Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

COVID-19 in patients with lung cancer.

BACKGROUND: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.

Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were ß-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Chemotherapy remains an essential element of personalized care for persons with lung cancers.

Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates.