scholarly journals Response assessment and outcome of combining immunotherapy and radiosurgery for brain metastasis from malignant melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2532-2532
Author(s):  
Emilie Le Rhun ◽  
Fabian Wolpert ◽  
Maud Fialek ◽  
Patrick Devos ◽  
Nicolaus Andratschke ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Response Assessment ◽  
Steroid Use ◽  
Best Response ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

2532 Background: The evaluation of response in the context of treatment with stereotactic radiotherapy (SRT) or immune checkpoint inhibitors (ICI) or both, which represent major therapeutic options for patients with melanoma brain metastases, remains challenging due to potential tumor hemorrhage, pseudoprogression, and radionecrosis. Methods: We reviewed clinical and neuroimaging data of 62 melanoma patients, including 26 patients with BRAF-mutant tumors, with newly diagnosed brain metastases treated with immune checkpoint inhibitors (ICI) alone (n = 10, group 1), SRT alone or in combination with other systemic therapies (n = 20, group 2) or ICI plus SRT (n = 32, group 3). Response was assessed retrospectively using RECIST 1.1, RANO or iRANO criteria. Results: The MRI scans of 52 patients were available for central review. Patients received steroids at BM diagnosis in 10% in group 1, 60% in group 2 and 50% in group 3. Pseudoprogression was documented in 7 patients: 3 patients in group 2 (19%) and 4 patients (12%) in group 3. Radionecrosis was documented in 7 patients: 2 patients in group 2 (12%) and 5 patients (16%) in group 3. Patients treated with ICI alone had the worst outcome. Using RANO criteria by central review instead of local investigator assessment increased the rate of progressive disease (PD) as best response for the evaluation of SRT targets but not for the evaluation of the overall brain. Using complete RANO (including clinical assessment and steroid use) instead of RECIST criteria increased the rate of PD as best response, due to clinical deterioration noted in patients with MRI findings that did not qualify for PD. This pattern was seen in patients from all three groups. In contrast, the complete response (CR) rate was unaffected by the criteria used. More PD were also observed when comparing MRI only iRANO criteria versus complete iRANO criteria including clinical status and steroid use. Conclusions: Pseudoprogression is uncommon with ICI alone, suggesting that growing lesions in such patients should trigger an intervention. Pseudoprogression rates were similar after SRT alone or in combination with ICI. Response assessment criteria should be considered carefully when designing clinical studies for patients with brain metastases who receive SRT.

scholarly journals Hypocalcemia with Immune Checkpoint Inhibitors: The Disparity among Various Reports

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Swarna Sri Nalluru ◽  
Paramarajan Piranavan ◽  
Ying Ning ◽  
Haritha Ackula ◽  
Ahmad D. Siddiqui ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Entire Study ◽  
Calcium Sensing ◽  
Parathyroid Function ◽  
Study Population ◽  
Group 2 ◽  
Group 1

Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPIs). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently reported. KEYNOTE-189 and CHECKMATE-067 trials reported a 21–29% hypocalcemia event rate, but the etiology of hypocalcemia was not reported. A chart review was performed to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Group 1 (n = 83) includes patients with no calcium altering conditions or medications. Group 2 (n = 98) includes patients on calcium supplements (n = 17), vitamin D (n = 44), bisphosphonates (n = 24), >stage IIIB chronic kidney disease (CKD) (n = 5), and bone metastasis (n = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (n = 1). No further workup was done to investigate the etiology as that patient passed away. Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.

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 Hypocalcemia with immune checkpoint inhibitors: The disparity among various reports.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15153-e15153
Author(s):  
swarna sri nalluru ◽  
Paramarajan Piranavan ◽  
Ying Ning ◽  
Haritha Ackula ◽  
Ahmad Daniyal Siddiqui ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Entire Study ◽  
Calcium Sensing ◽  
Parathyroid Function ◽  
Study Population ◽  
Group 2 ◽  
Group 1

e15153 Background: Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPI). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently published by Piranavan et al. KEYNOTE-189 and CHECKMATE-067 trials reported a 21-29% hypocalcemia event rate. The purpose of our study is to identify the hypocalcemia incidence in patients receiving ICPI at a single institution with multiple sites. Also, we aimed to investigate hypoparathyroidism as the etiology in these patients, if hypocalcemia was detected. Methods: A chart review to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Results: Group 1 (N = 83) includes patients with no calcium altering conditions or medications. Group 2 (N = 98) includes patients on calcium supplements (N = 17), vitamin D (N = 44), bisphosphonates (N = 24), > stage IIIB CKD (N = 5), and bone metastasis (N = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (N = 1). No further workup was done to investigate the etiology as that patient passed away. Conclusions: Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.

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.

scholarly journals Immune Checkpoint Inhibitors for Brain Metastases: A Primer for Neurosurgeons

Neurosurgery ◽  
2020 ◽  
Vol 87 (3) ◽  
pp. E281-E288
Author(s):  
Elisa Aquilanti ◽  
Priscilla K Brastianos
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Recognition ◽  
Therapeutic Modalities ◽  
Programmed Death 1

Abstract Immune checkpoint inhibitors enhance immune recognition of tumors by interfering with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD1) pathways. In the past decade, these agents brought significant improvements to the prognostic outlook of patients with metastatic cancers. Recent data from retrospective analyses and a few prospective studies suggest that checkpoint inhibitors have activity against brain metastases from melanoma and nonsmall cell lung cancer, as single agents or in combination with radiotherapy. Some studies reported intracranial response rates that were comparable with systemic ones. In this review, we provide a comprehensive summary of clinical data supporting the use of anti-CTLA4 and anti-PD1 agents in brain metastases. We also touch upon specific considerations on the assessment of intracranial responses in patients and immunotherapy-specific toxicities. We conclude that a subset of patients with brain metastases benefit from the addition of checkpoint inhibitors to standard of care therapeutic modalities, including radiotherapy and surgery.

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