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 < 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 < 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.

Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: A systematic review and meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15080-e15080
Author(s):  
Filippo G. Dall'Olio ◽  
Alessandro Rizzo ◽  
Veronica Mollica ◽  
Maria Massucci ◽  
Ilaria Maggio ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Prognostic Impact ◽  
Cancer Type ◽  
Landmark Analysis ◽  
Immortal Time Bias ◽  
Number Of Patients

e15080 Background: A number of studies have addressed the association between Immune related Adverse Events (IrAE) and outcome in patients treated with Immune Checkpoint Inhibitors (ICI). Only a minority of them considered the effect of immortal time bias (ITB), and results of these papers are conflicting. The aim of our meta-analysis was to assess the relationship between IrAE and outcomes for patients treated with ICIs, with a focus on ITB in weighing the role of this association. Methods: PubMed, Embase (Ovid), and Scopus were searched through January 2, 2020. Studies reporting the prognostic impact of IrAE development on outcome in advanced cancer patients treated with anti PD-1 or PD-L1.Two investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Author name, cancer type, PD-1 and PD-L1 inhibitor used, number of patients, number and type of all adverse events, presence of a landmark analysis, median OS and PFS and difference between patient with or without IrAE in terms of OS and PFS (Hazard Ratio) and ORR (Odds Ratio) were extracted. Data were pooled using a random-effects model. Main outcome were Overall Survival (OS), Progression Free Survival (PFS) and Overall Response Rate (ORR). Analysis was performed with dedicated software (R studio version 1.2.1335, metafor package). Results: A total of 29 articles comprising 7430 patients were included. 7 papers published the results of survival analysis according to landmark analysis, 2 papers published only the naïve analysis while stating that a landmark analysis resulted non significant, and the others did not perform a landmark analysis. IrAEs were associated with improved outcomes with high heterogeneity ( I2 70.8%, p < 0.001 for OS; 65.7%, p 0.002 for PFS; 62.1%, p 0.001 for ORR). When subgroup analysis was performed according to the adoption of a landmark approach, the association between IrAE and outcome remains significant for OS, PFS and ORR but the effect size was smaller ( HR 0.61 vs 0.41 for OS, ANOVA Q-test for difference between subgroup p = 0.015; HR 0.66 vs 0.47 for PFS, ANOVA Q-test p 0.029; OR 2.59 vs 6.77 for ORR, ANOVA Q-test p < 0.001) while heterogeneity was substantially reduced (I2 for papers using LM 43% for OS, p 0.115; 9.7% for PFS, p 0.355; 0.0% for ORR, p 0.556). Conclusions: Our analysis suggests a significant confounding effect of ITB as well as a real effect of IrAE development on outcome.

scholarly journals Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a ‘Real-Life’ Setting

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3707
Author(s):  
Marcus Skribek ◽  
Konstantinos Rounis ◽  
Dimitrios Makrakis ◽  
Sofia Agelaki ◽  
Dimitris Mavroudis ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Local Treatment ◽  
Real Life ◽  
Response Assessment ◽  
Neurological Symptoms

There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic driven NSCLC with BM who were treated with ICIs at two medical oncology institutes in Sweden and Greece from 2016 to 2019. IC efficacy was assessed in patients who had not received local treatment for BM less than three months prior to the initiation of ICIs and had adequate radiological evaluation. We screened 280 patients, of which 51 had BM. BM was an independent predictor for inferior PFS (HR = 2.27; 95% CI, 1.53–3.36) but not OS (HR = 1.58; 95% CI, 0.97–2.60) for the whole patient population. IC response assessment was done on 33 patients. IC objective response rate (ORR) was 24.2%. The presence of neurological symptoms related to BM did not affect IC ORR (p = 0.48). High PD-L1 levels from extracranial biopsies were not a predictive factor for IC ORR (p = 0.13). ICIs are active in NSCLC patients with BM regardless of the presence of neurological symptoms and can achieve durable IC disease stabilization in a subgroup of patients.

scholarly journals MET-11 Recent advances in targeted therapies and immunotherapy for metastatic brain tumors

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi26-vi26
Author(s):  
Yuichi Ando
Keyword(s):  
Malignant Melanoma ◽  
Brain Tumors ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Systemic Treatment ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Targeted Drugs ◽  
Metastatic Brain Tumors

Abstract This presentation outlines CQ2 of Chapter 2 from the forthcoming updated version of the Clinical Practice Guidelines for Brain Tumors, edited by the Society. These guidelines discuss chemotherapy and other drug therapies for metastatic brain tumors in adult patients. First, there is no noteworthy change in the principle of prioritizing local treatment of symptomatic metastatic brain tumors or those that require local treatment in the near future. However, with recent advances in molecular-targeted drugs and/or immune checkpoint inhibitors, many physicians now consider starting systemic treatment prior to local treatment of brain metastases, even in patients with solid tumors that were once considered insensitive to chemotherapy, given that their symptoms are well-controlled and do not require urgent treatment. In the treatment of non-small cell lung cancer (NSCLC), the molecular subtypes of metastatic brain tumors with EGFR mutations and ALK fusion genes have yielded favorable responses to molecular-targeted drugs. Because small molecule drugs are well delivered to the central nervous system, systemic drug therapy with such targeted drugs is commonly selected for patients with untreated metastatic brain tumors. A recent phase II trial has shown the effectiveness of anti-PD-1 antibody pembrolizumab monotherapy for metastatic brain tumors from NSCLC. Because untreated metastatic brain tumors from renal cell carcinoma are prone to bleeding, local treatment of brain metastases should be prioritized before systemic treatment, even if the patient is asymptomatic. Regardless of BRAF mutation status, immune checkpoint inhibitors alone or in combination (nivolumab and ipilimumab) are effective against malignant melanoma with brain metastases; moreover, a combined treatment with BRAF and MEK inhibitors is effective against BRAF mutation-positive malignant melanoma with brain metastases. A novel HER2 inhibitor, tucatinib (unapproved), is expected to be effective against metastatic brain tumors from HER2-positive breast cancer.

scholarly journals 62. PRESENCE OF EXTRACRANIAL TUMORS INFLUENCES RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN A PRE-CLINICAL MODEL OF MELANOMA BRAIN METASTASIS

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Jackson Stocking ◽  
Michael Brehm ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intracranial Tumors ◽  
Clinical Model ◽  
Melanoma Brain Metastasis ◽  
Syngeneic Mouse Model ◽  
The Brain

Abstract Up to 75% of patients with melanoma develop brain metastases. While immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA4 have revolutionized the treatment of metastatic melanoma, responses within the immune-specialized microenvironment of the brain are not well understood and there is a paucity of animal models to investigate the effect of ICI intracranially. We characterized responses to checkpoint inhibitors in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous melanoma. D3UV3 cells (obtained from David Fisher’s laboratory) were derived using UVB irradiation from D4M.3A melanoma cell line and implanted into the striatum using stereotactic injection or subcutaneously injected into the flank of C57BL/6 mice. Mice were then treated with anti-PD-1 antibody, anti-CTLA4 antibody, a combination of anti-PD-1 and anti-CTLA4, or isotype controls. While mice with intracranial melanoma alone had no response to monotherapy with anti-PD-1 or anti-CTLA4 antibody (p=1 and 0.1, respectively), and only a slight response to combination therapy (p=0.049), mice with concurrent subcutaneous tumors had significantly improved responses to anti-PD-1, anti-CTLA4 and combination treatment (p=0.002, 0.01 and 0.01 respectively compared to mice with intracranial tumors alone with equivalent treatment). These results demonstrate that the presence of an extracranial tumor influences response to ICI in pre-clinical mouse models of melanoma brain metastasis. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of melanoma brain metastases and lead to a better understanding of the setting in which ICI are effective for patients with this devastating complication.

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