPC showed poorer survival than patients without MPC. In addition, patients with a metachronous MPC showed late survival disadvantage, while patients with a synchronous MPC showed early survival disadvantage. Furthermore, we were able to develop and internally validate a nomogram to predict the metachronous MPC after curative gastrectomy (C-index = 0.72).
Patients at high risk of developing metachronous MPC after curative resection of GC were identified. Individual risk of developing metachronous MPC could be predicted by a novel nomogram. Further external validation with independent patient cohorts is required to improve the accuracy of prediction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We aimed to evaluate the long-term surgical outcomes of patients with hypertrophic obstructive cardiomyopathy and explore the risk factors for mortality, especially those related to atrial ...fibrillation.
We retrospectively reviewed 150 consecutive patients with hypertrophic obstructive cardiomyopathy who underwent surgical treatment between March 2003 and December 2020.
Fifty (33.3%, age 53.7±16.1 years) patients underwent isolated septal myectomy (SM), 79 (52.7%, age 52.3±12.6 years) underwent SM with mitral valve intervention (SM + MVI), and 21 (14.0%, age 57.1±13.5 years) underwent SM with mitral valve replacement (SM + MVR). Overall peak left ventricular outflow tract pressure gradient at rest was significantly decreased from 91.9±43.2 to 13.3±13.0 mmHg (P<0.0001). Survival rates were 96.7%, 89.1%, and 81.5% at 30 days, 5 years, and 10 years, respectively. Patients in the SM + MVI group survived longer than those in SM + MVR or isolated SM groups (94.1%
75.4%
88.0%, respectively, at 5 years, P=0.05). Patients with preoperative atrial fibrillation had a worse 5-year survival rate than those without atrial fibrillation (73.4%
92.8%, respectively, P<0.001). Preoperative atrial fibrillation was an independent risk factor for late mortality in multivariable analysis. Notably, those whose atrial fibrillation was successfully eradicated by surgical ablation had a better 5-year survival rate than other patients (87.7%
28.6%, respectively, P<0.001).
Surgical outcomes in hypertrophic obstructive cardiomyopathy are favorable in the long-term, except in patients with preoperative atrial fibrillation. Therefore, intraoperative ablation for preoperative atrial fibrillation in hypertrophic obstructive cardiomyopathy should be actively considered to improve patient outcomes.
Abstract
Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), which contributes to the development and progression of GC. BRD4 is one of the leaders for ...epigenetic regulation and is known to regulate the expression of oncogenes such as c-MYC, BCL-2, and CDK4. In a previous study, we evaluated the efficacy of iBET-151 in a large panel of GC cell lines and xenograft mouse models. We found that iBET-151 showed a modest growth-inhibitory effect in GC cells. Recent report showed, lowering the expression of BCL-2 and BCL-xL, which are the targets of BRD4, induces sensitivity to paclitaxel, frequently used antimitotic agent in GC. Therefore, we evaluate iBET-151 plus paclitaxel as a new combination treatment regimen for GC. The synergistic effect and possible mechanisms of iBET-151 with paclitaxel were evaluated in 49 GC cell lines or 10 GC organoids using cell proliferation assay, flow cytometry, western blotting, colony formation, and migration assays. We found that the addition of iBET-151 increased the sensitivity to paclitaxel alone treatment from 15% to 50% in approximately 70% (34/49) of GC cells. iBET-151 plus paclitaxel significantly promoted cell-cycle arrest at G1 or G2/M phase and increased sub-G1 phase and cleaved PARP expression, which correlates to increased cell death. Also, combined treatment suppressed c-Myc, Bcl-2, and Bcl-xL expression in AGS, YCC-1, YCC-32, and YCC-34. We found BET proteins were overexpressed in most patient-derived GC organoids whereas c-Myc, BCL-2, and BCL-xL were expressed at variable levels. We observed that there was a synergistic growth inhibition in 6 out of 10 (60%) organoids. The data suggests iBET-151 and paclitaxel have a synergistic effect not only in GC cell lines but also in GC organoids. In summary, our data show the combination of iBET-151 and paclitaxel resulted in markedly higher anti-tumor effects compared with either treatment alone for GC. With further studies to validate the efficacy and biomarker explorations, the combination of iBET-151 and paclitaxel represents a promising therapeutic strategy in GC.
Citation Format: Sun Kyoung Kang, Sang Woo Cho, Woo Sun Kwon, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha. Increasing efficacy of iBET-151, a small molecule inhibitor of BET protein in combination with paclitaxel in gastric cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5700.
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Background: The MORPHEUS platform comprises multiple Ph Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Due to the ...immune-mediated effects of BL-8040, a high-affinity antagonist for CXCR4, it was tested with atezo (anti-PD-L1) in pts with advanced/metastatic (m) PDAC and GC. Methods: In 2 separate randomized trials, pts with mPDAC or advanced/mGC who progressed on 1L chemo received either atezo + BL-8040 (BL-8040 1.25 mg/kg SC D1-5, then BL-8040 1.25 mg/kg SC TIW + atezo 1200 mg IV Q3W) or control tx (M-PDAC: mFOLFOX-6 or gemcitabine + nab-paclitaxel; M-GC: paclitaxel + ramucirumab). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: Efficacy from evaluable pts followed for ≥18 wks in M-PDAC and ≥8 wks in M-GC is summarized in the table; 24-wk M-GC data will be presented. There were 15 safety-evaluable pts in each M-PDAC arm, as well as 13 in the atezo + BL-8040 and 12 in the control arm of M-GC. Gr 3-5 AEs were seen in 47% of pts on atezo + BL-8040 and 67% on control in M-PDAC, and 77% on atezo + BL-8040 and 67% on control in M-GC. Tx-related SAEs in M-PDAC occurred in 7% of pts on atezo + BL-8040 and 20% on control, and in M-GC, in 8% of pts on control. No Gr 5 AEs occurred in atezo + BL-8040 arms. Tx-related AEs led to 7% and 8% of pts discontinuing tx in the M-PDAC and M-GC control arms, respectively, and 15% discontinuing BL-8040 in M-GC due to Gr 3 injection-related reactions. Biomarker and PK data will be presented. Conclusions: Atezo + BL-8040 had limited efficacy for PDAC or GC. Tx-related AEs with atezo + BL-8040 were consistent with each agent’s known safety profile. Clinical trial information: NCT03281369; NCT03193190 . Table: see text
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