scholarly journals IMMU-02. THE SURVIVAL OUTCOMES ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS FOR NON-SMALL CELL LUNG CARCINOMA PATIENTS WITH BRAIN METASTASES IN THE UNITED STATES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii104-ii105
Author(s):  
Nayan Lamba ◽  
Timothy Smith ◽  
Bryan Iorgulescu
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Newly Diagnosed ◽  
Survival Analyses ◽  
Stage 4 ◽  
Insured Patients

Abstract BACKGROUND Management of advanced NSCLC has been transformed by PD-1/PD-L1 immune checkpoint inhibitors (ICI), with FDA approvals in 2015 (second-line) and 2016 (first-line). Because patients with brain metastases (BMs) were disproportionately excluded from the pioneering trials, herein we evaluated the overall survival (OS) associated with ICI in NSCLC BMs nationally. METHODS Patients newly-diagnosed with stage 4 NSCLC, including BMs, from 2010–2016 were identified from the National Cancer Database (comprising >70% of all newly-diagnosed cancers in the U.S.) Post-approval, median time from diagnosis to ICI was 58days, and this timepoint was selected for all landmark survival analyses (logrank test and multivariable Cox regression) and for multivariable logistic regression to identify predictors of ICI utilization. RESULTS 50,858 patients presented with advanced NSCLC that involved the brain: representing 27.6% of all newly-diagnosed stage 4 cases. Following initial FDA approvals in 2015, ICI rates for BM patients rose from 7.2% in 2015 to 12.7% in 2016. OS for NSCLC BMs for patients diagnosed post-approval (median 6.3 months, 95%CI: 6.0–6.6) was substantially better than those diagnosed pre-approval (median 5.5 months, 95%CI: 5.4–5.7, p< 0.001) and, in fact, than those diagnosed in 2014 (median 5.9 months, 95%CI: 5.6–6.1, p=0.002). Among patients diagnosed post-approval, ICI receipt demonstrated substantially improved OS in landmark survival analyses (median 13.8 months, 95%CI: 12.2–15.1; vs. 8.5 months, 95%CI: 8.3–8.9, p< 0.001); benefits which persisted in multivariable landmark survival analyses (HR 0.83, 95%CI: 0.71–0.96, p=0.02), independent of patient characteristics, other therapies, and extracranial disease. For patients diagnosed post-approval, who reached the landmark timepoint, ICI receipt was independent of patient demographics, socioeconomic status, and hospital type—with the exception of Medicaid-insured patients, who were less likely than privately-insured patients to receive ICI (OR 0.77, 95%CI: 0.60–0.97, p=0.03). CONCLUSIONS Nationally, the dramatic OS benefits of ICIs for advanced NSCLC were also demonstrated for patients with BMs.

196 Checkpoint blockade therapy for brain-metastatic non-small cell lung cancer: a comparative effectiveness analysis of national data

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A211-A211
Author(s):  
Nayan Lamba ◽  
Bryan Iorgulescu
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Second Line ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
Survival Analyses ◽  
Stage 4 ◽  
Insured Patients

BackgroundManagement of advanced non-small cell lung carcinoma (NSCLC) has been transformed by PD-1/PD-L1 immune checkpoint inhibitors (ICI), with FDA approvals in 2015 (second-line) and 2016 (first-line). Despite ~40% of NSCLC patients developing brain metastases, these patients were disproportionately excluded from the pioneering ICI trials. Thus herein we evaluate the overall survival (OS) associated with ICI in NSCLC brain metastases nationally.MethodsPatients newly-diagnosed with stage 4 NSCLC, including brain metastases, from 2010–2016 were identified from the National Cancer Database (comprising >70% of all newly-diagnosed cancers in the U.S.) Landmark survival analysis was used to address immortal time bias. Post-approval, median time from diagnosis to ICI was 58 days, and this timepoint was selected for all landmark survival analyses (OS estimated by Kaplan-Meier technique, and compared by logrank test and multivariable Cox regression) and for multivariable logistic regression to identify predictors of ICI utilization.Results50,858 patients presented with advanced NSCLC that involved the brain: representing 27.6% of all newly-diagnosed stage 4 cases. Following initial FDA approvals in 2015, ICI use in brain metastasis patients rose from 7.2% in 2015 to 12.7% in 2016. OS for NSCLC brain metastasis patients diagnosed post-approval (i.e. 2015, median 6.3 months, 95% [confidence interval] CI: 6.0–6.6) was substantially better than those diagnosed pre-approval (median 5.5 months, 95%CI: 5.4–5.7, p<0.001) and, in fact, than those diagnosed in 2014 (median 5.9 months, 95%CI: 5.6–6.1, p=0.002). Among patients diagnosed post-approval (in 2015, n=7,431), ICI receipt demonstrated substantially improved OS in landmark survival analyses (median 13.8 months, 95%CI: 12.2–15.1; vs. 8.5 months, 95%CI: 8.3–8.9, p<0.001) – benefits which persisted in multivariable landmark survival analyses (hazard ratio [HR] 0.83, 95%CI: 0.71–0.96, p=0.02), independent of patient characteristics, other therapies, and extracranial disease. For patients diagnosed post-approval, who reached the landmark timepoint, ICI receipt was independent of patient demographics, socioeconomic status, and hospital type—with the exception of Medicaid-insured patients, who were less likely than privately insured patients to receive ICI (OR 0.77, 95%CI: 0.60–0.97, p=0.03).ConclusionsNationally, the use of ICI for NSCLC brain metastasis patients is increasing, generally without significant socioeconomic barriers. Brain metastasis patients diagnosed in the post-approval second-line ICI era (2015) demonstrated significantly better OS than patients diagnosed pre-approval and even than patients diagnosed only in 2014. ICI was associated with a >60% relative increase in median OS. Together our findings from a real-world population demonstrate that the dramatic OS benefits of ICIs for advanced NSCLC also extended to brain metastasis patients.

scholarly journals Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases

2018 ◽  
Vol 140 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Tyler P. Robin ◽  
Robert E. Breeze ◽  
Derek E. Smith ◽  
Chad G. Rusthoven ◽  
Karl D. Lewis ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Newly Diagnosed ◽  
Melanoma Brain Metastases

63 Microsatellite instability/mismatch repair biomarker testing disparities in patients with advanced colorectal cancer: Implications for immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A68-A68
Author(s):  
Bryan Iorgulescu
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Care Setting ◽  
Colorectal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Newly Diagnosed ◽  
Stage 4 ◽  
Race Ethnicity

BackgroundImmune checkpoint inhibitors have revolutionized outcomes for patients with a spectrum of cancer types, including the first tissue/site-agnostic FDA approvals (in 2017 for 2nd-line and 2020 for 1st-line) for advanced cancers with DNA microsatellite instability-high/mismatch repair deficiency (MSI-High/MMRd). However, the factors associated with patients‘ access to MSI/MMR testing are unknown.MethodsPatients ≥20-years-old who newly presented with histopathologically-confirmed stage 4 colorectal adenocarcinoma from 2010–2016 were identified from the National Cancer Database, which comprises >70% of all newly-diagnosed cancer patients in the U.S. Patients were excluded if they lacked data about MSI/MMR testing or were initially diagnosed at another institution. The primary outcome was receiving MSI/MMR testing, either via immunohistochemistry or molecular diagnostic. Patient demographic, socioeconomic, and care setting characteristics were evaluated for association with MSI/MMR testing, as well as between MSI/MMR testing and immunotherapy receipt, using multivariable logistic regression.ResultsOf 45,326 newly-diagnosed stage 4 colorectal adenocarcinoma patients, only 26.5% (n=11,998) received MSI/MMR testing – rising from 14.4% in 2010 to 41.1% in 2016 (adjusted odds ratio [aOR] 1.26/year, 95% confidence interval [95%CI] 1.25–1.29, p<0.001). Overall, patients who were older (referent 60–69-years-old; 70–79-years-old aOR 0.83, 95%CI: 0.77–0.89, p<0.001; 50–59-years-old aOR 1.25, 95%CI: 1.16–1.33, p<0.001), male (aOR 0.94, 95%CI: 0.90–0.99, p=0.01), or of Black non-Hispanic race/ethnicity (aOR 0.87 vs. White non-Hispanic, 95%CI: 0.82–0.94, p<0.001) were independently less likely to receive testing.Additionally, patients who were either uninsured (referent private insurance, aOR 0.78, 95%CI: 0.70–0.86, p<0.001), Medicaid-insured (aOR 0.87, 95%CI: 0.80–0.94, p=0.001), or Medicare-insured (aOR 0.87, 95%CI: 0.81–0.93, p<0.001); or diagnosed at community (referent academic/NCI-comprehensive cancer program, aOR 0.60, 95%CI: 0.56–0.66, p<0.001) or comprehensive community (aOR 0.76, 95%CI: 0.72–0.80, p<0.001) cancer programs, were also significantly less likely to be tested. Even for patients diagnosed in 2016, untested patients received independently less immunotherapy than tested patients (aOR 0.61, 95%CI: 0.53–0.68, p<0.001).ConclusionsMSI/MMR testing rates for stage 4 colorectal cancer patients have dramatically improved in recent years, but appeared underutilized in patients that were older, of Black non-Hispanic race/ethnicity, uninsured or Medicaid-insured, or diagnosed at community programs. Our findings suggest that socioeconomic and care setting opportunities exist for improving access to testing of this important predictive biomarker for immune checkpoint blockade.

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

scholarly journals Plasma Biomarkers Screening by Multiplex ELISA Assay in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 97
Author(s):  
Adrien Costantini ◽  
Paul Takam Kamga ◽  
Catherine Julie ◽  
Alexandre Corjon ◽  
Coraline Dumenil ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Elisa Assay ◽  
Small Cell Lung ◽  
Plasma Biomarkers

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III–IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-α, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3–4 IrAEs in advanced NSCLC treated with ICIs.

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

scholarly journals Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Li Wang ◽  
Zhixuan Ren ◽  
Bentong Yu ◽  
Jian Tang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Cancer Genomics ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Introduction Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the expression of PD-L1, TMB, TIICs, MMR and MSI-H. However, there are no official biomarkers to guide the treatment of ICIs and to determine the prognosis. Therefore, it is essential to explore a systematic nomogram to predict the prognosis of ICIs treatment in NSCLC Methods In this work, we obtained gene expression and clinical data of NSCLC patients from the TCGA database. Immune-related genes (IRGs) were downloaded from the ImmPort database. The detailed clinical annotation and response data of 240 advanced NSCLC patients who received ICIs treatment were obtained from the cBioPortal for Cancer Genomics. Kaplan–Meier survival analysis was used to perform survival analyses, and selected clinical variables to develop a novel nomogram. The prognostic significance of FGFR4 was validated by another cohort in cBioPortal for Cancer Genomics. Results 3% of the NSCLC patients harbored FGFR4 mutations. The mutation of FGFR4 were confirmed to be associated with PD-L1, and TMB. Patients harbored FGFR4 mutations were found to have a better prolonged progression-free survival (PFS) to ICIs treatment (FGFR4: P = 0.0209). Here, we built and verified a novel nomogram to predict the prognosis of ICIs treatment for NSCLC patients. Conclusion Our results showed that FGFR4 could serve as novel biomarkers to predict the prognosis of ICIs treatment of advanced NSCLC. Our systematic prognostic nomogram showed a great potential to predict the prognosis of ICIs for advanced NSCLC patients.

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