Jarushka Naidoo

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab

Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7u2005years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes.

BACKGROUNDnLarge cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC.nnnMATERIALS AND METHODSnCases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.nnnRESULTSnForty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (nxa0= 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (nxa0= 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (nxa0= 26) received platinum/etoposide and 30% (nxa0= 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort.nnnCONCLUSIONnPatients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

Should Patients with Extrapulmonary Small-Cell Carcinoma Receive Prophylactic Cranial Irradiation?

Introduction: Extrapulmonary small-cell carcinoma (EPSCC) is a rare disease. Management is based on small-cell lung carcinoma. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment, and survival of patients with brain metastases in a national cohort. Disease biology and epidemiology are also investigated. Methods: Patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland from 1995 to 2007 were identified. The number of patients who developed brain metastases, their survival, and treatment data were documented. Patients who received PCI were investigated. Patient and disease characteristics, treatment, and survival data were stratified by stage and primary site. Results: Two hundred eighty patients were identified; 141 (50.4%) were men and 139 (49.6%) were women. One hundred eighty six patients (66.4%) had extensive-stage disease, 65 (23.2%) had limited-stage disease, and in 29 patients (10.3%) the stage was unknown. Eighteen patients (6.4%) developed brain metastases, with a median overall survival of 10.1 months. Eleven (61%) received cranial irradiation, and 12 (67%) received palliative chemotherapy. Two patients in the entire cohort (0.17%) received PCI. The most common primary sites included the esophagus (n = 43; 15.4%), cervix uteri (n = 17; 6.0%), bladder (n = 13; 4.6%), and prostate (n = 10; 3.6%). Median overall survival was 15.2 months (10.2–20.6) for limited-stage disease, 2.3 months (1.7–3.1) for extensive-stage EPSCC, and 3.7 months (1.3–8.3) for disease of unknown stage. Conclusion: Brain metastases were uncommon in EPSCC compared with small-cell lung carcinoma. PCI is thus probably not warranted in this disease.

Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

PURPOSEnTo characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs).nnnMETHODS AND MATERIALSnWe retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab).xa0Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2xa0weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI.xa0Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs.nnnRESULTSnA total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9xa0months, 14.5xa0months, and 24.7xa0months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64).nnnCONCLUSIONSnDelivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.

Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen

INTRODUCTIONnImmune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.nnnMETHODSnPatients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.nnnRESULTSnOf 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.nnnCONCLUSIONnThese data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.

The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials

OBJECTIVESnThe role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy.nnnMATERIALS AND METHODSnWe included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology.nnnRESULTSnThe addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI.nnnCONCLUSIONnThe addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.

Rediagnosis of Lung Cancer as NUT Midline Carcinoma Based on Clues From Tumor Genomic Profiling

Tumor DNA sequencing can identify rare driver genomic alterations that suggest targets for cancer therapy, even when these drivers cannot be suspected on clinical grounds. In some cases, genomic alterations identified in the tumor can lead to a change in diagnosis with implications for prognosis and therapy. This report describes a case in which evaluation of tumor sequencing results by a molecular tumor board (MTB) led to rediagnosis of a non-small cell lung cancer as highly aggressive NUT midline carcinoma, with implications for targeted therapy using an investigational bromodomain and extraterminal (BET) inhibitor. We discuss the molecular biology and diagnosis of this rare tumor, and suggest how improved annotation of tumor sequencing reports and multidisciplinary expertise of MTBs can facilitate timely diagnosis of rare tumors and application of potential targeted therapies.

P2.01-103 Neutrophil-to-Lymphocyte Ratio as a Predictor of Immunotherapy Treatment Outcomes in Advanced Non-Small Lung Cancer

P2.01-101 Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405) J. Duan, S. Wang, Z. Wang, H. Bai, J. Zhao, H. Gao, Y. Cheng, J. Wang National Cancer Center/cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing/CN, Thoracic Oncology, Beijing Cancer Hospital, Changchun/CN, 307 Hospital of PLA, Beijing/CN, Thoracic Oncology, Jilin Provincial Cancer Hospital, Changchun/CN

Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors

ABSTRACT Checkpoint inhibitor pneumonitis (CIP) is an immune‐related adverse event that can occur after initiation of anti–programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial‐enrolled and non–trial‐enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti–programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%–5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher‐grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life‐threatening complication of ICI therapy.

Treatment of Complications from Immune Checkpoint Inhibition in Patients with Lung Cancer

Opinion statementImmune checkpoint inhibitors have revolutionized the management of advanced NSCLC. With the intention of generating an anti-tumor immune response, ICIs can also lead to inflammatory side effects involving a wide variety of organs in the body, termed immune-related adverse events. Although no prospective clinical trial exists to guide recommendations for optimal and more specific immunosuppressive treatments rather than corticosteroids, further studies may lead to a more mechanistic-based approach towards these toxicities in the future. In relation to current practice, we recommend adherence to the recent published guidelines which emphasize the importance of early recognition and administration of temporary immunosuppressive therapy with corticosteroids in most cases, depending on the organ system involved, and the severity of toxicity. Recognition of these toxicities is increasingly important as the use of these agents expand within different indications for patients with lung cancers, and to other tumor types.