Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases

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.

Download Full-text

MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors

Neuro-Oncology ◽

10.1093/neuonc/noz141 ◽

2019 ◽

Vol 21 (12) ◽

pp. 1578-1586 ◽

Cited By ~ 5

Author(s):

Ankush Bhatia ◽

Maxwell Birger ◽

Harini Veeraraghavan ◽

Hyemin Um ◽

Florent Tixier ◽

...

Keyword(s):

Multivariate Analysis ◽

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Magnetic Resonance Images ◽

Higher Order ◽

Imaging Biomarkers ◽

Melanoma Brain Metastases

Abstract Background Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. Methods Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. Results Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19–91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. Conclusion Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.

Download Full-text

Improved Outcomes in Patients with Melanoma Brain Metastases Treated with Whole-Brain Radiation and Immune Checkpoint Inhibitors

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.06.2327 ◽

2019 ◽

Vol 105 (1) ◽

pp. E72

Author(s):

D.M. Cannon ◽

L.M. Burt ◽

B.N. Voorhies ◽

Y.J. Hitchcock ◽

D.C. Shrieve

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Whole Brain ◽

Whole Brain Radiation ◽

Improved Outcomes ◽

Melanoma Brain Metastases ◽

Brain Radiation

Download Full-text

Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations—Chances and Challenges

American Journal of Clinical Dermatology ◽

10.1007/s40257-018-0346-9 ◽

2018 ◽

Vol 19 (4) ◽

pp. 529-541 ◽

Cited By ~ 3

Author(s):

Marvin Kuske ◽

Ricarda Rauschenberg ◽

Marlene Garzarolli ◽

Michelle Meredyth-Stewart ◽

Stefan Beissert ◽

...

Keyword(s):

Brain Metastases ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Melanoma Brain Metastases

Download Full-text

MRI texture features and outcomes to immune checkpoint inhibitors in melanoma brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.2069 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 2069-2069 ◽

Cited By ~ 1

Author(s):

Ankush Bhatia ◽

Maxwell Birger ◽

Harini Veeraraghavan ◽

Hyemin Um ◽

Anna Sophia McKenney ◽

...

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Texture Features ◽

Melanoma Brain Metastases

Download Full-text

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.435 ◽

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.

Download Full-text