NCCN Guidelines® Insights: Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 2.2023.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-Small Cell Lung Cancer.

For the use of immunotherapy in metastatic non-small cell lung cancer (NSCLC), the NCCN Guidelines for NSCLC reflect the importance of assessing levels of PD-L1 expression to determine the best use of PD-1/PD-L1 inhibitors, whether alone or in combination with chemotherapy. Patients who lack a driver mutation and have tumor PD-L1 expression ≥50% are recommended to receive single-agent pembrolizumab, although combining with carboplatin/pemetrexed is also a reasonable choice, especially if there is higher burden of disease. For tumors with PD-L1 expression <50%, it is important to distinguish between nonsquamous and squamous cell carcinoma (SCC). For patients with non-SCC disease, pembrolizumab + carboplatin/pemetrexed is preferred. Alternately, a 4-drug regimen of carboplatin/paclitaxel/bevacizumab/atezolizumab is reasonable, especially for patients ineligible for pemetrexed. In patients with SCC, carboplatin + paclitaxel or nab-paclitaxel with pembrolizumab is a category 1 recommendation. Tumor mutational burden is emerging as a biomarker for efficacy but is not yet ready to be used in patient selection. Optimal management of the unique toxicities associated with immunotherapy, which can be more frequent with these combinations, is also critical for good outcomes.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018.

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Immunotherapies for Lung Cancer.

In 2017, immunotherapy is the standard of care for patients with non-small cell lung cancer (NSCLC) either in the first or second line depending on programmed death ligand-1 (PD-L1) and mutation status. For first-line therapy, pembrolizumab is currently the standard of care for patients whose tumors express PD-L1 >50%. All patients with NSCLC should undergo PD-L1 testing before initiating treatment on pembrolizumab. For patients not eligible in the first line, immunotherapy is the standard of care for most in the second line. Nivolumab and atezolizumab are approved in all patients as second-line therapies after platinum-based doublet failure regardless PD-L1 expression level, although pembrolizumab is approved as second-line therapy for those whose tumors express PD-L1 >1%.

Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

Real-World Biomarker Test Ordering Practices in Non-Small Cell Lung Cancer: Interphysician Variation and Association With Clinical Outcomes.

PURPOSE: Patients with metastatic or advanced non-small cell lung cancer (NSCLC) need biomarker testing, including, in most cases, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and PD-L1, to identify options for targeted therapies and to optimally incorporate immune checkpoint inhibitors into therapeutic regimens. We sought to examine real-world patterns of biomarker testing, quantify interphysician practice variation, and correlate testing with clinical outcomes. METHODS: We extracted real-world data from a nationwide electronic health record-derived deidentified database from 17,165 patients diagnosed with advanced NSCLC between 2018 and 2021 and receiving care in the community setting. We analyzed data using descriptive analyses, fixed- and mixed-effects logistic regression models, and proportional hazard models. RESULTS: Only 67% of all 17,165 patients and 77% of patients with nonsquamous, metastatic NSCLC had ALK, EGFR, and PD-L1 testing within 90 days of diagnosis. Later diagnosis year (2019-2021 compared with 2018) was associated with higher rates of ALK, EGFR, and PD-L1 testing; stage IIIB/C disease (compared with stage IV), squamous histology, and Black or African American race were associated with lower rates. Interphysician variation was substantial with a median odds ratio between physicians (adjusted for patient factors) of 1.78 for ALK, EGFR, and PD-L1 testing. Patients with nonsquamous, metastatic NSCLC had significantly prolonged survival if tested with all three biomarkers (median, 364 days for all three v 180 for none of the three; hazard ratio, 0.67; P < .001). CONCLUSION: Rates of biomarker testing appear suboptimal with substantial interphysician variation. Testing correlates with improved survival, although causality cannot be proven from this study. Additional work is needed to address the underlying causes of suboptimal test ordering.

Survival outcomes for lung neuroendocrine tumors in California differ by sociodemographic factors.

Lung neuroendocrine tumors (NETs) have few known predictors of survival. We investigated associations of sociodemographic, clinicopathologic, and treatment factors with overall survival (OS) and lung cancer-specific survival (LCSS) for incident lung NET cases (typical or atypical histology) in the California Cancer Registry (CCR) from 1992 to 2019. OS was estimated with the Kaplan-Meier method and compared by sociodemographic and disease factors univariately with the log-rank test. We used sequential Cox proportional hazards regression for multivariable OS analysis. LCSS was estimated using Fine-Gray competing risks regression. There were 6038 lung NET diagnoses (5569 typical, 469 atypical carcinoid); most were women (70%) and non-Hispanic White (73%). In our multivariable model, sociodemographic factors were independently associated with OS, with better survival for women (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.57-0.68, P < 0.001), married (HR 0.76, 95% CI 0.70-0.84, P < 0.001), and residents of high socioeconomic status (SES) neighborhoods (HRQ5vsQ1 0.73, 95% CI 0.62-0.85, P < 0.001). Compared to cases with private insurance, OS was worse for cases with Medicare (HR 1.24, 95% CI 1.10-1.40, P < 0.001) or Medicaid/other public insurance (HR 1.45, 95% CI 1.24-1.68, P < 0.001). In our univariate model, non-Hispanic Black Californians had worse OS than other racial/ethnic groups, but differences attenuated after adjusting for stage at diagnosis. In our LCSS models, we found similar associations between sex and marital status on survival, but no differences in outcomes by SES or insurance. By race/ethnicity, American Indian cases had worse LCSS. In summary, beyond disease-related and treatment variables, sociodemographic factors were independently associated with survival in lung NETs.

American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Importance: The treatment of locally advanced non-small cell lung cancer (LA-NSCLC) has been informed by more than 5 decades of clinical trials and other relevant literature. However, controversies remain regarding the application of various radiation and systemic therapies in commonly encountered clinical scenarios. Objective: To develop case-referenced consensus and evidence-based guidelines to inform clinical practice in unresectable LA-NSCLC. Evidence Review: The American Radium Society (ARS) Appropriate Use Criteria (AUC) Thoracic Committee guideline is an evidence-based consensus document assessing various clinical scenarios associated with LA-NSCLC. A systematic review of the literature with evidence ratings was conducted to inform the appropriateness of treatment recommendations by the ARS AUC Thoracic Committee for the management of unresectable LA-NSCLC. Findings: Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement. Committee recommendations were vetted by the ARS AUC Executive Committee and a 2-week public comment period before official approval and adoption. Standard of care management of good prognosis LA-NSCLC consists of combined concurrent radical (60-70 Gy) platinum-based chemoradiation followed by consolidation durvalumab immunotherapy (for patients without progression). Planning and delivery of locally advanced lung cancer radiotherapy usually should be performed using intensity-modulated radiotherapy techniques. A variety of palliative and radical fractionation schedules are available to treat patients with poor performance and/or pulmonary status. The salvage therapy for a local recurrence after successful primary management is complex and likely requires both multidisciplinary input and shared decision-making with the patient. Conclusions and Relevance: Evidence-based guidance on the management of various unresectable LA-NSCLC scenarios is provided by the ARS AUC to optimize multidisciplinary patient care for this challenging patient population.

Executive Summary of the American Radium Society® (ARS) Appropriate Use Criteria (AUC) for Non-Small Cell Lung Cancer in a Central/Ultra-Central Location: Systematic Review and Guidelines.

INTRODUCTION: Definitive radiation therapy is considered standard therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). However, for patients with tumors located near to structures like the proximal tracheobronchial tree, esophagus, heart, spinal cord, and brachial plexus, the optimal management regimen is controversial. The objective was to develop expert multidisciplinary consensus guidelines on the management of medically inoperable NSCLC located in a central or ultra-central location relative to critical organs-at-risk. MATERIALS AND METHODS: Case variants regarding centrally and ultra-centrally located lung tumors were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel. A comprehensive review of the English medical literature was performed from 1/1/46 to 12/31/23 to inform consensus guidelines. Modified Delphi methodology was used by the panel to evaluate the variants and procedures, with ≤3 rating points from median defining agreement/consensus. The guideline was then approved by the ARS Executive Committee and released for public comment per established ARS procedures. RESULTS: The Thoracic ARS AUC Panel identified 90 relevant references and obtained consensus in all variants. Radiotherapy alone was considered appropriate, with additional immunotherapy to be considered primarily in the clinical trial setting. Hypofractionated radiotherapy in 8-18 fractions was considered appropriate for ultra-central lesions near proximal tracheobronchial tree, upper trachea, and esophagus. For other ultra-central lesions near heart, great vessels, brachial plexus, and spine, or for non-ultra-central but still central lesions, 5-fraction SBRT was also considered an appropriate option. Intensity-modulated radiotherapy was considered appropriate and 3D-conformal radiotherapy inappropriate for all variants. Other treatment planning techniques to decrease the risk of overdosing critical organs-at-risk were also considered. DISCUSSION: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of stage I NSCLC in a central or ultra-central location.

Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs. Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage. Results: We found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04). Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

PURPOSE: To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. RESULTS: A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). CONCLUSION: Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

American Radium Society Appropriate Use Criteria for Radiation Therapy in the Multidisciplinary Management of Thymic Carcinoma.

Importance: Thymic carcinoma is rare, and its oncologic management is controversial due to a paucity of prospective data. For this reason, multidisciplinary consensus guidelines are crucial to guide oncologic management. Objective: To develop expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma. Evidence Review: Case variants spanning the spectrum of stage I to IV thymic carcinoma were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel to address management controversies. A comprehensive review of the English-language medical literature from 1980 to 2021 was performed to inform consensus guidelines. Variants and procedures were evaluated by the panel using modified Delphi methodology. Agreement/consensus was defined as less than or equal to 3 rating points from median. Consensus recommendations were then approved by the ARS Executive Committee and subject to public comment per established ARS procedures. Findings: The ARS Thoracic AUC panel identified 89 relevant references and obtained consensus for all procedures evaluated for thymic carcinoma. Minimally invasive thymectomy was rated as usually inappropriate (regardless of stage) due to the infiltrative nature of thymic carcinomas. There was consensus that conventionally fractionated radiation (1.8-2 Gy daily) to a dose of 45 to 60 Gy adjuvantly and 60 to 66 Gy in the definitive setting is appropriate and that elective nodal irradiation is inappropriate. For radiation technique, the panel recommended use of intensity-modulated radiation therapy or proton therapy (rather than 3-dimensional conformal radiotherapy) to reduce radiation exposure to the heart and lungs. Conclusions and Relevance: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of thymic carcinoma, perhaps the most well referenced on the topic.