ICI In Patients Research Articles

The incidences of adverse events in small-cell lung cancer patients after radiotherapy and immunotherapy treatment: a systematic review and meta-analysis.

Immunotherapy is important in treating small-cell lung cancer (SCLC), and its anti-tumor effects are better when combined with radiotherapy. However, the toxicity of this combination is little known. This study assessed the incidences of adverse events when adding radiotherapy to ICIs in patients with SCLC. We searched the online databases to identify eligible studies and included nine references. For extensive-stage SCLC patients, the median PFS ranged from 4.5 to 12.5 months, and median OS ranged from 8.4 to NR months, respectively. The incidences of grade 3 or higher pneumonitis, lung infection, diarrhea, and fatal adverse events were 8.7% (95% CI: 5%-14.7%), 6.7% (95% CI: 2.5%-16.5%), 12.6% (95% CI: 7.6%-20%), and 5.1% (95% CI: 2.1%-11.6%), respectively. Our findings suggest that radiotherapy plus ICIs may provide acceptable safety and favorable efficacy for SCLC patients.

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

BackgroundImmune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit...

P8‐54: Is combination chemotherapy with ICI and cytotoxic agents always better than monotherapy with ICI in patients with advanced NSCLC?

P8‐54: Is combination chemotherapy with ICI and cytotoxic agents always better than monotherapy with ICI in patients with advanced NSCLC?

Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy

BackgroundImmune checkpoint inhibitors (ICIs) are approved to treat multiple cancers. Retrospective analyses demonstrate acceptable safety of ICIs in most patients with autoimmune disease, although disease exacerbation may occur. Psoriasis vulgaris...

Pancreatic volumes in immune checkpoint inhibitor-induced diabetes.

2644 Background: Immune checkpoint inhibitor-mediated insulin dependent diabetes (ICI-DM) is a rare and irreversible adverse event often presenting with life-threatening diabetic ketoacidosis (DKA). Pancreatic volume changes have been studied in classic Type 1 and Type 2 diabetes as a surrogate for functional β-cell mass. In this study, we investigate longitudinal changes in pancreatic volumes in patients who develop ICI-DM. Methods: Among patients with ICI-DM seen at our institution between 2014 and 2020, 20 patients who had serial CT scans of the abdomen and pelvis before and after ICI DM diagnosis were identified for inclusion in this study. Demographic data and clinical variables were obtained from the electronic medical record. Weight-adjusted pancreatic volumes were calculated from CT scans at three time points. The most recent CT scan prior to ICI initiation was used as baseline, the CT scan immediately prior to ICI DM diagnosis was used as a midpoint, and the most recent CT scan prior to the end of the study period was used as the final time point for comparison. Results: Median age was 63 years old (range 35 to 83). Renal cell carcinoma and melanoma were the most common cancer types. Male gender predominated (80%). 18/20 patients were on a PD-1 inhibitor with the remaining two on a PD-L1 inhibitor. After initiation of ICI therapy there was a variable response in pancreatic volumes prior to the diagnosis of ICI-DM with 20% patients experiencing a volume loss of > 10% and 25% experiencing a volume gain of > 10%. Volume loss nor volume gain prior to diabetes diagnosis was associated with presentation with DKA. 9/13 (69%) of patients who had pancreatic enzymes checked at diagnosis of ICI-DM had elevated levels. Pancreatic atrophy with a median volume loss of 41% was seen in all patients at a median of 14.9 months (range 3-77 months) after ICI-DM diagnosis. Most had more than 20% volume loss from baseline to most recent scan with no correlation in degree of volume loss with the time interval. There was no evidence of pancreatic ductal dilation, increased pancreatic fat nor any changes consistent with chronic pancreatitis. Conclusions: This study shows a variable response in pancreatic volumes after initiation of ICI in patients who progress to developing ICI-DM, though most had a significant decline in volume after the diagnosis of ICI-DM with long-term pancreatic atrophy. As β-cell mass is thought to comprise 1-2% of the pancreas, these findings may suggest both endocrine and exocrine compartment changes because of ICI-DM, though exocrine dysfunction has not been clinically described in this patient population. As these patients receive frequent imaging during treatment, fluctuations in pancreatic volumes with new or worsening hyperglycemia may portend the onset of ICI-DM and clinicians should have a low threshold to screen for this diagnosis as many will present with life-threatening DKA.

Durability of CNS disease control in NSCLC patients with brain metastases treated with immune checkpoint inhibitors plus cranial radiotherapy

BackgroundImmune checkpoint inhibitors (ICIs) have excellent systemic activity and are standard first line treatment in EGFR/ALK wild type metastatic non-small cell lung cancer (NSCLC). However, their role in patients with brain metastases, which affects over 20% of patients and cause significant morbidity, is less clear. MethodsWe reviewed patients with EGFR/ALK wild-type mNSCLC with CNS metastases. Serial MRIs were reviewed to determine the time to intracranial progression (iPFS). Multivariate regression was performed to adjust for the disease-specific graded prognostic score (ds-GPA). ResultsWe identified 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases and available serial MRIs (average frequency:3.5 months). Baseline radiation was given except for 2 chemotherapy-treated patients with asymptomatic solitary metastasis. The CNS burden of disease was higher in the ICI-treated group (ICI:22% vs. chemotherapy:0% had >10 lesions; p = 0.02), but the utilization of WBRT was not (ICI:31% vs. chemotherapy:45%; p = 0.09). At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared to 64 % of chemotherapy controls (p = 0.02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9; 95%CI 1.1-–3.4). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥ 50%, 50% in ICI-treated PD-L1 < 50% and 58% in chemotherapy-treated patients (p = 0.03). ConclusionsRemarkable CNS disease control is seen with baseline RT plus ICIs in patients with PD-L1 ≥ 50%. Strategies for delaying WBRT should be investigated in this subgroup of patients.

Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.

BackgroundImmune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.MethodsThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.ResultsOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39–84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.ConclusionThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.

Outcomes of Patients With Interstitial Lung Disease Receiving Programmed Cell Death 1 Inhibitors: A Retrospective Case Series

BackgroundImmune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, are used to treat multiple cancers. Limited data exist as to the use of ICIs in patients with coexistent interstitial lung disease (ILD). We conducted a retrospective case series to assess clinical and radiologic outcomes of patients with ILD treated with PD-1 inhibitors. MethodsEligible patients were 18 years of age or older, treated with pembrolizumab or nivolumab for oncologic indications, and had evidence of ILD on chest computed tomography scan not attributable to radiotherapy before initiation of ICI therapy. Outcomes of interest included mortality, hospitalizations for respiratory-related causes, development of pneumonitis, and radiologic change in ILD over a 1-year follow-up period. ResultsWe included 41 patients in the analysis. At 1 year, 17 patients (41.5%) were alive, 23 had died (56.1%), and 1 (2.4%) was lost to follow-up. Of 23 deaths, 16 (69.6%) were due to cancer, 4 (17.4%) to causes excluding cancer and ILD, and 3 (13.0%) to hypoxemic respiratory failure from ILD- or ICI-induced pneumonitis. Three patients (7.3%) required hospitalization owing to ILD, including drug-induced pneumonitis, and 3 (7.3%) developed pneumonitis attributable to anti–PD-1 therapy. On follow-up computed tomography scans, 32 patients (78.0%) had stable or improved ILD and 9 (22.0%) had progression. ConclusionPatients with ILD receiving PD-1 inhibitors more frequently died of cancer-related causes than from ILD. Further research is needed to determine the safety of ICIs in patients with ILD and if ILD subtype may help to refine ICI-associated risks.

Safety and Efficacy of Immune Checkpoint Inhibitors for Patients With Metastatic Urothelial Carcinoma and End-Stage Renal Disease: Experiences From Real-World Practice.

BackgroundImmune checkpoint inhibitors (ICIs) are used widely for treating metastatic urothelial carcinoma (mUC). In practical settings, evidence is lacking on the efficacy of ICIs in some difficult-to-treat patients, such as those with end-stage renal disease (ESRD). Herein, we evaluate the safety and efficacy of ICIs for patients with mUC and ESRD.MethodsFor this retrospective study, patients with mUC who were given ICIs at Kaohsiung Chang Gang Memorial Hospital and Linkou Chang Gung Memorial Hospital between April 2016 and November 2019 were consecutively enrolled. All clinicopathologic data, treatment responses, and adverse events were recorded. The immune-related adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between ESRD and non-ESRD groups.ResultsIn total, 129 patients with mUC were enrolled, with 11 patients categorized as the ESRD group. Among these patients with ESRD receiving ICIs, 7 of 11 (63.6%) had high-grade (grade ≥3) AEs, chiefly hematologic toxicity. Some rarely encountered AEs were noted, including toxic epidermal necrolysis, tuberculosis reactivation, ascites, and cytokine release syndrome. Patients in the ESRD group had numerically higher ORR (54.5% vs. 28.8%, p = 0.09), PFS (7.1 vs. 3.5 months, p = 0.42), and OS (not reached vs. 15.4 months) than the non-ESRD group. A multivariate Cox regression model demonstrated that leukocytosis (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.23–5.63; p = 0.01) and neutrophil-to-lymphocyte ratio (HR 2.91; 95% CI: 1.30–6.53; p = 0.01) were independent prognostic factors.ConclusionAdministration of ICIs in patients with mUC and ESRD demonstrated a modest antitumor activity, and should be used with caution for increasing risk of hematologic toxicity.

Immuno-oncology-the new paradigm of lung cancer treatment.

Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios. In the present review, we discuss the role of the immune system in lung cancer and the previous failures of immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019.

P781 Role of serum biomarkers combined with two-dimensional speckle tracking echocardiography for screening of immunotherapy-induced cardiotoxicity

Abstract Background Immune checkpoint inhibitors (ICIs) are a novel class of antineoplastic drugs which have dramatically changed the management of non-small cell lung cancer. ICI-associated cardiotoxicity is rare, but potentially fatal, presenting in most of cases as autoimmune acute myocarditis during the first phase of treatment. However, since an extensive cardiac monitoring is not routinely performed in most immunotherapy trials, the true incidence of ICIs related cardiac effects is largely unknown. Aim Aim of our study is to ascertain a possible subclinical cardiac involvement in patients with non-small cell lung cancer treated with ICIs. Methods We prospectively recruited 40 patients (13 males; mean age 64.3 ± 8.3 years) starting immunotherapy with PD-1/PDL-1 inhibitors for non-small lung cancer between January and August 2018. Demographic and clinical data were recorded and all patients underwent a standard 12-lead ECG and a transthoracic echocardiogram with assessment of left ventricular global longitudinal strain (LV GLS). Furthermore, blood samples for pro BNP-nt and high sensitivity Troponin T (hsTnT) measurements were collected. Serial assessments were performed before and 1 and 3 months after initiation of immunotherapy. Results A history of previous coronary artery disease was documented in eight cases (20%). At follow-up no cardiovascular events were recorded. Compared with baseline, echocardiographic parameters of ventricular function did not significantly changed at 1 and 3 months (LVEF 61 ± 6% at baseline, 61 ± 5% at 1 month, 60,2 ± 5% at 3 months, p =0.1; E/E’at baseline 9.2 ± 3, 9.2 ± 2.8 at 1 month, 9.1 ±3,5 at 3 months, p = 0.2;TAPSE 20 ± 3.4 mm at baseline, 21.3 ± 2.8 mm at 1 month, 20 ± 3.8 mm at 3 months, p =0.1; LV GLS -20.3 ± 3.6% at baseline, -20.8 ± 2.3% at 1 month, -20.6 ± 3% at 3 months; p = 0.4). Analogously, no significant increase in circulating levels of cardiac biomarkers was found with hsTnT &amp;lt;0.015 ng/ml in all patients at baseline, 1 month and 3 months and median proBNP-nt 118 pg/ml (IQR 47-200) at baseline, 171 pg/ml (IQR 91-520) at 1 month, and 182 pg/ml (IQR 78-470) at 3 months, p = 0.9. Conclusions In our study no significant clinical or subclinical evidence of myocardial involvement was detected during treatment with ICIs in patients with non-small cell lung cancer, thus suggesting the potential cardiovascular safety of this promising class of antineoplastic drugs.

Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BackgroundImmune checkpoint inhibitors (ICI) are active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in advanced non–small-cell lung cancer. We evaluated response to chemotherapy in patients who had progressed on ICI in patients with R/M SCCHN. Patients and methodsA retrospective study was conducted at 4 French centres. Eligibility criteria were patients who progressed after treatment with ICI for R/M SCCHN and received SCT and for whom efficacy data were available between September 2014 and January 2018. ResultsOf 232 patients treated with ICI, 82 met eligibility criteria: 84% were male. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxanes (56.1%), cetuximab in combination with taxanes or platinum (50%), platinum-based regimen (36.6%). The median number of treatment lines before SCT was 2 (range 1–6). The objective response rate (ORR) to SCT was 30%. Three patients (4%) presented complete response and 22 patients (27%) had partial response. Median progression-free survival was 3.6 months and median overall survival was 7.8 months. The age at SCT, initial tumour location, number of prior chemotherapy regimens, type of chemotherapy before ICI, best response to ICI, site of relapse and Eastern Cooperative Oncology Group at SCT were not associated with response to SCT on univariate analysis. ConclusionIn R/M SCCHN, the ORR to SCT was high (30%) suggesting that exposure to ICI may increase tumour sensitivity to chemotherapy.

Stereotactic Radiosurgery With and Without Checkpoint Inhibition for Patients with Metastatic Non-Small Cell Lung Cancer to the Brain: A Matched Cohort Study

Abstract INTRODUCTION Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non-small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICI in patients with NSCLC excluded patients with untreated brain metastases (BM). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, we sought to define the safety, radiologic/clinical outcomes for patients with NSCLC-BM treated with concurrent ICI/SRS. METHODS A retrospective, matched cohort study was performed on patients who underwent SRS to one or more NSCLC-derived BM. Two matched cohorts were identified: one who received ICI within 3-mo of SRS (concurrent-ICI) and one who did not (ICI-naive). Locoregional tumor control, peritumoral edema, and central nervous system adverse events were compared. RESULTS A total of 17 patients (45-BMs) and 34 patients (92-BMs) comprised the concurrent-ICI and ICI-naive cohorts, respectively. Per RANO criteria, there was no difference in overall-survival (HR 0.99, 95% CI: 0.39-2.52) or CNS progression-free-survival (HR 2.18, 95% CI 0.72-6.62) between both groups. Similarly, the 12-mo local tumor control rate was 84.9% and 76.3% for tumors in the concurrent-ICI and ICI-naive cohorts, respectively (P = .94). Nevertheless, patients receiving concurrent-ICI had increased rates of complete response for BMs treated with SRS (50% vs 15.6%; P = .012) per RANO criteria. There was a shorter median time to BM regression in the concurrent-ICI cohort (2.5-mo vs 3.1-mo, P &lt; .001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in patients receiving concurrent-ICI (concurrent-ICI: 5.9%; ICI-naive: 2.9%, P = .99). There was no difference in the rate of peritumoral edema progression across both groups (concurrent-ICI: 11.1%, ICI-naive: 21.7%; P = .162). CONCLUSION The use of ICI/SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent-ICI did not increase rates of peritumoral edema, radiation necrosis, or intratumoral hemorrhage. Further studies are needed to evaluate whether concurrent ICI/SRS improves PFS/OS for patients with metastatic NSCLC.

Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study.

Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non-small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS. A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts. Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39-2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72-6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162). The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.

Genetic Predictors of Efficiency and Safety of ICIs in Patients With Different Malignancies (ICIPRESIST-0519)

Genetic Predictors of Efficiency and Safety of ICIs in Patients With Different Malignancies (ICIPRESIST-0519)

Proton pump inhibitors and response to immune check-point inhibitors: Single center study.

e14092 Background: Checkpoint inhibitors (blocking antibodies to PD-1, PD-L1, CTLA-4) have proven effective against several tumor types. While the response is impressive in some patients, we still don’t understand all the patient factors that determine resistance to this class of medication. Studies of host factors have identified composition of the gut microbiome at baseline as a positive predictor of ICI response. Proton pump inhibitors have been reported to interfere with gut microbiome composition. In this single center, retrospective study, we studied the effect of concomitant treatment of proton pump inhibitors on response to ICIs in patients with locally advanced and metastatic cancer. Methods: A retrospective cohort of Non-small cell lung cancer, renal cell carcinoma and Melanoma patients that were treated from January 2016 to May 2018 at the Mount Sinai Medical Center were included in this study. Demographics, prior systemic treatment, performance status, ICI agent, and use of PPI (with in 30 days prior to 30 days after the first dose of ICI administration) were collected. Primary objective of the study was progression free survival (PFS) by utilization of PPIs. PFS was calculated using the log-rank test and survival curve was generated using the Kaplan-Meier method. Information was collected from electronic medical records. Results: Of the 97 patients that met the study criteria, 63 patients had complete data and included in the analysis. 46 patients had Non-small cell lung cancer, 13 had melanoma and 4 renal cancer. Checkpoint inhibitors most commonly prescribed included: Pembrolizumab (29 patients : 46%), Nivolumab (22 patients:35%), Nivolumab + Ipilimumab (9:14 %). 25 patients were taking PPI upon initiation of ICI treatment. In addition, 26 patients received steroids with in 30 days of treatment initiation. There was no statistically significant difference in PFS between patients on PPIs and not on PPIs. The median PFS was 672 days (95% CI: 32, 1311) for PPI users and 341 days (95% CI: 123, 558) for non PPI users. P = 0.244. Conclusions: In this, single-center, retrospective study, we did not detect a significant difference in PFS between patients who used PPI at baseline and patients who did not. Limitations of this study mainly included retrospective analysis, a small sample size, single center population and heterogeneity in disease pathology. We did not collect information on other tumor and treatment related factors like PDL 1 expression, tumor mutation burden, use of antibiotics, and immunotherapy related adverse reactions.

Stereotactic Radiosurgery (SRS) with Immune Checkpoint Inhibitor Therapy (ICI) for Patients with Brain Metastasis (BM): The Impact of Timing and Sequencing

The optimal timing and sequencing of ICI in patients with BM undergoing SRS is not adequately defined. We analyzed objective response rates in patients receiving ICI and SRS in order to determine sequencing and timing predictors for maximal intracranial control. BM patients who underwent SRS and received ICI (PD1 or PDL1 inhibitor) were divided into three cohorts based on the timing of receipt of therapy: any therapy, “concurrent” (+/- ≤5 half-lives), or “immediate” (+/- one half-life) ICI. The primary outcome was magnitude of best objective lesion-specific response (BOR) (unidimensional RECIST). Secondary outcomes included the proportion of lesions achieving RECIST-defined complete (CR) or partial responses (PR), or stable (SD) or progressive disease (PD); response durability; rate of adverse radiation effects; and overall survival. Multivariable linear regression analysis for BOR was conducted on a per-lesion basis. A total of 150 patients underwent SRS to 1003 brain metastases and received ICI during the course of their disease: 564 of the lesions (56%) were treated with SRS and "concurrent" ICI. A total of 1,073 brain MRIs were reviewed, resulting in 5,508 measurements (average of 5.5 measurements per lesion, Range: 2-26). Lesions treated with SRS and “concurrent” ICI demonstrated superior BOR, overall objective response, and durable response. These findings were most pronounced among lesions treated with "immediate" ICI (BOR: -100 vs. -57%, p<0.001; CR: 50 vs. 32%; 6-month durable response: 89 vs. 74%, p<0.001; 12-month durable response: 94 vs. 71%, p<0.001). Among lesions with 12 months of follow-up (293, 29%), those treated with "immediate" ICI had a markedly improved CR rate (85 vs. 43%, p<0.001) and significantly reduced PD rate (4 vs. 19%, p<0.001). After adjusting for confounding covariates, “concurrent” ICI was associated with a 6 % improvement in BOR (p=0.040) and “immediate” ICI with a 11% improvement in BOR (p<0.001). Pre-exposed ICI lesions treated with SRS had poorer BOR (-45%) compared to ICI naive lesions (-63%, p<0.001), with the best response rates observed in ICI naive lesions receiving SRS and "immediate" ICI (-100%, p<0.001) with no added benefit to "immediate" neoadjuvant ICI (-100%, p=0.52). Significant differences in response rates were observed across primary tumor histologies and different ICI agents. The 24-month cumulative incidence of adverse radiation effects with death as a competing risk was low among patients receiving "concurrent" (3.3%) or "immediate" ICI (3.6%). This study demonstrates that the timing of ICI and SRS in patients with brain metastasis is associated with overall response, best response, and durability of response with the most substantial effect in ICI naive patients undergoing "immediate" combined modality therapy, which is also tolerated well. Further analysis will help to individualize strategies for the optimal sequencing of systemic therapy based on tumor histology and the selected agent.

Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke.

Following a hemispheric stroke, various degrees of neuronal reorganization around the lesion occur immediately after disease onset and thereafter up to several months. These include transcallosal excitability, changes of the intact motor cortex and ipsilateral motor responses after transcranial magnetic stimulation (TMS) on the intact hemisphere. To elucidate the relationship between lesion localization and motor cortex excitability (intracortical inhibition; ICI) in the intact hemisphere, we applied a paired conditioning-test TMS paradigm in 12 patients with unilateral cortical stroke (cortical group) and nine patients with subcortical stroke caudal to the corpus callosum (subcortical group), with interstimulus intervals varying from 1 to 10 ms. All patients exhibited unilateral complete hand palsy. ICI was significantly less in the cortical group than in age-matched healthy control subjects. It was especially more marked in the cortical group patients with a disease duration of less than 4 months after onset. Patients in the cortical group with a duration longer than 4 months showed a tendency for ICI to be normalized, and there was a significant correlation between ICI and disease duration. Patients in the subcortical group showed normal excitability curves. All patients in the cortical group showed no transcallosal inhibition (TCI) in the active unaffected hand muscle after TMS of the affected motor cortex, whereas all the subcortical patients showed some TCI. No ipsilateral motor responses were elicited in the paretic hand in any of the patients. The reduced ICI in the cortical group might have been a result of disruption of TCI. The normalization of ICI in the patients with longer disease duration and the normal ICI in the subcortical group patients do not support the functional significance of motor cortex hyperexcitability in the unaffected hemisphere, at least in a patient population with poor motor recovery.