Immune Checkpoint Inhibitor Pneumonitis Research Articles

A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

Abstract 16249: A Case of Myocarditis and Pneumonitis Associated With Pembrolizumab Therapy

Introduction: Immune checkpoint inhibitors (ICI) are a novel therapy that activates antitumor immunity but can have varied immune-related adverse effects. As ICI therapy is used to treat malignancy, cases of autoimmune myocarditis and heart failure increase, thought to be due to PD-1 inhibition, which may be potentially fatal. Case presentation: A 37 yo female with history of autoimmune hepatitis and stage III melanoma on Pembrolizumab (ninth cycle 1.5 months prior) presented with chest pain, tachycardia, fatigue, dyspnea, and fever. Lab studies were notable for elevated troponin, lactic acidosis, and disseminated intravascular coagulation (DIC). CT thorax showed asymmetric ground glass opacities, concerning for ICI pneumonitis. Echocardiogram showed an LVEF of 15% with global hypokinesis. She was treated for severe sepsis, DIC, and respiratory failure, temporarily requiring intra-aortic balloon pump. Heart failure guideline-directed medical therapy (GDMT) was started. Clinical presentation was concerning for acute myocarditis related to ICI therapy as a cause for new cardiomyopathy. A cardiac MRI (CMR) revealed subepicardial late gadolinium enhancement (LGE) along the basal inferior/inferolateral wall segments concerning for myocarditis. Corticosteroids with a prolonged taper were started. Endomyocardial biopsy of the septum (EMB) was negative. Her clinical status improved and repeat echo showed LVEF recovery up to 45%. Discussion: Endomyocardial biopsy (EMB) provides definitive diagnosis of myocarditis and is recommended (Class I) for new-onset heart failure with hemodynamic compromise and/or arrhythmias. Although our patient’s EMB was negative (likely due to limitation of sample location), she met the 2013 ESC guideline diagnostic criteria for myocarditis with elevated troponin, functional and structural abnormalities on cardiac imaging. With increased utilization of ICI therapy in the management of aggressive malignancies, it is important to monitor for potentially adverse effects such as autoimmune myocarditis. Standard treatment is prompt initiation of corticosteroids, though newer studies report successful treatment with immunomodulators, such as abatacept and ruxolitinib, if steroids are unsuccessful.

Association Between Pretreatment Chest Imaging and Immune Checkpoint Inhibitor Pneumonitis Among Patients With Lung Cancer.

Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. A total of 471 patients with lung cancer were included, of which 402 had non-small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69-16.92; P<.001; and HR, 2.81; 95% CI, 1.50-5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17-18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3-5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Heterogenous lung inflammation CT patterns distinguish pneumonia and immune checkpoint inhibitor pneumonitis and complement blood biomarkers in acute myeloid leukemia: proof of concept.

Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers. We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add diagnostic value. Habitat imaging revealed intrinsic lung inflammation patterns by identifying 5 distinct subregions, correlating to lung parenchyma, consolidation, heterogenous ground-glass opacity (GGO), and GGO-consolidation transition. Consequently, our proposed habitat model (accuracy of 79%, sensitivity of 48%, and specificity of 88%) outperformed the clinical-blood model (accuracy of 68%, sensitivity of 14%, and specificity of 85%) for classifying pneumonia versus pneumonitis. Integrating imaging and blood achieved the optimal performance (accuracy of 81%, sensitivity of 52% and specificity of 90%). Using this imaging-blood composite model, the post-test probability for detecting pneumonitis increased from 23% to 61%, significantly (p = 1.5E - 9) higher than the clinical and blood model (post-test probability of 22%). Habitat imaging represents a step forward in the image-based detection of pneumonia and pneumonitis, which can complement known blood biomarkers. Further work is needed to validate and fine tune this imaging-blood composite model and further improve its sensitivity to detect pneumonitis.

Common methodological pitfalls in ICI pneumonitis risk prediction studies.

Pneumonitis is one of the most common adverse events induced by the use of immune checkpoint inhibitors (ICI), accounting for a 20% of all ICI-associated deaths. Despite numerous efforts to identify risk factors and develop predictive models, there is no clinically deployed risk prediction model for patient risk stratification or for guiding subsequent monitoring. We believe this is due to systemic suboptimal approaches in study designs and methodologies in the literature. The nature and prevalence of different methodological approaches has not been thoroughly examined in prior systematic reviews. The PubMed, medRxiv and bioRxiv databases were used to identify studies that aimed at risk factor discovery and/or risk prediction model development for ICI-induced pneumonitis (ICI pneumonitis). Studies were then analysed to identify common methodological pitfalls and their contribution to the risk of bias, assessed using the QUIPS and PROBAST tools. There were 51 manuscripts eligible for the review, with Japan-based studies over-represented, being nearly half (24/51) of all papers considered. Only 2/51 studies had a low risk of bias overall. Common bias-inducing practices included unclear diagnostic method or potential misdiagnosis, lack of multiple testing correction, the use of univariate analysis for selecting features for multivariable analysis, discretization of continuous variables, and inappropriate handling of missing values. Results from the risk model development studies were also likely to have been overoptimistic due to lack of holdout sets. Studies with low risk of bias in their methodology are lacking in the existing literature. High-quality risk factor identification and risk model development studies are urgently required by the community to give the best chance of them progressing into a clinically deployable risk prediction model. Recommendations and alternative approaches for reducing the risk of bias were also discussed to guide future studies.

Incidence, outcomes, and risk factors of acute immune checkpoint inhibitor (ICI) pneumonitis post-chemoradiation with durvalumab for patients with locally advanced non-small cell lung cancer (LA-NSCLC): A population-based multicenter study.

8561 Background: The PACIFIC trial has drastically changed the LA-NSCLC treatment paradigm and improved survival outcomes with consolidation durvalumab post-chemoradiotherapy. Despite these promising results, real-world practice has demonstrated that ICI pneumonitis can have significant clinical complications and terminate consolidation therapy prematurely. This study aimed to identify clinical predictors, outcomes, and healthcare utilization in ICI pneumonitis in LA-NSCLC patients who received consolidation durvalumab in real-world practice. Methods: Using the Alberta Immunotherapy Database, we retrospectively evaluated all NSCLC patients who received durvalumab in Alberta, Canada from January 2018 to December 2021. Pneumonitis cases were identified based on radiographic changes and oncologists’ clinical assessments. We examined incidence and predictive values of severe pneumonitis (≥grade 3), with secondary outcomes of overall survival (OS) and time-to-treatment failure (TTF). Exploratory multivariate analyses were performed to identify predictive values to developing severe pneumonitis and worse OS/TTF. Results: Of 189 total patients, most were ECOG 0-1 (91%) and had partial response from chemoradiation (85%) prior to durvalumab. 49% received full year of therapy (n = 93). Median TTF was 11.2 months, and median OS of 19.7 months with 1-year OS 64% (n = 121). 26% (n = 49) developed any grade of pneumonitis. 9% (n = 17) had severe pneumonitis. Corticosteroids were administered to 86% of the pneumonitis patients (n = 42); 53% (n = 26) required admission. 13% (n = 9) of deaths were attributed to pneumonitis. Male gender and pre-existing autoimmune condition were associated with severe pneumonitis whereas V20 (percentage of irradiated lung volume ≥20Gy) was associated with developing any grade pneumonitis. In multivariable analysis, male gender and V20 was significantly associated with worse OS whereas older age, smoking status, pneumonitis, and male gender with lower TTF. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Conclusions: We report a pneumonitis incidence comparable to prior retrospective studies and higher rate of severe pneumonitis compared to PACIFIC trial. Our results corroborate that V20, a previously established risk factor for durvalumab associated pneumonitis, is a significant predictor for developing pneumonitis and worse OS. In contrast to smaller retrospective studies, we observed male gender and pre-existing autoimmune conditions appear to predict severe durvalumab associated ICI pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population.

Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis.

Immune checkpoint inhibitors (ICIs) are a first-line treatment for various metastatic solid tumors. Pneumonitis is a potentially devastating complication of ICI treatment and a leading cause of ICI-related mortality. Here, we evaluate whether abnormal pre-treatment pulmonary function tests (PFTs) or interstitial abnormalities on computed tomography of the chest (CT chest) prior to ICI are associated with the development of ICI-pneumonitis (ICI-p). We conducted a retrospective cohort study of consecutive patients who received at least one dose of ICI from 2011 to 2017 at The Ohio State University. Potential risk factors for ICI-p, including abnormal PFTs and CT chest, were recorded. These risk factors were compared between patients with and without pneumonitis. In total, 1097 patients were included, 46 with ICI-p and 1051 without. Ninety percent of patients had pre-treatment chest imaging, while only 10% had pre-treatment PFTs. On multivariable analysis, interstitial abnormalities and reduced total lung capacity (TLC) were significantly associated with development of ICI-p (hazard ratio of 42.42 [95% CI; 15.04-119.67] and hazard ratio of 4.04 [95% CI; 1.32-12.37]), respectively. No other PFT abnormality was associated with increased risk of ICI-p. There was no significant difference in overall survival in patients who did or did not develop ICI-p (p = 0.332). Pre-existing interstitial abnormalities on CT chest and reduced TLC were strongly associated with developing ICI-p. Prospective studies are warranted to further explore the role of PFTs as a potential tool for identifying patients at highest risk for developing ICI-p.

The Predictive Model Construction for Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immunotherapy.

It is possible to predict immune-related adverse events (irAEs) in the treatment of immune checkpoint inhibitors (ICIs) based on clinical and hematological parameters. Nevertheless, the specific parameters which can predict irAEs are still in the exploration. The purpose of this retrospective study was to develop a predictive model for irAEs in non-small cell lung cancer (NSCLC) patients in the treatment of ICIs. Researchers enrolled NSCLC patients treated with at least 1 type of ICIs at Harbin Medical University Cancer Hospital between January 30, 2019 and December 31, 2021. Baseline parameters including demographic, clinicopathology, treatment information, and peripheral blood markers were selected retrospectively. Type, onset time, grade, and treatment of irAEs were also assessed. By analyzing the risk factors for irAEs, an irAEs prediction model was established using univariate and multivariate logistic regression. In a total of 484 patients, 81 patients experienced 112 irAEs in which thyroid dysfunction was the most common irAE (n = 38, 33.9%) and ICI pneumonitis was the most serious irAE (n = 6, 33.3%). Finally, a prediction model based on lines and combination therapy of ICIs, ECOG performance status, neutrophils/lymphocytes ratio (NLR), platelet (PLT), and lymphocyte (LYM) was established. Multivariate logistic regression analysis showed that 2 or ≥3 lines of immunotherapy, ICIs combination therapy, and ECOG PS 1-2 were independent risk factors for irAEs. Baseline LYM was positively associated with irAEs (OR = 2.599, P = 0.048) while baseline NLR and PLT were negatively associated with irAEs (OR = 0.392, P = 0.047; OR = 0.992, P = 0.035, respectively). The model showed great prediction performance with the AUC value of 0.851 and 0.779 in the training cohort and validation cohort, respectively. Our study identified the risk factors related to irAEs occurrence and constructed and assessed the predictive model of irAEs in patients with NSCLC treated by ICIs using clinical and hematological parameters, thus guiding clinicians to select precisely the population receiving immunotherapy and develop individualized treatment therapy.

Evaluating Radiation-Related Risk Factors for Pneumonitis in Patients with Stage III NSCLC Receiving Durvalumab after Definitive Chemoradiation

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation up to 12 mo became the standard of care for patients (pts) with stage III NSCLC after the publication of the PACIFIC trial. Both radiation pneumonitis (RP) and immune checkpoint inhibitor pneumonitis (ICI-p) are serious toxicities that can occur in this population, and radiation and ICI modality individually is known to contribute to pneumonitis risk; when combined, they could work synergistically or additively to increase this risk. We set out to evaluate radiation treatment specific risk factors for symptomatic pneumonitis in pts receiving CCRT followed by durvalumab. We hypothesize that adjuvant ICI (durvalumab) will increase the pneumonitis risk from CCRT predicted by current consensus guidelines. <h3>Materials/Methods</h3> We conducted a retrospective study of pts with stage III NSCLC treated with CCRT followed by durvalumab from 2018 -21. Median follow up time was 18.8 mo from the last day of RT to last contact. RT dose parameters were extracted from each treatment plan. Normal lung volume (NLV) was defined as total lung volume minus clinical target volume (Lung -CTV). Percentage of NLV receiving more than 5, 10, or 20 Gy (V5, V10, V20), and mean lung dose (MLD) were calculated. The primary endpoint was development of symptomatic pneumonitis (≥gr 2), assessed via clinical presentation and available imaging. The association between the % NLV of radiation and the probability of developing pneumonitis was analyzed using logistic regression, and odds ratios (OR) were estimated. <h3>Results</h3> Of the 80 patients included in this study, 21 (26.3%) developed symptomatic pneumonitis following durvalumab initiation. 69 (86.3%) received carboplatin-paclitaxel and 11 (13.8%) received cisplatin-etoposide chemotherapy. 73 (91.2%) had received standard RT dose of 60 Gy, while 7 (8.8%) received an additional 12-16 Gy SBRT boost to the primary tumor on a separate study. We found no significant association between symptomatic pneumonitis and RT dose or type of chemotherapy. However, smaller treatment volumes receiving 5 or 10 Gy were associated with lower pneumonitis risk: V10 < 40%, vs ≥ 40% (OR = 0.347, 95% CI 0.11-1.07, P=0.067) and V5 <65% vs ≥65% (OR = 0.42, 95% CI: 0.15-1.17, P = 0.096). Mean MLD was 14.9 Gy (3.9-21.9 Gy), Mean V20 was 25.7% (4.5-40.1%), both well below current consensus guidelines. We did not identify a notable association between pneumonitis and other known clinical risk factors. <h3>Conclusion</h3> This data is from our institution's first cohort of pts treated as in the PACIFIC study after durvalumab was approved by FDA for this indication. Our data suggest pts with a lower radiation treatment volume at 5 or 10 Gy (V5/V10) prior to durvalumab may have a lower risk of developing pneumonitis when other parameters (MLD, V20) are kept under the current recommended radiation tolerance without adjuvant ICI. Further research with larger study populations is needed to confirm this and inform guideline development.

EP08.01-098 Evaluating Risk Factors for Pneumonitis in Stage III NSCLC Patients Receiving Durvalumab after Definitive Chemoradiation

Both radiation pneumonitis (RP) and immune checkpoint inhibitor pneumonitis (ICI-p) are toxicities that can occur in stage III NSCLC patients undergoing concurrent chemoradiation (CCRT) followed by durvalumab consolidation. We set out to evaluate potential risk factors for the development of symptomatic pneumonitis in a cohort receiving varied doses of combined CCRT and durvalumab.

HSR22-165: Pulmonary Function Tests (PFTs) and Immune Checkpoint Inhibitor Pneumonitis

HSR22-165: Pulmonary Function Tests (PFTs) and Immune Checkpoint Inhibitor Pneumonitis

Imaging of Oncologic Treatment-Related Pneumonitis: A Focused Review on Emerging Issues of Immune Checkpoint Inhibitor Pneumonitis, From the AJR Special Series on Inflammation.

Treatment-related pneumonitis represents a major challenge in oncology patients undergoing therapy, and imaging plays an essential role in detection, diagnosis, and monitoring of pneumonitis in these patients. Among various types of pneumonitis from different kinds of cancer treatments, immune checkpoint inhibitor (ICI)-related pneumonitis has been recognized as an important topic in the radiology and oncology communities since 2015, given the increasing clinical indications for ICI therapy in patients with cancer. Moreover, clinical applications of ICIs continue to advance rapidly with novel combination approaches, leading to further emerging challenges. This focused review describes the current knowledge about ICI pneumonitis and discusses several newly emerging issues involving recurrence and flare of ICI pneumonitis, as well as involving pneumonitis from new combination approaches including ICI with epidermal growth factor receptor (EGFR) inhibitors and ICI with radiotherapy. The article concludes with a summary of unmet needs in the care of patients with ICI pneumonitis as well as of future directions in the advancement of knowledge about ICI pneumonitis and patient care for ICI pneumonitis. Given the proven multifaceted value of imaging in ICI pneumonitis, radiologists will remain central in the ongoing multidisciplinary journey to further understand and overcome this challenging toxicity for patients with cancer.

Immune Checkpoint Inhibitor and Radiotherapy-Related Pneumonitis: An Informatics Approach to Determine Real-World Incidence, Severity, Management, and Resource Implications.

Pneumonitis is a well-described, potentially life-threatening adverse effect of immune checkpoint inhibitors (ICI) and thoracic radiotherapy. It can require additional investigations, treatment, and interruption of cancer therapy. It is important for clinicians to have an awareness of its incidence and severity, however real-world data are lacking and do not always correlate with findings from clinical trials. Similarly, there is a dearth of information on cost impact of symptomatic pneumonitis. Informatics approaches are increasingly being applied to healthcare data for their ability to identify specific patient cohorts efficiently, at scale. We developed a Structured Query Language (SQL)-based informatics algorithm which we applied to CT report text to identify cases of ICI and radiotherapy pneumonitis between 1/1/2015 and 31/12/2020. Further data on severity, investigations, medical management were also acquired from the electronic health record. We identified 248 cases of pneumonitis attributable to ICI and/or radiotherapy, of which 139 were symptomatic with CTCAE severity grade 2 or more. The grade ≥2 ICI pneumonitis incidence in our cohort is 5.43%, greater than the all-grade 1.3–2.7% incidence reported in the literature. Time to onset of ICI pneumonitis was also longer in our cohort (mean 4.5 months, range 4 days-21 months), compared to the median 2.7 months (range 9 days−19.2 months) described in the literature. The estimated average healthcare cost of symptomatic pneumonitis is £3932.33 per patient. In this study we use an informatics approach to present new real-world data on the incidence, severity, management, and resource burden of ICI and radiotherapy pneumonitis. To our knowledge, this is the first study to look at real-world incidence and healthcare resource utilisation at the per-patient level in a UK cancer hospital. Improved management of pneumonitis may facilitate prompt continuation of cancer therapy, and improved outcomes for this not insubstantial cohort of patients.

HERPES SIMPLEX VIRUS PNEUMONIA MASQUERADING AS DRUG-INDUCED PNEUMONITIS

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Drug induced pneumonitis is a major cause of adverse events during cancer therapy, and has become increasingly common with the use of immune-checkpoint inhibitor (ICI) therapy. Due to its rarity, ICI pneumonitis is a diagnosis of exclusion, and infection and malignancy must be ruled out. While multiple types of infection are typically assessed for, Herpes Simplex Virus (HSV) pneumonia is often not considered. We report the case of a 75 year old man with non-small cell lung cancer (NSCLC) on pembrolizumab who died despite aggressive treatment for a presumed ICI pneumonitis, and was found on autopsy to have had HSV pneumonia. CASE PRESENTATION: A 75 year old man with NSCLC presented to hospital with two days of dyspnea. The patient was being treated with a multi-drug chemotherapy regimen, including pembrolizumab. His last cycle was five days prior to admission. On admission, he was found to be hypoxic, saturating 70% on room air, with course bilateral crackles, and extensive bilateral ground glass opacities on chest CT. He did not have leukocytosis. Multiple infectious studies, including COVID-19, CMV, respiratory viral panel, legionella, mycoplasma, beta-D glucan, and galactomannan were negative. ICI pneumonitis was highest on the differential, and the patient was therefore started on solumedrol. After two days of no improvement, the solumedrol was increased and infliximab was added. The patient's respiratory status continued to worsen, and he was ultimately intubated. The patient underwent bronchoscopy once intubated, however, he expired before the studies resulted. Autopsy revealed a severe HSV pneumonia. DISCUSSION: ICI pneumonitis occurs in approximately 5% of patients treated with PD(L)-1 inhibitors, of which approximately 25% of cases are graded as severe or life-threatening. While the vast majority of patients with non-severe disease are successfully treated by withholding the ICI alone or in conjunction with glucocorticoids, those with more severe disease may require additional immunosuppression, and a small number of these patients die despite treatment. Due to its rarity, ICI pneumonitis is a diagnosis of exclusion, and diagnoses such as infection and malignancy should always be ruled out. The fact that its radiographic presentation is so heterogenous, with patterns as variable as those seen with COP, NSIP, HP, and AIP/ARDS, makes it all the more difficult to diagnose. HSV pneumonia is known to infrequently cause pneumonia in severely immunocompromised patients. A prospective observational study conducted in 2018 on immunocompromised adults with pneumonia not responding to empiric antibiotic therapy found it to be much more common than expected, with 42% of patients testing positive for HSV-1 on BAL, and 24% meeting criteria for HSV pneumonia. CONCLUSIONS: HSV pneumonia should be more frequently considered in immunocompromised patients suspected of having an ICI pneumonitis. REFERENCE #1: Nishino M, et al. Drug-related pneumonitis in the era of precision cancer therapy. JCO Precision Oncology. 2017 May 26; 1: 1-12. REFERENCE #2: Naidoo J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clinical Oncology. 2017 Mar; 35 (7): 709-717. REFERENCE #3: Luzzati R, et al. Herpex simplex virus (HSV) pneumonia in the non-ventilated immunocompromised host: burden and predictors. J Infect. 2019 Feb; 78 (2): 127-133. DISCLOSURES: No relevant relationships by Jeffrey Ordner, source=Web Response No relevant relationships by Ariella Pratzer, source=Web Response No relevant relationships by Mark Sloane, source=Web Response No relevant relationships by Kristen Thomas, source=Web Response No relevant relationships by Karen Yang, source=Web Response

ES17.03 Imaging of Pneumonitis

Pneumonitis is one of the major adverse events from systemic anti-cancer therapy and provides clinical challenges in oncology practice. Imaging plays a key role in detection, diagnosis, and monitoring of pneumonitis in cancer patients. This lecture will discuss 1) diagnosis and monitoring of pneumonitis using CT patterns on imaging, 2) spectrum of CT patterns of pneumonitis focusing on immune-checkpoint inhibitors (ICI) and epidermal growth factor receptor (EGFR) inhibitors, and 3) emerging challenges and pitfalls in the era of COVID-19 pandemic. When approaching pneumonitis on imaging, it is very important to note that pneumonitis represents lung’s response to injury. The lung’s response patterns to injury has several histologic manifestations with corresponding CT patterns, which are originally described in idiopathic interstitial pneumonias and are also noted in the setting of pneumonitis secondary to cancer therapy. The assessment of extent and distribution of the lung abnormalities on CT is very important to recognize the distinct CT patterns. The spectrum of CT patterns is noted in pneumonitis from cancer therapies, and are associated with clinical severity of pneumonitis. Recognition of CT patterns helps to diagnosis, monitor, and prognosticate pneumonitis in cancer patients. In terms of pneumonitis from individual agents, the lecture will focus on pneumonitis from ICI and EGFR inhibitors, which are two representative agents used in lung cancer that can cause pneumonitis. ICI pneumonitis is relatively rare, but clinically serious and potentially life-threatening toxicity from ICI therapy, and is a leading cause of anti-PD-1/PD-L1-related deaths. The incidence of ICI pneumonitis is higher in lung cancer than in other cancers, indicating that pneumonitis is a particularly important issue in patients with lung cancer. The representative CT patterns of ICI pneumonitis include AIP/ARDS pattern, COP pattern, NSIP pattern, and HP pattern. Among these patterns, COP pattern is most common, noted in about two thirds of the patients. AIP/ARDS patten has the most severe clinical presentation and requires immediate clinical attention. The details of each of these CT patterns will be described with case presentations to demonstrate the characteristic features with clinical correlation. Pneumonitis is also a recognized class-effect for EGFR inhibitors. A higher incidence rate in Japanese population is noted, with a high mortality rate in the cohort studies from Japan, which is confirmed by the recent meta-analysis of 153 EGFR inhibitor trials in non-small cell lung cancer. The spectrum of CT patterns is also noted in EGFR inhibitor pneumonitis, and correlates with clinical severity and outcome. As the emerging issues with the advances of cancer therapies and the recent COVID pandemic, pneumonitis from combination ICI and radiotherapy is discussed, featuring the imaging manifestations from both ICI pneumonitis and radiation pneumonitis. Finally, the overlapping imaging features of ICI pneumonitis and COVID-19 pneumonia are presented, to demonstrate a unique challenge in the era of COVID-19 pandemic. The lecture concludes emphasizing the importance of multidisciplinary approach to further understand these emerging challenges to optimize diagnosis and management of pneumonitis in cancer patients. Abbreviations: AIP = Acute Interstitial Pneumonia; ARDS = Acute Respiratory Distress Syndrome; COP = Cryptogenic Organizing Pneumonia; HP = Hypersensitivity Pneumonitis; NSIP = Non-Specific Interstitial Pneumonia

The knowns & unknowns of pulmonary toxicity following immune checkpoint inhibitor therapies: a narrative review.

Since their discovery immune checkpoint inhibitors (ICI) have dramatically changed the treatment landscape for many cancers. In addition to their efficacy they are generally well tolerated, however, they have led to a new range of immune-related adverse events (irAEs) including pneumonitis. While not the most frequently reported immune-related adverse event in the clinical trial setting, recent real-world data suggests a significantly higher rate of pneumonitis leading to treatment suspension or cessation. It also appears to disproportionately contribute to immune-related mortality, particularly with anti-PD-1/PD-L1 treatment. While indicators have emerged regarding risk factors, incomplete prospective recording of patient characteristics hampers strong conclusions. Presenting symptoms are non-specific and the differential diagnosis is broad, made more complex by concomitant treatment with traditional chemotherapy or radiotherapy. Radiological findings are diverse and inconsistent terminology makes comparison and more complete characterization difficult. Further, little is known about the role of baseline testing or surveillance for early detection of pneumonitis, or the real-world role of bronchoscopy or biopsy in assessment. Scant literature exists to direct these complex decisions, so treatment guidelines have been published based on expert consensus. Here we provide a narrative review of what is known about ICI pneumonitis and propose key questions to enhance our understanding into the future.

Chronic immune checkpoint inhibitor (ICI) pneumonitis in patients (pts) with non-small cell lung cancer (NSCLC).

9103 Background: ICI pneumonitis is an immune-related adverse event (irAE) of the lung and often requires discontinuation of ICI. While some pneumonitis cases resolve within the recommended 4-6-week period of corticosteroid therapy, others either fail to improve or have multiple flares necessitating longer or repeated courses of steroids. We investigated the clinical features and courses of pts with chronic pneumonitis. Methods: We analyzed 869 pts with NSCLC initiated on ICIs at our institution between 2011 and 2019 for development of ICI pneumonitis. Chronic pneumonitis was defined as any pneumonitis requiring a total of ≥12 weeks of steroids, given either continuously or over multiple courses of treatment. Cases of chronic pneumonitis in which the initial course of steroids lasted ≥12 weeks without interruption were termed “primary refractory pneumonitis”. Subsequent episodes of pneumonitis were categorized as either “recurrent pneumonitis” from ICI rechallenge or “pneumonitis flare” after steroid taper without ICI rechallenge. Chest CT scans were analyzed to classify the imaging patterns. Results: Of the 869 pts analyzed, 44 developed ICI pneumonitis (5.1%) and 22 of the 44 (50%) experienced chronic pneumonitis (Grade 2 in 11, Grade 3 in 9, and Grade 4 in 2). A cryptogenic organizing pneumonia (COP) pattern was the most common CT pattern among all pneumonitis cases (30/44) and in chronic pneumonitis cases (14/22). Among chronic pneumonitis cases, the median number of total weeks on corticosteroid therapy was 25.9 (range: 12.4 – 114.4 weeks). Four pts required additional immunosuppressive agents including mycophenolate or infliximab. Fourteen of 22 pts with chronic pneumonitis had primary refractory pneumonitis, while the remaining 8 pts were weaned off of steroids within 12 weeks but later developed additional episode(s) of pneumonitis, ultimately resulting in a total steroid duration of ≥12 weeks. The 14 pts with primary refractory pneumonitis had significantly shorter time to pneumonitis onset compared to the other 8 pts (median time to onset: 1.8 vs. 5.5 months, Wilcoxon ranksum p = 0.04). Seventeen of 22 patients had their ICI permanently discontinued; of these, 9 pts subsequently experienced pneumonitis flare after steroid taper, necessitating additional course(s) of steroid therapy. 5 of the 22 patients were rechallenged with ICI, and 4 of them had recurrent pneumonitis with ICI rechallenge. Conclusions: Half of the pts diagnosed with pneumonitis developed chronic pneumonitis requiring at least 12 weeks in aggregate of glucocorticoid therapy. Some patients had an initial prolonged steroid course while others initially improved and then flared, even after ICI discontinuation. Recognition of chronic pneumonitis as a distinct and common clinical entity is important in management of pts with ICI pneumonitis.

Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors.

BackgroundNon‐small cell lung cancer (NSCLC) patients with pre‐existing respiratory diseases have been excluded in clinical trials of immune checkpoint inhibitor (ICI) therapy, and it is unknown whether the same degree of response can be expected as that in patients without pre‐existing respiratory diseases and if they are associated with increased risk for various immune‐related adverse events (irAEs) and ICI pneumonitis. This study aimed to evaluate predictive factors of clinical response, prognostic factors, risk factors of irAEs, and ICI pneumonitis in NSCLC patients with or without pre‐existing respiratory diseases.MethodsWe conducted a retrospective study of 180 NSCLC patients who received ICI monotherapy of nivolumab, pembrolizumab, or atezolizumab from 1 January 2016 to 31 March 2019.ResultsA total of 119 patients had pre‐existing respiratory diseases, including 20 with pre‐existing idiopathic interstitial pneumonias (IIPs). A total of 85 patients experienced irAEs, of which ICI pneumonitis was the most frequent adverse event, occurring in 27 patients. Of the three patients who died from irAEs, all from ICI pneumonitis, two had pulmonary emphysema and one had pre‐existing IIP. In multivariate analyses, irAEs were associated with objective response rate (ORR) and favorable OS, and IIPs were associated with increased risk for ICI pneumonitis. However, IIPs were not associated with low ORR or poor OS.ConclusionsPre‐existing IIPs were a risk factor for ICI pneumonitis. However, this study showed that ICI therapy can be offered to patients with pre‐existing respiratory diseases with the expectation of the same degree of response as that in patients without pre‐existing respiratory diseases.Key pointsSignificant findings of the study: Pre‐existing IIPs were a risk factor for ICI pneumonitis, but objective response rate and prognosis of patients with IIPs were similar to those of other patients.What this study adds: In patients with pre‐existing IIPs, ICI pneumonitis should be noted. However, ICI therapy can be offered to patients with pre‐existing respiratory diseases with the expectation of the same degree of response as that in patients without pre‐existing respiratory diseases

Differentiation of COVID-19 Pneumonitis and ICI Induced Pneumonitis.

Immune checkpoint inhibitors (ICI) have become the standard of care treatment for several tumor types. ICI-induced pneumonitis is a serious complication seen with treatment with these agents. Cancer has been reported to be one of the risk factors for severe coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that has engulfed the world in the last couple of months. In patients with cancer treated with ICI who present at the emergency department with respiratory symptoms during the COVID-19 pandemic, correct diagnosis can be challenging. Symptoms and radiological features of ICI pneumonitis can be overlapping with those of COVID-19 related pneumonia. For the latter, dexamethasone and remdesivir have shown encouraging results, while vaccines are currently being evaluated in phase III trials. The mainstay of treatment in ICI pneumonitis is immunosuppressive therapy, as this is a potentially fatal adverse event. It has been speculated that immunosuppression may be associated with increased risk of progression to severe COVID-19, especially during the early stage of infection with SARS-CoV-2. Therefore, distinction between these two entities is warranted. We summarize the clinical, radiological features as well as additional investigations of both entities, and suggest a diagnostic algorithm for distinction between the two. This algorithm may be a supportive tool for clinicians to diagnose the underlying cause of the pneumonitis in patients treated with ICI during this COVID-19 pandemic.