Association of KMT2C mutations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2600-2600
Author(s):  
Chunling Liu ◽  
Qianqian Duan ◽  
Qin Zhang
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Multiple Cancer ◽  
Multiple Tumor ◽  
Potential Biomarker ◽  
Chinese Cohort ◽  
Pan Cancer

2600 Background: The KMT2 (lysine methyltransferase) family of histone modifying proteins play important roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many solid tumor cancers. Recently, there is emerging evidence that KMT2 family genes are involved in sensitivity to immune checkpoint inhibitors (ICIs) by modulating the immune environment. Here we explored the relationship between KMT2C mutation and its efficacy of immunotherapy. Methods: 1661 patients with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC clinical cohort were used to explore the association with KMT2C mutation and TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 6624 pan-cancer patients who also detected MSI and PD-L1 expression from the Chinese clinical dataset were also analyzed relevance of mutation and these immune-related indicators. Results: In total, 9.81% (163/1661) patients in MSKCC cohort harbored KMT2C mutation. In the Chinese cohort, the KMT2C mutation ratio (11.19%, 741/6624) was similar to MSKCC. The TMB level of KMT2C mutation group in both MSKCC cohort and Chinese pan-cancer patient cohort was significantly higher than wild-type group (P < 0.001). A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was significantly associated with better OS (hazard ratio, 0.69; 95%CI, 0.52-0.90; P = 0.006), and association remained significant with bladder (P = 0.039), colorectal (P = 0.024), melanoma (P < 0.001) and renal (P < 0.001), adjusting for cancer age, sex, metastases or primary. In addition, in Chinese cohort, KMT2C mutation was associated with higher PD-L1 positive expression (≥1%) (P = 0.01203) and MSI-H (P < 0.001). Conclusions: KMT2C mutation shows impressive association with efficacy of ICIs. Meanwhile, KMT2C-mutant group has a higher TMB, PD-L1 expression and MSI-H. These results indicated that KMT2C mutation may serve as a good potential biomarker of ICI benefit in patients with multiple cancer types.

The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer

Oncology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Oded Jacobi ◽  
Yosef Landman ◽  
Daniel Reinhorn ◽  
Oded Icht ◽  
Michal Sternschuss ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Negative Relationship ◽  
Progression Free Survival ◽  
Significant Negative Correlation ◽  
Cox Proportional Hazards ◽  
Diabetic Patients

<b><i>Introduction:</i></b> Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. <b><i>Methods:</i></b> All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, <i>t</i> tests, and χ<sup>2</sup> tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. <b><i>Results:</i></b> Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01–2.06], <i>p</i> = 0.011, and HR 1.5 [1.08–2.08], <i>p</i> = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], <i>p</i> = 0.79, and HR 1.29 [0.69–2.39], <i>p</i> = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. <b><i>Conclusion:</i></b> Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

scholarly journals Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 678 ◽  
Author(s):  
Adrien Procureur ◽  
Audrey Simonaggio ◽  
Jean-Emmanuel Bibault ◽  
Stéphane Oudard ◽  
Yann-Alexandre Vano
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Immunogenic Cell Death ◽  
Dna Damages ◽  
Multiple Tumor ◽  
Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

scholarly journals Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

2020 ◽  
Vol 22 (1) ◽  
pp. 190
Author(s):  
Fulvio Borella ◽  
Mario Preti ◽  
Luca Bertero ◽  
Giammarco Collemi ◽  
Isabella Castellano ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Survival Rates ◽  
Younger Women ◽  
Multiple Tumor ◽  
Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

TERT promoter mutation as a prognostic marker in patients with advanced urothelial carcinoma treated with immune checkpoint inhibitors.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 476-476
Author(s):  
Ivan de Kouchkovsky ◽  
Li Zhang ◽  
Errol Philip ◽  
Francis Wright ◽  
Daniel Myung Kim ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Genomic Profiling ◽  
Clinical Variables ◽  
Tert Promoter ◽  
Visceral Metastases

476 Background: Reliable predictive markers are lacking in patients (pts) with locally advanced or metastatic urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICI). We sought to determine whether specific genomic alterations could be used to predict overall survival (OS) in this patient population. Methods: We undertook a retrospective cohort study of pts with aUC who received ICI and underwent genomic profiling by next-generation sequencing (NGS). All patients underwent NGS using commercially available platforms (e.g. Foundation Medicine, Strata, Invitae), or testing on the CLIA-certified institutional panel UCSF500. Associations between the 20 most frequently altered genes and OS were first examined by Cox regression. Genes with a p <0.1 on univariate analysis and relevant clinical variables were then included in a multivariable analysis. Results: We identified 78 pts treated with ICI for aUC with available genomic profiling results. Median age at ICI initiation was 71; the majority of patients had visceral metastases (70.5%), ECOG performance status ≤1 (62.8%) and received ICI in the post-platinum setting (52.6%). Objective response rate in this cohort was 35.9%, median progression free survival was 4.0 months (95% CI 2.6-10.5) and median OS was 17.5 months (95% CI 14.1-NR) from ICI start. The most commonly altered genes were the TERT promoter (TERTp) (61%), TP53 (52%), RB1 (31%), CDKN2A(29%) and CDKN2B (27%). On univariable analysis there was a trend towards longer OS in pts with TERTp mutations (HR 0.53, 95% CI 0.27-1.06, p = 0.07), and shorter OS in pts with CDKN2B mutations (HR 1.91, 95% CI 0.98-3.73, p = 0.06). Both mutations were included in a multivariable analysis. After adjusting for known prognostic variables (ECOG PS, visceral metastases, albumin, hemoglobin, body mass index [BMI], neutrophil to lymphocyte ratio [NLR], and histology), the presence of a TERTp mutation was significantly associated with improved OS (HR 0.30, 95% CI 0.10-0.93, p = 0.04; Table). Conclusions: The presence of a TERTp mutation was an independent predictor of improved OS in a cohort of aUC pts treated with ICI. Other common mutations and clinical variables were not associated with OS on a multivariable analysis. These findings are hypothesis-generating and prospective validation is needed. [Table: see text]

scholarly journals Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Juan Chen ◽  
Aiqun Ren ◽  
Liang Zheng ◽  
En-Dian Zheng ◽  
Tao Jiang
Keyword(s):  
Combination Therapy ◽  
Liver Metastases ◽  
Predictive Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intrinsic Resistance ◽  
The Impact ◽  
Pan Cancer ◽  
Negative Predictive Factor

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P &lt; 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P &lt; 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.

Host metabolic factors and prognosis in patients treated with immune checkpoint inhibitors for advanced malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14162-e14162
Author(s):  
Federica Biello ◽  
Marco Audisio ◽  
Silvia Genestroni ◽  
Gloria Borra ◽  
Francesca D'Avanzo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Advanced Melanoma ◽  
Host Metabolism ◽  
Increase In Risk

e14162 Background: It is well established that an altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced melanoma, kidney and non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1). Methods: The relationship between presence of type 2 diabetes mellitus (DMII) at baseline and outcome was assessed in 187 patients treated with immune checkpoint inhibitors in two cancer centers. Progression Free Survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to age, gender, BMI (normal < 25 kg/m2, overweight 25-30 kg/m2, obese > 30 kg/m2), type of cancer and line of treatment. Results: One-hundred-sixty-eight patients were available for our analysis. Twenty-eight patients (17%) were diabetic at baseline. Median age was 65 (range 25-80); 83 patients were males (49%); 82 (48%) had advanced melanoma, 83 (49%) NSCLC and 3 (3%) kidney cancer. One-hundred-two (60%) patients had BMI < 25, 51 (30%) were overweight and 16 (10%) were obese. The first line of treatment was immunotherapy in 83 (49%) patients. By univariable analysis median PFS was 4.2 months in non diabetics vs 6.4 in diabetics patients (HR 0.95; 95%CI 0.58-1.58); median OS was 6.17 and 9.1 months, respectively (HR 1.00; 95%CI 0.58-1.75). At multivariable analysis, taking into account DMII, BMI, sex, age, line of treatment and type of cancer, we found that BMI ≤25 was associated with a two fold increase in risk of progression (PD) or death (p = 0.005), whereas patients who received immunotherapy as second or subsequent line had a two fold increase in risk of PD or death (p = 0.003). Conclusions: The results of our analysis show that in patients with advanced cancer treated with immune checkpoint inhibitors, the presence of DMII does not adversely affect the clinical outcome. Conversely, lower BMI was associated with a significantly worse PFS and OS, independently from type of cancer, age and gender. As expected, patients who received immunotherapy in later lines of treatment had a significantly shorter survival.

Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15100-e15100 ◽  
Author(s):  
Prantesh Jain ◽  
Jahir Gutierrez Bugarin ◽  
Avirup Guha ◽  
Chhavi Jain ◽  
Tingke Shen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Liver Disease ◽  
Cancer Patients ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cox Proportional Hazards ◽  
Cancer Type ◽  
Real World Data

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

Efficacy of immune checkpoint inhibitors in patients with brain metastasis from NSCLC, RCC, and melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 214-214 ◽  
Author(s):  
Adam Lauko ◽  
Bicky Thapa ◽  
Xuefei Jia ◽  
Manmeet Singh Ahluwalia
Keyword(s):  
Brain Metastasis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Tertiary Care ◽  
Multivariable Analysis ◽  
Volumetric Analysis ◽  
Cell Lung Carcinoma ◽  
Combination Methods

214 Background: Immune checkpoint inhibitors are revolutionizing the treatment of multiple advanced malignancies, however, there is limited data on the efficacy of immune checkpoint blockade in brain metastasis. We conducted a study to analyze the overall survival (OS) and progression-free survival (PFS) among patients with brain metastasis from Non-Small Cell Lung Carcinoma (NSCLC), Renal Cell Carcinoma (RCC), and Melanoma treated with either Nivolumab, Pembrolizumab, Ipilimumab or a combination. Methods: After IRB approval, we retrospectively evaluated patients with brain metastasis treated at our tertiary care institution from 2011-2017 who underwent immunotherapy and one or more of the following; whole brain radiation therapy (WBRT), surgery, stereotactic radiosurgery (SRS) or systemic chemotherapy. Univariable and multivariable analysis was utilized to analyze OS and PFS. Volumetric analysis to assess treatment response is ongoing. Results: A total of 128 patients were identified with a median age of 60.6 years. 49% of patients were male; 77% of patients had a good (0 or 1) ECOG performance scores at the time of the brain metastasis; 83 patients had supratentorial brain metastasis, 11 had infratentorial and 24 had both. The prevalence of mutations was 34% in NSCLC patients, 58% in melanoma, and 0% in RCC. The median OS from the start of immunotherapy was not reached for RCC and was 17.1 and 28.9 months for Melanoma and NSCLC respectively. Median PFS was 5.9, 6.7 and 3.6 months for RCC, Melanoma, and NSCLC respectively. On multivariable analysis, SRS, sex and the number of cycles of immunotherapy had statistically significant hazard ratios. Conclusions: Immune checkpoint inhibitors are efficacious in the treatment of brain metastasis. Further analysis including response criteria using volumetric analysis is ongoing and final results will be presented at the meeting. [Table: see text]

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