Robotic bronchoscopy in diagnosing lung cancer-the evidence, tips and tricks: a clinical practice review.

The development of robotic-assisted bronchoscopy has empowered bronchoscopists to access the periphery of the lung with more confidence and promising accuracy. This is due in large to the superior maneuverability, further reach, and stability of these technologies. Despite the advantages of robotic bronchoscopy, there are some drawbacks to using these technologies, such as the loss of tactile feedback, the need to overcome computed tomography (CT)-to-body divergence, and the potential for overreliance on the navigation software. There are currently two robotic bronchoscopy platforms on the US market, the MonarchTM Platform by Auris Health© (Redwood City, CA, USA) and the IonTM endoluminal robotic bronchoscopy platform by Intuitive Surgical© (Sunnyvale, CA, USA). In this clinical practice review, we highlight the evidence and strategies for successful clinical use of both robotic bronchoscopy platforms for pulmonary lesion sampling. Specifically, we will review pre-procedural considerations, such as procedural mapping, room set-up and anesthesia considerations. We will also review the technical aspects of using the robotic bronchoscopy platforms, such as how to compensate for the loss of tactile feedback, optimize visualization, use of ancillary technology to accommodate for CT-to-body divergence, employ best practices for sampling techniques, and utilize information from rapid on-site evaluation (ROSE) to aid in improving diagnostic yield.

The role of bronchoscopy in the multidisciplinary approach to benign tracheal stenosis.

Benign tracheal stenosis can cause dyspnea, wheezing, and cough mimicking other obstructive lung diseases which often leads to a delay in the diagnosis. Risk factors and etiologies for tracheal strictures include autoimmune diseases, infection, gastro-esophageal reflux disease (GERD), radiation injury and iatrogenic factors such as post-intubation and post-tracheostomy. Once suspected, tracheal strictures are diagnosed by performing a thorough evaluation involving clinical exam, laboratory workup, pulmonary function test, chest imaging and bronchoscopy. Bronchoscopy plays a pivotal role in the diagnosis of stenosis and along with the imaging and physiologic assessments leads to a proper description of the stenosis based on all parameters that matters for management. Surgical resection provides a definitive management in most patients with idiopathic or post intubation/tracheostomy stenosis, however, factors such as severe co-morbidities, length and location of the stricture can preclude patients from undergoing curative surgery. Several bronchoscopic interventions including mechanical or laser assisted dilation, electrosurgery (ES), airway stenting and pharmacological treatment with mitomycin C (MMC) and intralesional steroid have been reported in the literature for management of patients who are not surgical candidates. Herein, we review the role of bronchoscopy and illustrate the importance of a multi-disciplinary team (MDT) approach comprising of interventional pulmonologists, thoracic surgeons and otorhinolaryngologists in the diagnosis and management of patients with benign tracheal stenosis.

The Effect of Definitions and Cancer Prevalence on Diagnostic Yield Estimates of Bronchoscopy: A Simulation-based Analysis.

Rationale: Studies of bronchoscopy have reported diagnostic yield (DY) using different calculation methods, which has hindered comparisons across studies. Objectives: To quantify the effect of the variability of four methods on DY estimates of bronchoscopy. Methods: We performed a simulation-based analysis of patients undergoing bronchoscopy using variations around base case assumptions for cancer prevalence (60%), distribution of nonmalignant findings, and degree of follow-up information at a fixed sensitivity of bronchoscopy for malignancy (80%). We calculated DY, the rate of true positives and true negatives (TNs), using four methods. Method 1 considered malignant and specific benign findings at index bronchoscopy as true positives and TNs, respectively. Method 2 included nonspecific benign findings as TNs. Method 3 considered nonspecific benign findings cases as TNs only if follow-up confirmed benign disease. Method 4 counted all cases with a nonmalignant diagnosis as TNs if follow-up confirmed benign disease. A scenario analysis and probabilistic sensitivity analysis were conducted to demonstrate the effect of parameter estimates on DY. A change in DY of >10% was considered clinically meaningful. Results: Across all pairwise comparisons of the four methods, a DY difference of >10% was observed in 76.7% of cases (45,992 of 60,000 comparisons). Method 4 resulted in DY estimates that were >10% higher than estimates made with other methods in >90% of scenarios. Variation in cancer prevalence had a large effect on DY. Conclusions: Across a wide range of clinical scenarios, the categorization of nonmalignant findings at index bronchoscopy and cancer prevalence had the largest impact on DY. The large variability in DY estimates across the four methods limits the interpretation of bronchoscopy studies and warrants standardization.

High-Definition Videobronchoscopy for the Diagnosis of Airway Involvement in Sarcoidosis: The Enhance Sarcoidosis Multicenter Study.

BACKGROUND: The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously. RESEARCH QUESTION: What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)? STUDY DESIGN AND METHODS: In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs. RESULTS: AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P = .001). Likewise, parenchymal disease on CT scan imaging was significantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P = .003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nodularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss κ = 0.34). INTERPRETATION: In a population with a large prevalence of White Europeans, HD videobronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT4743596; URL: www. CLINICALTRIALS: gov.

Advanced Imaging for Robotic Bronchoscopy: A Review.

Recent advances in navigational platforms have led bronchoscopists to make major strides in diagnostic interventions for pulmonary parenchymal lesions. Over the last decade, multiple platforms including electromagnetic navigation and robotic bronchoscopy have allowed bronchoscopists to safely navigate farther into the lung parenchyma with increased stability and accuracy. Limitations persist, even with these newer technologies, in achieving a similar or higher diagnostic yield when compared to the transthoracic computed tomography (CT) guided needle approach. One of the major limitations to this effect is due to CT-to-body divergence. Real-time feedback that better defines the tool-lesion relationship is vital and can be obtained with additional imaging using radial endobronchial ultrasound, C-arm based tomosynthesis, cone-beam CT (fixed or mobile), and O-arm CT. Herein, we describe the role of this adjunct imaging with robotic bronchoscopy for diagnostic purposes, describe potential strategies to counteract the CT-to-body divergence phenomenon, and address the potential role of advanced imaging for lung tumor ablation.

Current Practices Supporting Rigid Bronchoscopy-An International Survey.

BACKGROUND: There are no guidelines for anesthesia or staff support needed during rigid bronchoscopy (RB). Identifying current practice patterns for RB pertinent to anesthesia, multidisciplinary teams, and algorithms of intra and post-procedural care may inform best practice recommendations. METHODS: Thirty-three-question survey created obtaining practice patterns for RB, disseminated via email to the members of the American Association of Bronchology and Interventional Pulmonology and the American College of Chest Physicians Interventional Chest Diagnostic Procedures Network. RESULTS: One hundred seventy-five clinicians participated. Presence of a dedicated interventional pulmonology (IP) suite correlated with having a dedicated multidisciplinary RB team ( P =0.0001) and predicted higher likelihood of implementing team-based algorithms for managing complications (39.4% vs. 23.5%, P =0.024). A dedicated anesthesiology team was associated with the increased use of high-frequency jet ventilation ( P =0.0033), higher likelihood of laryngeal mask airway use post-RB extubation ( P =0.0249), and perceived lower rates of postprocedural anesthesia adverse effects ( P =0.0170). Although total intravenous anesthesia was the most used technique during RB (94.29%), significant variability in the modes of ventilation and administration of muscle relaxants was reported. Higher comfort levels in performing RB are reported for both anesthesiologists ( P =0.0074) and interventional pulmonologists ( P =0.05) with the presence of dedicated anesthesia and RB supportive teams, respectively. CONCLUSION: Interventional bronchoscopists value dedicated services supporting RB. Multidisciplinary dedicated RB teams are more likely to implement protocols guiding management of intraprocedural complications. There are no preferred modes of ventilation during RB. These findings may guide future research on RB practices.

Factors Associated With Diagnostic Accuracy of Robotic Bronchoscopy With 12-Month Follow-up.

BACKGROUND: Robotic bronchoscopy (RB) aims to increase the diagnostic yield of guided bronchoscopy by providing improved navigation, farther reach, and stability during lesion sampling. METHODS: We reviewed data on consecutive cases in which RB was used to diagnose lung lesions from June 15, 2018, to December 15, 2019, at the University of Chicago Medical Center. RESULTS: The median lesion size was 20.5 mm. All patients had at least 12 months of follow-up. The overall diagnostic accuracy was 77% (95 of 124). The diagnostic accuracy was 85%, 84%, and 38% for concentric, eccentric, and absent radial endobronchial ultrasound (r-EBUS) views, respectively (P < .001). A positive r-EBUS view and lesions size of 20 to 30 mm had higher odds of achieving a diagnosis on multivariate analysis. The 12-month diagnostic accuracy, sensitivity, specificity, and positive and negative predictive value for malignancy were 77%, 69%, 100%, 100%, and 58%, respectively. Pneumothorax was noted in 1.6% (n = 2) patients with bleeding reported in 3.2% (n = 4). No postprocedure respiratory failure was noted. CONCLUSIONS: The overall diagnostic accuracy using RB for pulmonary lesion sampling in our cohort with 12-month follow-up compared favorably with established guided bronchoscopy technologies. Lesion size ≥20 mm and confirmation by r-EBUS predicted higher accuracy independent of concentric or eccentric r-EBUS patterns.

Safety and Feasibility of Photodynamic Therapy for Ablation of Peripheral Lung Tumors.

BACKGROUND: Newer navigational bronchoscopy technologies render peripheral lung lesions accessible for biopsy and potential treatment. We investigated whether photodynamic therapy (PDT) delivered via navigational bronchoscopy is feasible and safe for ablation of peripheral lung tumors. METHODS: Two studies evaluated PDT in patients with solid peripheral lung tumors followed by clinical follow-up (nonresection study, N=5) or lobectomy (resection study, N=10). Porfimer sodium injection was administered 40 to 50 hours before navigational bronchoscopy. Lesion location was confirmed by radial probe endobronchial ultrasonography. An optical fiber diffuser was placed within or adjacent to the tumor under fluoroscopic guidance; laser light (630 nm wavelength) was applied at 200 J/cm of diffuser length for 500 seconds. Tumor response was assessed by modified Response Evaluation Criteria in Solid Tumors at 3 and 6 months postprocedure (nonresection study) and pathologically (resection study). RESULTS: There were no deaths, discontinuations for adverse events, or serious or grade ≥3 adverse events related to study treatments. Photosensitivity reactions occurred in 8 of 15 patients: 6 mild, 1 moderate, 1 severe (elevated porphyrins noted in blood after treatment). Among 5 patients with clinical follow-up, 1 had complete response, 3 had stable disease, and 1 had progressive disease at 6 months follow-up. Among 10 patients who underwent lobectomy, 1 had no evidence of tumor at resection (complete response), 3 had 40% to 50% tumor cell necrosis, 2 had 20% to 35%, and 4 had 5% to 10%. CONCLUSION: PDT for nonthermal ablation of peripheral lung tumors was feasible and safe in this small study. Further study is warranted to evaluate efficacy and corroborate the safety profile.

Interventional Pulmonary Fellowship Training: End of the Beginning.

Interventional pulmonology (IP) fellowship training has undergone increased popularity and growth. The Accreditation Council of Graduate Medical Education recently recognized IP medicine as a new subspecialty, which leads to new challenges and opportunities for a young subspecialty. Although the specialty-specific requirements are in progress, IP fellowship programs must plan ahead for the known common program requirements and anticipated accreditation process. The educational leadership in IP must identify and execute solutions to sustain continued excellence. This includes transitioning to a new regulatory environment with issues of funding new fellowships, keeping up to date with training/assessment of new procedures, and shaping the future through recruitment of talent to lead the young subspecialty.

The Feasibility of Using the "Artery Sign" for Pre-Procedural Planning in Navigational Bronchoscopy for Parenchymal Pulmonary Lesion Sampling.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) and robotic-assisted bronchoscopy (RAB) systems are used for pulmonary lesion sampling, and utilize a pre-procedural CT scan where an airway, or "bronchus sign", is used to map a pathway to the target lesion. However, up to 40% of pre-procedural CT's lack a "bronchus sign" partially due to surrounding emphysema or limitation in CT resolution. Recognizing that the branches of the pulmonary artery, lymphatics, and airways are often present together as the bronchovascular bundle, we postulate that a branch of the pulmonary artery ("artery sign") could be used for pathway mapping during navigation bronchoscopy when a "bronchus sign" is absent. Herein we describe the navigation success and safety of using the "artery sign" to create a pathway for pulmonary lesion sampling. METHODS: We reviewed data on consecutive cases in which the "artery sign" was used for pre-procedural planning for conventional ENB (superDimension™, Medtronic) and RAB (Monarch™, Johnson & Johnson). Patients who underwent these procedures from July 2020 until July 2021 at the University of Minnesota Medical Center and from June 2018 until December 2019 at the University of Chicago Medical Center were included in this analysis (IRB #19-0011 for the University of Chicago and IRB #00013135 for the University of Minnesota). The primary outcome was navigation success, defined as successfully maneuvering the bronchoscope to the target lesion based on feedback from the navigation system. Secondary outcomes included navigation success based on radial EBUS imaging, pneumothorax, and bleeding rates. RESULTS: A total of 30 patients were enrolled in this analysis. The median diameter of the lesions was 17 mm. The median distance of the lesion from the pleura was 5 mm. Eleven lesions were solid, 15 were pure ground glass, and 4 were mixed. All cases were planned successfully using the "artery sign" on either the superDimension™ ENB (n = 15) or the Monarch™ RAB (n = 15). Navigation to the target was successful for 29 lesions (96.7%) based on feedback from the navigation system (virtual target). Radial EBUS image was acquired in 27 cases (90%) [eccentric view in 13 (43.33%) and concentric view in 14 patients (46.66%)], while in 3 cases (10%) no r-EBUS view was obtained. Pneumothorax occurred in one case (3%). Significant airway bleeding was reported in one case (3%). CONCLUSIONS: We describe the concept of using the "artery sign" as an alternative for planning EMN and RAB procedures when "bronchus sign" is absent. The navigation success based on virtual target or r-EBUS imaging is high and safety of sampling of such lesions compares favorably with prior reports. Prospective studies are needed to assess the impact of the "artery sign" on diagnostic yield.

Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Bronchoscopy in Patients With Known or Suspected COVID-19: Results From the Global Pandemic SARS-CoV-2 Bronchoscopy Database (GPS-BD).

BACKGROUND: Amid the Coronavirus Disease 2019 (COVID-19) pandemic, the benefits and risks of bronchoscopy remain uncertain. This study was designed to characterize bronchoscopy-related practice patterns, diagnostic yields, and adverse events involving patients with known or suspected COVID-19. METHODS: An online survey tool retrospectively queried bronchoscopists about their experiences with patients with known or suspected COVID-19 between March 20 and August 20, 2020. Collected data comprised the Global Pandemic SARS-CoV-2 Bronchoscopy Database (GPS-BD). All bronchoscopists and patients were anonymous with no direct investigator-to-respondent contact. RESULTS: Bronchoscopy procedures involving 289 patients from 26 countries were analyzed. One-half of patients had known COVID-19. Most (82%) had at least 1 pre-existing comorbidity, 80% had at least 1 organ failure, 51% were critically ill, and 37% were intubated at the time of the procedure. Bronchoscopy was performed with diagnostic intent in 166 (57%) patients, yielding a diagnosis in 86 (52%). and management changes in 80 (48%). Bronchoscopy was performed with therapeutic intent in 71 (25%) patients, mostly for secretion clearance (87%). Complications attributed to bronchoscopy or significant clinical decline within 12 hours of the procedure occurred in 24 (8%) cases, with 1 death. CONCLUSION: Results from this international database provide a widely generalizable characterization of the benefits and risks of bronchoscopy in patients with known or suspected COVID-19. Bronchoscopy in this setting has reasonable clinical benefit, with diagnosis and/or management change resulting from about half of the diagnostic cases. However, it is not without risk, especially in patients with limited physiological reserve.

Photodynamic therapy for stage I and II non-small cell lung cancer: A SEER-Medicare analysis 2000-2016.

ABSTRACT: We analyzed mortality (all-cause and lung cancer-specific) and time to follow-up treatment in stage I and II non-small cell lung cancer (NSCLC) patients treated with photodynamic therapy (PDT) compared with ablation therapy and radiation therapy.From Surveillance, Epidemiology, and End Results-Medicare linked data, patients diagnosed with stage I and II NSCLC between 2000 and 2015 were identified. Outcomes were mortality (overall and lung cancer-specific) and time to follow-up treatment. We analyzed mortality using Cox proportional hazard models. We used generalized linear model to assess time to follow-up treatment (PDT and ablation groups). Models were adjusted for inverse probability weighted propensity score.Of 495,441 NSCLC patients, 56 with stage I and II disease received PDT (mono or multi-modal), 477 received ablation (mono or multi-modal), and 14,178 received radiation therapy alone. None from PDT group had metastatic disease (M0) and 70% had no nodal involvement (N0). Compared with radiation therapy alone, PDT therapy was associated with lower hazard of overall (hazard ratio = 0.56, 95% CI = 0.39-0.80), and lung cancer-specific mortality (hazard ratio = 0.64, 95% CI = 0.43-0.97). Unadjusted mean time to follow-up treatment was 70days (standard deviation = 146) for PDT group and 67 days (standard deviation = 174) for ablation group. Compared with ablation, PDT was associated with an average increase of 125days to follow-up treatment (P = .11).Among stage I and II NSCLC patients, PDT was associated with improved survival, compared with radiation alone; and longer time to follow-up treatment compared with ablation. Currently, PDT is offered in various combinations with surgery and radiation. Larger studies can investigate the efficacy and effectiveness of these combinations.

Single-Use and Reusable Flexible Bronchoscopes in Pulmonary and Critical Care Medicine.

Flexible bronchoscopy plays a critical role in both diagnostic and therapeutic management of a variety of pulmonary disorders in the bronchoscopy suite and the intensive care unit. In the set-ting of the ongoing viral pandemic, single-use flexible bronchoscopes (SUFB) have garnered attention as various professional pulmonary societies have released guidelines regarding uses for SUFB given the concern for risk of viral transmission when using reusable flexible bronchoscopes (RFB). In addition to offering sterility, SUFBs are portable, easily accessible, and may be more cost-effective than RFB when considering the potential costs of treating bronchoscopy-related infections. Furthermore, since SUFBs are one time use, they do not require reprocessing after use, and therefore may translate to reduced cleaning and storage costs. Despite these advantages, RFBs are still routinely used to perform advanced diagnostic and therapeutic bronchoscopic procedures given the need for optimal maneuverability, handling, angle of deflection, image quality, and larger channel size for passing of ancillary instruments. Here, we review the published evidence on the applications of single-use and reusable bronchoscopes in bronchoscopy suites and intensive care units. Specifically, we will discuss the advantages and disadvantages of these devices as pertinent to fundamental, advanced, and therapeutic bronchoscopic interventions.

NAVIGATE 24-Month Results: Electromagnetic Navigation Bronchoscopy for Pulmonary Lesions at 37 Centers in Europe and the United States.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive, image-guided approach to access lung lesions for biopsy or localization for treatment. However, no studies have reported prospective 24-month follow-up from a large, multinational, generalizable cohort. This study evaluated ENB safety, diagnostic yield, and usage patterns in an unrestricted, real-world observational design. METHODS: The NAVIGATE single-arm, pragmatic cohort study (NCT02410837) enrolled subjects at 37 academic and community sites in seven countries with prospective 24-month follow-up. Subjects underwent ENB using the superDimension navigation system versions 6.3 to 7.1. The prespecified primary end point was procedure-related pneumothorax requiring intervention or hospitalization. RESULTS: A total of 1388 subjects were enrolled for lung lesion biopsy (1329; 95.7%), fiducial marker placement (272; 19.6%), dye marking (23; 1.7%), or lymph node biopsy (36; 2.6%). Concurrent endobronchial ultrasound-guided staging occurred in 456 subjects. General anesthesia (78.2% overall, 56.6% Europe, 81.4% United States), radial endobronchial ultrasound (50.6%, 4.0%, 57.4%), fluoroscopy (85.0%, 41.7%, 91.0%), and rapid on-site evaluation use (61.7%, 17.3%, 68.5%) differed between regions. Pneumothorax and bronchopulmonary hemorrhage occurred in 4.7% and 2.7% of subjects, respectively (3.2% [primary end point] and 1.7% requiring intervention or hospitalization). Respiratory failure occurred in 0.6%. The diagnostic yield was 67.8% (range: 61.9%-70.7%; 55.2% Europe, 69.8% United States). Sensitivity for malignancy was 62.6%. Lung cancer clinical stage was I to II in 64.7% (55.3% Europe, 65.8% United States). CONCLUSIONS: Despite a heterogeneous cohort and regional differences in procedural techniques, ENB demonstrates low complications and a 67.8% diagnostic yield while allowing biopsy, staging, fiducial placement, and dye marking in a single procedure.

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study.

INTRODUCTION: Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti-programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data. METHODS: Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months. RESULTS: A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached. CONCLUSIONS: Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.