Daratumumab Plus Atezolizumab in Previously Treated Advanced or Metastatic NSCLC: Brief Report on a Randomized, Open-Label, Phase 1b/2 Study (LUC2001 JNJ-54767414).

INTRODUCTION: The programmed death-ligand 1 inhibitor atezolizumab improves progression-free survival (PFS) and overall survival (OS) for patients with previously treated advanced NSCLC. Preclinical studies indicate that targeting CD38-positive cells with daratumumab may synergistically enhance atezolizumab's antitumor activity by increasing the effector T-cell activity. METHODS: This phase 1b-2 study included a safety run-in (one cycle of daratumumab plus atezolizumab) and randomized phases (daratumumab plus atezolizumab versus atezolizumab alone). The primary objective of the randomized phase was to compare overall response rates. The secondary objectives included evaluations of safety, clinical benefit rate (stable disease or better), PFS, OS, and pharmacokinetics. RESULTS: In total, 99 patients were enrolled (safety run-in, n = 7; randomized, n = 46 per arm). In the randomized phase, the overall response rate was 4.3% for daratumumab plus atezolizumab and 13.0% for atezolizumab alone (OR: 0.30; 95% confidence interval: 0.03-1.92). The respective clinical benefit rates were 52.2% and 43.5%. No improvements were observed in the median PFS or median OS for combination therapy. The study was terminated because of the limited efficacy of daratumumab plus atezolizumab. CONCLUSIONS: Daratumumab plus atezolizumab therapy did not improve efficacy versus atezolizumab monotherapy for patients with previously treated advanced NSCLC.

Efficacy and Safety of Glembatumumab Vedotin in Patients With Advanced or Metastatic Squamous Cell Carcinoma of the Lung (PrECOG 0504).

INTRODUCTION: Glycoprotein NMB is a transmembrane protein linked with poor prognosis and is expressed in most squamous lung cancer. Glembatumumab vedotin is an antibody-drug conjugate targeting glycoprotein NMB, administered intravenously every 3 weeks in this phase 1 study to determine the safety, tolerability, and maximum tolerated dose in patients who had progressed on any number of previous therapies. RESULTS: A total of 13 patients were enrolled; adverse events (of any grade) including dyspnea, neutropenia, respiratory failure, anemia, increased aspartate transaminase/alanine transaminase, diarrhea, and hypophosphatemia were seen in 15% of patients. Grade 5 events included two cases of respiratory failure, either completely or partially attributed to cancer progression. The only other grade 5 event was "disease progression." The most common adverse events (23%) were decreased appetite, fatigue, rash, and weight loss.The median overall and progression-free survivals were 5.7 months (90% confidence interval: 2.5-16.8) and 2.5 months (90% confidence interval: 1.6-5.8) respectively. CONCLUSIONS: Glembatumumab vedotin exhibited no serious or unexpected toxicity in this heavily pretreated population, except those caused by disease progression. Modest anticancer activity was observed with a recommendation for a phase 2 dose of 1.9 mg/kg. This portion of the study was not undertaken owing to the company's decision to discontinue drug development.

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy.

BACKGROUND: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. METHODS: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival. RESULTS: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients. CONCLUSION: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents. IMPLICATIONS FOR PRACTICE: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.

Lung Stereotactic Body Radiation Therapy and Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis.

PURPOSE: Radical treatment of metastases with stereotactic body radiation therapy (SBRT) is commonly implemented in patients receiving concurrent immune checkpoint inhibition (ICI), despite limited safety and toxicity data. The purpose of this study was to evaluate the safety and tolerability of lung SBRT with concurrent ICI. METHODS AND MATERIALS: Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SBRT alone was included for reference. Treatment-related adverse effects occurring within 30 days (acute) and 180 days (subacute) of SBRT were evaluated. RESULTS: Our study included 117 patients; 54 received SBRT with concurrent ICI (56 courses, 69 target lesions), and 63 received SBRT alone (68 courses, 79 lesions). Median follow-up was 9.2 months in the SBRT + ICI cohort. Among the patients, 67.9% received ICI monotherapy, 17.9% ICI/chemotherapy, and 14.3% ICI/ICI combinations; 25% received ICI between SBRT fractions, and 42.9% received ICI both before and after SBRT. The risk of grade 3 pneumonitis was higher in the SBRT + ICI versus SBRT alone cohort (10.7% vs 0%, P < .01) and any-grade pneumonitis was similar (33.9% vs 27.9%, SBRT + ICI vs SBRT, P = .47). The risk of any-grade pneumonitis appeared elevated with ICI/ICI combinations (62.5% vs 29.2%). Receipt of ICI, planning treatment volume, and lobes involved in SBRT were linked to high-grade pneumonitis. Subacute grade 3+ adverse effects occurred in 26.8% of SBRT + ICI and 2.9% of SBRT-alone patients. CONCLUSIONS: Overall, concurrent lung SBRT + ICI is safe. Given the clinically meaningful risk of pneumonitis, closer monitoring should be considered for SBRT + ICI patients, especially those receiving radiation therapy with ICI/ICI combinations.

Trimodality Therapy in the Treatment of Stage III N2-Positive Non-Small Cell Lung Cancer: A National Cancer Database Analysis.

BACKGROUND: Significant controversy remains regarding the care of patients with clinical stage III (N2-positive) NSCLC. Although multimodality therapy is effective, the roles of surgery, chemotherapy, and radiotherapy are not fully defined and the optimal treatment approach is not firmly established. We analyzed outcomes and predictors associated with trimodality therapy (TT) in the National Cancer Database. MATERIALS AND METHODS: The NCDB was queried from 2004 to 2014 for patients with NSCLC diagnosed with stage III (N2) disease and treated with chemotherapy and radiation (CRT). Three cohorts of patients were studied: CRT only/no surgery (NS), CRT plus lobectomy (LT), and CRT plus pneumonectomy (PT). The univariate and multivariable analyses (MVA) were conducted using Cox proportional hazards model and log-rank tests. RESULTS: A total of 29,754 patients were included in this analysis: NS 90.1%, LT 8.4%, and PT 1.5%. Patient characteristics: median age 66 years; male 56% and white 85%. Patients treated at academic centers were more likely to receive TT compared with those treated at community centers (odds ratio: 1.85 [1.53-2.23]; p < .001). On MVA, patients that received TT were associated with better survival than those that received only CRT (hazard ratio: 0.59 [0.55-0.62]; p < .001). The LT group was associated with significantly better survival than the PT and NS groups (median survival: 62.8 months vs. 51.8 months vs. 34.2 months, respectively). In patients with more than two nodes involved, PT was associated with worse survival than LT and NS (median survival: 51.4 months in LT and 39 months in NS vs. 37 months in PT). The 30-day and 90-day mortality rates were found to be significantly higher in PT patients than in LT. CONCLUSION: TT was used in less than 10% of patients with stage III N2 disease, suggesting high degree of patient selection. In this selected group, TT was associated with favorable outcomes relative to CRT alone. IMPLICATIONS FOR PRACTICE: This analysis demonstrates that trimodality therapy could benefit a selected subset of patients with stage III (N2) disease. This plan should be considered as a treatment option following patient evaluation in a multidisciplinary setting in experienced medical centers with the needed expertise.

Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non-Small-Cell Lung Cancer (GALAXY-2).

PURPOSE: Ganetespib, a highly potent heat shock protein 90 inhibitor, blocks multiple oncogenic pathways, resulting in antitumor activity. We evaluated the combination of ganetespib and docetaxel for second-line therapy of patients with advanced adenocarcinoma of the lung. PATIENTS AND METHODS: In this international phase III trial, patients with stage IIIB or IV adenocarcinoma diagnosed > 6 months before study entry and 1 prior systemic therapy were randomly assigned (1:1) to ganetespib 150 mg/m2 on days 1 and 15 with docetaxel 75 mg/m2 on day 1 of a 21-day cycle or to docetaxel alone. The primary end point was overall survival (OS). RESULTS: Of 677 enrolled patients, 335 were randomly assigned to ganetespib and docetaxel and 337 were assigned to docetaxel. The trial was stopped early as a result of futility at a planned interim analysis. The median OS time was 10.9 months (95% CI, 9.0 to 12.3 months) in the ganetespib and docetaxel arm compared with 10.5 months (95% CI, 8.6 to 12.2 months) in docetaxel arm (hazard ratio [HR], 1.11; 95% CI, 0.899 to 1.372; P = .329). Median progression-free survival was 4.2 months in the ganetespib and docetaxel arm and 4.3 months in the docetaxel arm (HR, 1.16; 95% CI, 0.96 to 1.403; P = .119). The addition of ganetespib did not improve outcomes compared with docetaxel alone for any secondary end point, including survival in the elevated lactate dehydrogenase or EGFR and ALK wild-type populations. The most common grade 3 or 4 adverse event in both arms was neutropenia (30.9% with ganetespib and docetaxel v 25% with docetaxel). CONCLUSION: The addition of ganetespib to docetaxel did not result in improved survival for salvage therapy of patients with advanced-stage lung adenocarcinoma.

Adiposity may predict survival in patients with advanced stage cancer treated with immunotherapy in phase 1 clinical trials.

BACKGROUND: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71). CONCLUSIONS: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.

Survival Outcomes With Thoracic Radiotherapy in Extensive-Stage Small-Cell Lung Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.

BACKGROUND: The prognosis of patients with extensive-stage small-cell lung carcinoma (ES-SCLC) is poor. The benefit of consolidative thoracic radiation therapy (TRT) in ES-SCLC has been inconclusive, and its use inconsistent. The objective of this study was to evaluate overall survival (OS) of ES-SCLC patients treated with chemotherapy (CT) with or without TRT using an administrative database approach. PATIENTS AND METHODS: The National Cancer Database was queried to identify patients with ES-SCLC diagnosed between 2010 and 2014. Those with brain metastases, those who received radiotherapy before CT, or radiotherapy outside the thorax, were excluded. Propensity score-matching (PSM) was used to compare OS of patients treated with CT and TRT with those who received CT alone. Patients who received >10 radiotherapy fractions were also compared with those who received 10 or fewer. RESULTS: We included 14,367 patients in the primary analysis; 12,019 received CT alone, and 2348 received CT with TRT. In multivariate analysis, CT was associated with an increased risk of death relative to CT with TRT (hazard ratio [HR], 1.74 [95% confidence interval (CI), 1.64-1.84]; log-rank P < .001), which remained significant with PSM. Median OS was 12.1 versus 8.2 months (CT with TRT vs. CT); 12-month OS was 50.5% versus 28.5%, and 5-year OS 7.6% versus 2.0% (HR, 1.80 [95% CI, 1.67-1.95], HR P < .001). Of 3099 patients who received TRT, >10 radiotherapy fractions was associated with superior OS (HR, 1.70 [95% CI, 1.49-1.95], log-rank P < .001); this finding remained significant with PSM. CONCLUSION: Use of TRT after CT in ES-SCLC patients was associated with long-term survival; its use should be considered in addition to standard of care CT.

New Treatment Options in Advanced Squamous Cell Lung Cancer.

The past few years have witnessed a rapid shift in the treatments for patients with squamous cell lung cancers (SQCLCs) after the U.S. Food and Drug Administration approval of a number of immune checkpoint inhibitors as second-line therapies for patients with non-small cell lung cancers. These series of approvals marked the first substantial improvement in overall survival for patients with SQCLC in over a decade. Further gains have been made more recently with the incorporation of immune checkpoint inhibition in the first-line setting, either as monotherapy or in combination with chemotherapy. These advances have, however, exposed existing deficiencies in the management of this disease. Despite a deeper understanding of the genomic alterations that characterize SQCLCs and years of trial work targeting these alterations, personalized therapies remain out of hand. Future studies will continue to focus on identifying targeted approaches to expand the treatment options for our patients.

Immunotherapy in Multiple Myeloma: Accelerating on the Path to the Patient.

Multiple myeloma (MM) is a plasma cell malignancy characterized by impaired immune surveillance mechanisms, such as altered antibody production, dysregulation of T cell and natural killer cell proliferation and activation, disruption of antigen presentation processes, and upregulation of checkpoint and immunosuppressive mediators. New and emerging immunotherapeutic agents, such as chimeric antigen receptor (CAR)-engineered T-cell therapies, vaccines, antibody-based therapy, and checkpoint inhibitors, have been developed as a means to target evasion tactics of MM. Herein we summarize the proceedings of "Immunotherapy in Multiple Myeloma: Accelerating on the Path to the Patient," a workshop held in Havana, Cuba, with contributions from 18 expert hematologic oncologists from the United States, European Union, and Cuba, as well as patient advocacy and industry representatives. The goal of the workshop was to evaluate and discuss key topics and issues regarding development and use of immunotherapies in MM and to collaborate on improving patient outcomes. Clinical significance of recent advances in immunotherapies in MM were discussed, in addition to their current status and therapeutic potential, key issues from various regional perspectives, and opportunities for collaboration to improve MM patient outcomes. In this review we summarize expert presentations on cellular (CAR T cell, allogeneic stem cell transplantation, and vaccine) therapies, antibody-based (daratumumab, elotuzumab, checkpoint inhibitor, anti-cluster of differentiation 28 antibody) therapies, genomics and immunotherapy, and biomarkers of response.

Advanced-Stage Non-Small Cell Lung Cancer: Advances in Thoracic Oncology 2018.

In 2018 research in the field of advanced NSCLCs led to an expanded reach and impact of immune checkpoint inhibitors (ICIs) as part of a frontline treatment strategy, regardless of histologic subtype, with ICI use extended to include stage III disease, shifting the prognosis of all these patients. This new standard first-line approach opens a gap in standard second-line treatment, and older combinations may again become standard of care after progression during treatment with an ICI. The characterization of predictive biomarkers, patient selection, the definition of strategies with ICI combinations upon progression during treatment with ICIs, as well as prospective evaluation of the efficacy of ICIs in subpopulations (such as patients with poor performance status or brain metastases) represent upcoming challenges in advanced thoracic malignancies. In oncogene-addicted NSCLC three major steps were taken during 2018: next-generation tyrosine kinase inhibitors have overtaken more established agents as the new standard of care in EGFR and ALK receptor tyrosine kinase gene (ALK)-positive tumors. Mechanisms of acquired resistance have been reported among patients treated with next-generation EGFR tyrosine kinase inhibitors, reflecting the diversity of the landscape. One major step forward was the approval of personalized treatment in very uncommon genomic alterations, mainly fusions. This raises a new question about the challenge of implementation of next-generation sequencing in daily clinical practice to detect new and uncommon genomic alterations and to capture the heterogeneity of the mechanisms of acquired resistance during treatment, as well as the need to extend research into new therapeutic strategies to overcome them.

Concurrent chemoradiotherapy with weekly versus triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck: Comparative analysis.

BACKGROUND: Cisplatin-based chemoradiotherapy is standard of care for locally advanced squamous cell carcinoma of the head and neck. This systemic review compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck. METHODS: Among 1500 prospective studies published from 1970 to 2015, 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clinical outcomes were analyzed using weighted estimates and 2-tailed t test for comparisons; significance level was 0.05. RESULTS: Locoregional control was 58% (CI 53%-63%) vs 61% (CI 56%-65%; P = .7). The 2-year overall survival (OS) was 74% (CI 66%-80%) for weekly vs 67% (64%-69%) triweekly groups (P = .67). The 2-year progression-free survival (PFS) was 69% (CI 59%-77%) for weekly vs 62% (CI 58%-65%) triweekly groups (P = .9). Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups. CONCLUSIONS: Weekly cisplatin was comparable in efficacy and safety to the triweekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck, with tolerability being a key factor in selection.

Characteristics and Outcomes of Patients With Metastatic KRAS-Mutant Lung Adenocarcinomas: The Lung Cancer Mutation Consortium Experience.

INTRODUCTION: Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS-mutant lung adenocarcinomas. METHODS: The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled more than 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival. RESULTS: Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. Four hundred fifty (27%) patients had a KRAS mutation, 58% were female, 93% were smokers, and there was a median age of 65 years. Main KRAS subtypes were: G12C 39%; and G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never-smokers (22%, p < 0.001). Patients with KRAS-mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 versus 2.22; P = 0.08) and lower 2-year survival rate (49% [95% confidence interval: 44%-54%] and 55% [95% confidence interval: 52%-58%], respectively). CONCLUSIONS: In the LCMC study, 27% of lung adenocarcinomas patients harbored a KRAS mutation and up to one-third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.

Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials.

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naïve patients had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49-12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naïve patients per Kaplan-Meier estimation. Within the ICI-naïve group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.

Potential Racial Disparities Using Current Lung Cancer Screening Guidelines.

RATIONALE: The current age threshold for lung cancer screening targets individuals beginning at age 55. These guidelines were developed based on results from the National Lung Cancer Screening Trial where only 4.4% of the enrollees were African American, when they represent 12.3% of US population. African Americans were also found to have higher incidence and younger onset of lung cancer. We hypothesized that implementation of screening at age 55 would not detect a substantial fraction of early onset lung cancer cases in African American population. OBJECTIVES: We used Surveillance, Epidemiology, and End Results (SEER) Program data to determine the frequency of early-onset lung cancers and to assess the stage at diagnosis in a biracial sample. METHODS: Microscopically confirmed lung cancer (primary site code C 34) cases were identified using SEER 18 registry (2004-2014). Early-onset cancers were defined as cancers diagnosed in persons aged 45 to 54 years. Cases were stratified by race and age groups. Comparisons were evaluated with chi-square tests. RESULTS: 468,403 lung cancers were diagnosed during this period. Nearly 9% of all lung cancers were early onset, with increased frequency in African Americans vs. Whites, 14.2 vs. 8.2%, p < 0.05. Age-adjusted incidence rates were significantly higher in African Americans with highest percent difference noted for age group 50-54. African Americans were more likely to be diagnosed at advanced stages of lung cancer compared to Whites. CONCLUSIONS: We conclude that the current age threshold for lung cancer screening may potentially miss a considerable number of lung cancer cases in African Americans. Further studies are needed to determine the appropriateness of screening age criteria for African Americans.

The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy.

BACKGROUND: Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO. METHODS: A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used. RESULTS: The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052). CONCLUSIONS: Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.

Targeted sequencing and intracranial outcomes of patients with lung adenocarcinoma brain metastases treated with radiotherapy.

BACKGROUND: Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next-generation sequencing results and investigate molecularly based outcomes for patients with AC-BMs treated with radiotherapy. METHODS: The records of 132 patients with AC-BMs treated at Emory University from September 2008 to August 2016 with successful next-generation sequencing were reviewed. Rates of local disease recurrence, distant brain failure (DBF), and salvage whole-brain radiotherapy (WBRT) were estimated using cumulative incidence with competing risk analysis. Univariate and multivariate analyses were performed. RESULTS: The most common aberrations included tumor protein 53 (TP53) (60%), KRAS (29%), epidermal growth factor receptor (EGFR) (20.5%), phosphatase and tensin homolog (PTEN) loss (15.5%), and MET amplification (13%). The majority of patients (62%) were treated with stereotactic radiosurgery alone. In these patients, KRAS mutation, anaplastic lymphoma kinase (ALK) rearrangement, and having ≥ 6 BMs were associated with an increased risk of salvage WBRT (P < .05). KRAS mutation remained significant for an increased risk of salvage WBRT when compared with EGFR/ALK/KRAS-negative patients (hazard ratio, 5.17; P < .05), despite a similar risk of DBF. PTEN loss was associated with increased risk of DBF (P < .05), whereas EGFR and ALK aberrations were associated with a decreased risk of local disease recurrence (P < .05). CONCLUSIONS: The results of the current study quantified the frequency of genetic aberrations in patients with AC-BMs and demonstrated their association with intracranial outcomes. In particular, a cohort of patients with KRAS mutations and ≥6 BMs were identified to be at high risk of requiring salvage WBRT after undergoing upfront stereotactic radiosurgery.

CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions.

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation-many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell-like PD-1+ CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.

Health care disparities among octogenarians and nonagenarians with stage III lung cancer.

BACKGROUND: To the authors' knowledge, the practice patterns for patients aged more than 80 years with stage III non-small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB). METHODS: In the NCDB, patients aged ≥80 years who were diagnosed with stage III NSCLC from 2004 to 2013 with complete treatment records were identified. Multivariable logistic regression and Cox proportional hazard models were generated and propensity score-matched analysis was used. RESULTS: A total of 12,641 patients met the entry criteria: 6018 (47.6%) had stage IIIA disease and 6623 (52.4%) had stage IIIB disease. The median age at the time of diagnosis was 83.0 years (range, 80-91 years). A total of 7921 patients (62.7%) received no therapy. Black race (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.06-1.43) and living in a lower educated census tract of residence (OR, 1.20; 95% CI, 1.03-1.40) were found to be associated with not receiving care, whereas treatment at an academic center (OR, 0.80; 95% CI, 0.70-0.92) was associated with receiving cancer-directed therapy. Receipt of no treatment (hazard ratio [HR], 2.69; 95% CI, 2.57-2.82) or definitive radiation alone (HR, 1.15; 95% CI, 1.07-1.24) compared with CRT was associated with worse OS. On propensity score matching, not receiving CRT was found to be associated with worse OS (HR, 1.58; 95% CI, 1.44-1.72). CONCLUSIONS: In this NCDB analysis, approximately 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care. Black race and living in a lower educated census tract were associated with not receiving cancer-directed care. OS was found to be improved in patients receiving CRT. Cancer 2018;124:775-84. © 2018 American Cancer Society.