Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights.

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.

Clinical Benefit from Docetaxel +/- Ramucirumab Is Not Associated with Mutation Status in Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed on Platinum Doublets and Immunotherapy.

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

Survival outcomes and toxicity of adjuvant immunotherapy after definitive concurrent chemotherapy with proton beam radiation therapy for patients with inoperable locally advanced non-small cell lung carcinoma.

INTRODUCTION: Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC. MATERIALS AND METHODS: We analyzed 354 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009 to 2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT + IO patients. Survival was estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards regression evaluated the effect of IO on disease outcomes. RESULTS: Median age was 70 years; 71 (20%) received CPBT + IO and 283 (80%) received CPBT only. After PSM, 71 CPBT patients were matched with 71 CPBT + IO patients. Three-year survival rates for CPBT + IO vs CPBT were: OS 67% vs 30% (P < 0.001) and PFS 59% vs 35% (P = 0.017). Three-year LRFS (P = 0.137) and DMFS (P = 0.086) did not differ. Receipt of adjuvant IO was a strong predictor of OS (HR 0.40, P = 0.001) and PFS (HR 0.56, P = 0.030), but not LRFS (HR 0.61, P = 0.121) or DMFS (HR 0.61, P = 0.136). There was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT + IO vs 17% CPBT, P = 0.037). CONCLUSION: This study, one of the first to investigate CPBT followed by IO for inoperable LA-NSCLC, showed that IO conferred survival benefits with no increased rates of toxicity.

The Role of Glycogen Synthase Kinase-3ß in the Zinc-Mediated Neuroprotective Effect of Metformin in Rats with Glutamate Neurotoxicity.

Metformin has been suggested to have protective effects on the central nervous system, but the mechanism is unknown. The similarity between the effects of metformin and the inhibition of glycogen synthase kinase (GSK)-3ß suggests that metformin may inhibit GSK-3ß. In addition, zinc is an important element that inhibits GSK-3ß by phosphorylation. In this study, we investigated whether the effects of metformin on neuroprotection and neuronal survival were mediated by zinc-dependent inhibition of GSK-3ß in rats with glutamate-induced neurotoxicity. Forty adult male rats were divided into 5 groups: control, glutamate, metformin + glutamate, zinc deficiency + glutamate, and zinc deficiency + metformin + glutamate. Zinc deficiency was induced with a zinc-poor pellet. Metformin was orally administered for 35 days. D-glutamic acid was intraperitoneally administered on the 35th day. On the 38th day, neurodegeneration was examined histopathologically, and the effects on neuronal protection and survival were evaluated via intracellular S-100ß immunohistochemical staining. The findings were examined in relation to nonphosphorylated (active) GSK-3ß levels and oxidative stress parameters in brain tissue and blood. Neurodegeneration was increased (p < 0.05) in rats fed a zinc-deficient diet. Active GSK-3ß levels were increased in groups with neurodegeneration (p < 0.01). Decreased neurodegeneration, increased neuronal survival (p < 0.01), decreased active GSK-3ß (p < 0.01) levels and oxidative stress parameters, and increased antioxidant parameters were observed in groups treated with metformin (p < 0.01). Metformin had fewer protective effects on rats fed a zinc-deficient diet. Metformin may exert neuroprotective effects and increase S-100ß-mediated neuronal survival by zinc-dependent inhibition of GSK-3ß during glutamate neurotoxicity.

Detection of clinically actionable gene fusions by next-generation sequencing-based RNA sequencing of non-small cell lung cancer cytology specimens: A single-center experience with comparison to fluorescence in situ hybridization.

BACKGROUND: Genomic profiling is needed to identify actionable alterations in non-small cell lung cancer (NSCLC). Panel-based testing such as next-generation sequencing (NGS) is often preferred to interrogate multiple alterations simultaneously. In this study, we evaluate the utility of an RNA-based NGS assay to detect genomic alterations in NSCLC cytology specimens and compare these results to fluorescence in situ hybridization (FISH) testing. METHODS: A retrospective review was performed of 264 NSCLC cytology specimens that were concurrently tested for gene fusions by RNA-based NGS and ALK, RET, and/or ROS1 by FISH. RESULTS: Genomic alterations were detected in 29 cases by NGS, including ALK, RET, ROS1, NTRK, NUTM1, and FGFR3 fusions and MET exon 14 skipping alterations. Of the 20 cases with ALK, RET, and ROS1 fusions detected by NGS, 16 (80%) were concordant with the corresponding FISH results. Three cases showed discordance, where EML4::ALK (n = 2) and SLC34A2::ROS1 (n = 1) fusions were not detected by the corresponding FISH assay; one case with EZR::ROS1 was inadequate for FISH. No gene fusions were detected in 181 cases by NGS and 54 cases failed testing. The concordance rates for detecting ALK, RET, and ROS1 fusions using NGS and FISH were 97%, 100%, and 99.5%, respectively. CONCLUSION: RNA-based NGS can be used to detect gene fusions in NSCLC cytology cases with high concordance with FISH results. However, RNA-based NGS may have high failure rates and therefore a low threshold for reflexing inadequate cases to an orthogonal testing method is essential for comprehensive genomic profiling.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases.

Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Distinct patterns of auto-reactive antibodies associated with organ-specific immune-related adverse events.

The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were associated with the subsequent development of organ-specific irAEs. Notably, ACHRG IgM was associated with pneumonitis, anti-cytokeratin 19 IgM with dermatitis, and anti-thyroglobulin IgG with hepatitis. These antibodies merit further investigation as potential biomarkers for identifying high-risk populations for irAEs and/or monitoring irAEs during immunotherapy treatment. Trial registration: ClinicalTrials.gov identifier: NCT03391869.

Pneumatosis intestinalis in cancer patients who received immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy may give rise to immune-related adverse events (irAEs). Pneumatosis intestinalis (PI), or gas within the bowel wall, has very rarely been observed following ICI therapy, and its clinical significance is unclear. We described the clinical characteristics and outcomes of PI as a possible irAE in cancer patients. METHODS: We retrospectively identified 12 adult cancer patients with radiologic evidence of PI within 1 year after ICI exposure during January 2010-January 2023. Clinical characteristics, treatment, and outcomes were evaluated. RESULTS: The median age of our sample was 64 years. The most common cancer types were thoracic/head & neck and gastrointestinal. Eleven patients (92%) received anti-PD-1/L1 monotherapy, while 1 patient (8%) received a combination of anti-PD-1/L1 and anti-CTLA-4. PI occurred a median of 7 months after the first ICI dose. Half the patients (50%) were asymptomatic on diagnosis, and the most common presenting symptom was abdominal pain (42%). Six patients experienced complications, namely pneumoperitoneum (n = 6, 50%) and microperforation (n = 1, 8%), identified on imaging. Nine patients were treated with antibiotics and 3 patients were monitored conservatively. Nine patients (75%) resumed cancer treatment after PI. CONCLUSION: PI may develop as an irAE. While half of cases were incidental radiologic findings, management with antibiotics as well as hospitalization for observation may still be appropriate. The decision to restart cancer therapy and possibly resume ICI therapy remains to be elucidated. Further large-scale studies may be warranted to clarify the association between PI and ICI therapy.

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

Background: 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. Materials and methods: 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. Results: 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%). Conclusion: 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.

Deep phenotyping of miRNAs in exercise-induced cardiac hypertrophy and fibrosis.

Cardiac hypertrophy (CH) is an adaptational enlargement of the myocardium, in exposure to altered stress conditions or in case of injury which can lead to heart failure and death. MicroRNAs (miRNAs) are noncoding RNAs that play a significant role in modulating gene expression. Here, we aimed to identify new miRNAs effective in an experimental CH model and to find an epigenetic biomarker that could demonstrate therapeutic targets responsible for the pathology of heart tissue and serum. In this study, Sprague-Dawley male rats were divided into the training group (TG, n=9) and the control group (CG, n=6). Systolic and diastolic dimensions of the left ventricle and myocardial wall thickness were measured by echocardiography to assess CH. After the exercise program of the rats, miRNA expression measurements and histological analyses were performed. The 25,000 genes in the rat genome were searched using microarray analysis. A total of 128 miRNAs were selected according to the fold change rates, and nine miRNAs were validated for expression analysis. The terminal deoxynucleotidyl transferase dUTP nick (TUNEL) method was used to detect apoptotic cells. Cell proliferation was evaluated by the proliferative cell nuclear antigen (PCNA) method. Necrosis, bleeding, and intercellular edema were detected in TG. The mean histopathological score was higher in TG (p=0.03). There were rarely positive cells for apoptosis of both groups in cardiomyocytes. In the receiver characteristic curve analysis (ROC), the heart tissue rno-miR-290 had an area under the curve (AUC) of 0.920 with 100% sensitivity and 89.90% specificity (p=0.045), rno-miR-194-5p had AUC of 0.940 with 83.33% sensitivity and 100% specificity (p=0.003), and the serum rno-miR-132-3p AUC was 0.880 with 66.67% sensitivity and 100% specificity (p=0.004) in TG. miR-194-5p was used as a therapeutic target for remodeling the cardiac process. While miR-290 contributes to CH as a negative regulator, miR-132 in serum is effective in the pathological and physiological cardiac remodeling process and is a candidate biomarker.

Case Report: Immune checkpoint inhibitor-induced multiorgan vasculitis successfully treated with rituximab.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. ICIs have a unique side effect profile, generally caused by inflammatory tissue damage, with clinical features similar to autoimmune conditions. Acute kidney injury from ICIs has been well studied; incidence ranges from 1% to 5%, with higher incidence when combination ICI therapies are used. Although the overall reported incidence of ICI-associated glomerulonephritis is less than 1%, vasculitis is the most commonly reported ICI-related glomerulonephritis. Other biopsy findings include thrombotic microangiopathy, focal segmental glomerulosclerosis, minimal change disease, and IgA nephropathy with secondary amyloidosis. We report a case in which a woman previously treated with the PD-L1 inhibitor durvalumab for locally advanced non-small cell lung cancer with pre-existing antineutrophil cytoplasmic (anti-PR3) antibody who later developed multi-organ vasculitis after ICI exposure, which was successfully treated with rituximab, with continued cancer remission for 3 years.

Radiographic response to neoadjuvant therapy in pleural mesothelioma should serve as a guide for patient selection for cytoreductive operations.

Background: Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR). Methods: Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria. Results: In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001). Conclusion: Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.

Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC.

Introduction: MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization. Methods: Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 patients included. Three patients received capmatinib plus OSI after progression on crizotinib plus OSI. Median age was 64 (38-89) years old and 75% were female. MET amplification was detected by FISH in 14 patients in the tissue, NGS in 10 patients, and circulating tumor DNA in three patients. Median MET gene copy number was 13.6 (6.4-20). Overall response rate was 34.8% (eight of 23). In assessable patients, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three patients responded to capmatinib plus OSI after progression on crizotinib plus OSI. Dual EGFR-MET inhibition was overall well tolerated. Two patients on crizotinib plus OSI and one pt on capmatinib plus OSI discontinued therapy due to pneumonitis. One pt discontinued crizotinib plus OSI due to gastrointestinal toxicity. Six patients were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and NGS on tumor and plasma were completed in six patients. Notable resistance mechanisms observed include acquired MET D1246H (n = 1), acquired EGFR C797S (n = 2), FGFR2 fusion (n = 1, concurrent with C797S), and EGFR G796S (n = 1, concurrent with C797S). Four patients lost MET amplification. Conclusions: Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.

Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial.

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC. PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS). RESULTS: Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7-24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%. CONCLUSION: Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

A novel statistical method for decontaminating T-cell receptor sequencing data.

The T-cell receptor (TCR) repertoire is highly diverse among the population and plays an essential role in initiating multiple immune processes. TCR sequencing (TCR-seq) has been developed to profile the T cell repertoire. Similar to other high-throughput experiments, contamination can happen during several steps of TCR-seq, including sample collection, preparation and sequencing. Such contamination creates artifacts in the data, leading to inaccurate or even biased results. Most existing methods assume 'clean' TCR-seq data as the starting point with no ability to handle data contamination. Here, we develop a novel statistical model to systematically detect and remove contamination in TCR-seq data. We summarize the observed contamination into two sources, pairwise and cross-cohort. For both sources, we provide visualizations and summary statistics to help users assess the severity of the contamination. Incorporating prior information from 14 existing TCR-seq datasets with minimum contamination, we develop a straightforward Bayesian model to statistically identify contaminated samples. We further provide strategies for removing the impacted sequences to allow for downstream analysis, thus avoiding any need to repeat experiments. Our proposed model shows robustness in contamination detection compared with a few off-the-shelf detection methods in simulation studies. We illustrate the use of our proposed method on two TCR-seq datasets generated locally.

Physician Views on the Provision of Information on Immune Checkpoint Inhibitor Therapy to Patients with Cancer and Pre-Existing Autoimmune Disease: A Qualitative Study.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).

Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on rates of symptom recurrence and survival outcomes. METHODS: This retrospective, multicenter study examined patients who were treated with ICI and developed irEC requiring SIT (infliximab or vedolizumab) for initial symptom control or to facilitate steroid tapering between May 2015 and June 2020. After symptom resolution, patients were restarted either on ICI alone or on concurrent ICI and SIT at the discretion of the treating physicians. The associations between irEC recurrence and treatment group were assessed via univariate analyses and multivariate logistic regression. Cox proportional hazards model was used for survival analysis. RESULTS: Of the 138 included patients who required SIT for initial irEC symptom control, 61 (44.2%) patients resumed ICI without concurrent SIT (control group) and 77 (55.8%) patients resumed ICI therapy with concurrent SIT: 33 with infliximab and 44 with vedolizumab. After symptom resolution, patients in the control group were more commonly restarted on a different ICI regimen (65.6%) compared with those receiving SIT (31.2%) (p<0.001). The total number of ICI doses administered after irEC resolution and ICI resumption was similar in both groups (four to five doses). Recurrence of severe colitis or diarrhea after ICI resumption was seen in 34.4% of controls compared with 20.8% of patients receiving concurrent SIT. Concurrent SIT was associated with reduced risk of severe irEC recurrence after ICI resumption in a multivariate logistic regression model (OR 0.34; 95% CI 0.13 to 0.92; p=0.034). There was no difference in survival outcomes between patients in the control group and patients concurrently treated with SIT. CONCLUSION: After resolution of irEC symptoms, reinitiation of ICI with concurrent SIT is safe, reduces severe irEC recurrence, and has no negative impact on survival outcomes.

Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience.

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. RESULTS: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). CONCLUSION: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.