Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

PURPOSE: Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. PATIENTS AND METHODS: Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. RESULTS: With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died. CONCLUSIONS: Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

Plain language summary of the CheckMate 816 study results: nivolumab plus chemotherapy given before surgery for non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). WHAT HAPPENED IN THE STUDY?: Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. WHAT WERE THE RESULTS?: Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 (ClinicalTrials.gov).

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2021 Update on Outcomes and Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) remains the largest and most robust thoracic surgical database in the world. Participating sites receive risk-adjusted performance reports for benchmarking and quality improvement initiatives. The GTSD also provides several mechanisms for high-quality clinical research using data from 271 participant sites and nearly 720,000 procedures since its inception in 2002. Participant sites are audited at random annually for completeness and accuracy. During the last year and a half, the GTSD Task Force continued to refine the data collection form, ensuring high-quality data while minimizing data entry burden. In addition, the STS Workforce on National Databases has supported robust GTSD-based research program, which led to 10 scholarly publications in 2020. This report provides an update on outcomes, volume trends, and database improvements as well as a summary of research productivity resulting from the GTSD over the preceding year.

Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy.

BACKGROUND: Definitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact outcomes. METHODS: Patients definitively treated with chemoradiation and immunotherapy from 2015 to 2019 at a single tertiary academic center were identified. Severe lymphopenia was defined as <0.5 × 109 cells/L. Progression-free survival (PFS) was calculated by Kaplan Meier methodology. Univariate and multivariate Cox Proportional Hazard modeling was used to correlate clinical variables with disease outcome. Immune-related adverse events (irAEs) were assessed according to CTCAE version 5.0 criteria. RESULTS: Seventy-eight patients were included in the final cohort. The median age was 66 years (IQR: 58-73), 55 % were males, and 88 % had a KPS of >70. At baseline, 90 % (n = 70/78) of patients had a normal ALC and one patient had severe lymphopenia. After chemoradiation, the median ALC decreased from 1.52 × 109cells/L (IQR: 1.23-1.98) to 0.72 × 109cells/L (IQR: 0.52-0.94) (p < 0.001), 22 % (n = 17/78) of patients had a normal ALC, and 23 % (n = 18/78) of patients developed severe lymphopenia. Patients who initiated consolidative immunotherapy with severe lymphopenia had worse PFS than those who did not (median 217 days [IQR: 120-434] vs. 570 days [IQR: 401-NR], p < 0.001). On multivariate modeling, severe lymphopenia at the time of immunotherapy initiation remained an independent predictor of worse PFS (HR 4.90, p < 0.001). CONCLUSIONS: This is the first report to associate severe TRL with disease progression in patients with locally advanced NSCLC receiving consolidative immunotherapy. Factors associated with development of lymphopenia and strategies to mitigate lymphopenic effects should be considered.

Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

PURPOSE: We aimed to assess the prognostic value of Neutrophil to Lymphocyte Ratio (NLR) on long-term outcomes and graft dysfunction after lung transplantation. METHODS: We retrospectively reviewed all patients receiving a lung transplant at our institution from 2011 to 2014. The primary exposure was elevated NLR at the time of transplant, defined by NLR>4. The primary outcomes were graft failure and three-year all-cause mortality. Multivariate logistic regression and Kaplan-Meier survival analysis were used to analyze outcomes. RESULTS: 95 patients were included. 40 patients (42%) had an elevated NLR. Elevated NLR was associated with graft failure (OR: 4.7 [1.2-18.8], p = 0.02), and three-year mortality (OR: 5.4 [1.3-23.2], p = 0.03) on multivariate logistic regression. Patients with elevated NLR demonstrated significantly lower survival on Kaplan-Meier analysis (50% versus 74%, p = 0.02). The c-statistic for our multivariate model was 0.91. CONCLUSION: Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

Variability in Smoking Status for Lobectomy Among Society of Thoracic Surgeons Database Participants.

BACKGROUND: Current smokers undergoing lobectomy are at greater risk of complications than are former smokers. The Society of Thoracic Surgeons (STS) composite score for rating program performance for lobectomy adjusts for smoking status, a modifiable risk factor. This study examined variability in the proportion of current smokers undergoing lobectomy among STS database participants. Additionally, the study determined whether each participant's rating changed if smoking was excluded from the risk adjustment model. METHODS: This is a retrospective analysis of the STS cohort used to develop the composite score for rating program performance for lobectomy. The study summarized the variability among STS database participants for performing lobectomy on current smokers and compared star ratings developed from models with and without smoking status. RESULTS: There were 24,912 patients with smoking status data: 23% current smokers, 62% former smokers, and 15% never smokers. There was significant variability among participants in the proportion of current smokers undergoing lobectomy (3% to 48.6%; P < .001). Major morbidity or mortality (composite) was greater in current smokers (12.1%) than in former smokers (8.6%) and never smokers (4.2%) (P < .001). Using the current risk adjustment model, participant star ratings were as follows: 1 star, n = 6 (3.2%); 2 stars, n = 170 (91.4%); and 3 stars, n = 10 (5.4%). When smoking status was excluded from the model, 1 participant shifted from a 2-star to a 3-star program. CONCLUSIONS: There is substantial variability among STS database participants with regard to the proportion of current smokers undergoing lobectomy. However, exclusion of smoking status from the model did not significantly affect participant star rating.

COVID-19 guidance for triage of operations for thoracic malignancies: A consensus statement from Thoracic Surgery Outcomes Research Network.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2020 Update on Outcomes and Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database (GTSD) remains the largest and most robust thoracic surgical database in the world. The GTSD provides participant sites with risk-adjusted performance reports for benchmarking and facilitates quality improvement initiatives. In addition the GTSD provides several mechanisms for high-quality research using data from over 283 participant sites and nearly 620,000 procedures since its inception in 2002. Participant sites are audited at random annually to ensure continued completeness and accuracy of the GTSD. In 2020 the GTSD migrated to a cloud-based interactive data platform, and the Task Force continues to refine the data collection form to decrease data entry burden while maintaining data quality, granularity, and relevance. This report provides an update on outcomes, volume trends, and database improvements as well as a summary of research productivity resulting from the GTSD over the preceding year.

Adjuvant and Neoadjuvant Immunotherapy in Non-small Cell Lung Cancer.

The advent of immune checkpoint blockade has revolutionized the management of advanced non-small cell lung cancer (NSCLC). Impressive results in the metastatic setting have prompted substantial interest in the application of these agents in earlier-stage disease. Applications of checkpoint blockade in the adjuvant setting are under investigation in several clinical trials. Early trials have demonstrated the safety and feasibility of the administration of checkpoint inhibitors in the neoadjuvant setting. Resection specimens demonstrate encouraging rates of pathologic response. There are several ongoing phase 3 studies comparing neoadjuvant combination chemotherapy and checkpoint blockade to chemotherapy alone in patients with resectable NSCLC.

COVID-19 Guidance for Triage of Operations for Thoracic Malignancies: A Consensus Statement From Thoracic Surgery Outcomes Research Network.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.

Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.