Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials.

BACKGROUND: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. METHODS: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. RESULTS: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). CONCLUSIONS: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. TRIAL REGISTRATION NUMBER: NCT02538666; NCT02267343.

Enrollment of Racial Minorities in Clinical Trials: Old Problem Assumes New Urgency in the Age of Immunotherapy.

Minority U.S. populations are underrepresented in cancer clinical trials. This review appraises the impact of the disparity in clinical trial participation by minority patients in the current era of cancer immunotherapy. Enrollment on pivotal trials leading to U.S. regulatory approval of immune checkpoint inhibitors showed poor representation of minority ethnic groups. Specifically, we found that black patients constitute less than 4% of all patients enrolled across multiple trials that supported the approval of immune checkpoint inhibitors for the treatment of lung cancer. Similar underrepresentation was observed for trials conducted in renal cell carcinoma and other tumor types. Since efficacy of immunotherapy is only observed in a subset of patients, the use of predictive biomarkers to identify responders along with new strategies to expand the benefit to a larger subset of patients are current areas of active investigation. The inadequate representation of minority patients on immunotherapy clinical trials could perpetuate outcome disparity because the unique biology of the host and the tumors from this subpopulation is not accounted for as new treatment algorithms to guide optimal use of immunotherapy are developed for use in the real world.

National Cancer Database Analysis of Proton Versus Photon Radiation Therapy in Non-Small Cell Lung Cancer.

PURPOSE: To analyze outcomes and predictors associated with proton radiation therapy for non-small cell lung cancer (NSCLC) in the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried to capture patients with stage I-IV NSCLC treated with thoracic radiation from 2004 to 2012. A logistic regression model was used to determine the predictors for utilization of proton radiation therapy. The univariate and multivariable association with overall survival were assessed by Cox proportional hazards models along with log-rank tests. A propensity score matching method was implemented to balance baseline covariates and eliminate selection bias. RESULTS: A total of 243,822 patients (photon radiation therapy: 243,474; proton radiation therapy: 348) were included in the analysis. Patients in a ZIP code with a median income of <$46,000 per year were less likely to receive proton treatment, with the income cohort of $30,000 to $35,999 least likely to receive proton therapy (odds ratio 0.63 [95% confidence interval (CI) 0.44-0.90]; P=.011). On multivariate analysis of all patients, non-proton therapy was associated with significantly worse survival compared with proton therapy (hazard ratio 1.21 [95% CI 1.06-1.39]; P<.01). On propensity matched analysis, proton radiation therapy (n=309) was associated with better 5-year overall survival compared with non-proton radiation therapy (n=1549), 22% versus 16% (P=.025). For stage II and III patients, non-proton radiation therapy was associated with worse survival compared with proton radiation therapy (hazard ratio 1.35 [95% CI 1.10-1.64], P<.01). CONCLUSIONS: Thoracic radiation with protons is associated with better survival in this retrospective analysis; further validation in the randomized setting is needed to account for any imbalances in patient characteristics, including positron emission tomography-computed tomography staging.

Trends, predictors, and impact of systemic chemotherapy in small cell lung cancer patients between 1985 and 2005.

BACKGROUND: The last 3 decades have witnessed limited therapeutic advances in small cell lung cancer (SCLC) management. This study evaluated real-world trends in the use of systemic therapies and the impact on patient outcomes in the United States. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to find patients diagnosed with SCLC between 1985 and 2005. The 1985-1990 period served as the baseline for a temporal analysis conducted at 5-year intervals (1985-1990, 1991-1995, 1996-2000, and 2001-2005). Cox proportional models were used to estimate the effect of chemotherapy on survival. Results were validated with a propensity-matched analysis. RESULTS: There were 47,351 eligible patients: 52% were male; the median age was 71 years; and 87% were white, 7% were black, and 1.4% were Asian. The proportion of patients treated with chemotherapy was low but increased over time (38%, 55%, 50%, and 53%; P < .001). Race, diagnosis period, age, stage, and location of residence significantly predicted chemotherapy use. Females (51%), Asians (53%), and rural residents (60%) were more likely to receive chemotherapy. The median overall survival with and without chemotherapy was 9.6 and 3.6 months, respectively. Linear trend analyses showed a modest reduction in the impact of chemotherapy on survival for patients treated with chemotherapy versus untreated patients (hazard ratios [HRs], 0.59, 0.61, 0.64, and 0.62; P < .001) but an overall trend of improved survival for treated (HRs, 1.0, 1.03, 1.00, and 0.96; P = .005) and untreated patients (HRs, 1.0, 0.99, 0.94, and 0.92; P < .001). There was no survival difference between patients treated with carboplatin and patients treated with cisplatin (HR, 0.99; confidence interval [CI], 0.81-1.19; P = .875). Additional therapy beyond platinum-based chemotherapy was associated with a survival benefit (HR, 0.78; CI, 0.75-0.81; P < .001). CONCLUSIONS: Chemotherapy use was associated with a survival benefit in Medicare patients with SCLC treated in a real-world setting.

Real-world effectiveness of systemic agents approved for advanced non-small cell lung cancer: a SEER-Medicare analysis.

OBJECTIVES: Disparity exists between patients with lung cancer enrolled in clinical trials and patients treated in the community setting. This study assessed the real-world effectiveness of cytotoxic agents that became available for the treatment of non-small cell lung cancer (NSCLC) in the last 2 decades. METHODS: We employed the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage IIIB/IV NSCLC between 1988 and 2005 to assess the effectiveness of newly approved agents. Effectiveness of specific agents was assessed at time periods immediately following the approval of the agent for NSCLC: baseline, 1988-1994; platinum, 1995-1999; docetaxel, 1999-2003; pemetrexed and bevacizumab, 2004-2005. Significant associations between specific drug treatment and survival improvement were determined using the Kaplan-Meier method, Cox proportional hazard model, and propensity score analyses. Significant differences were established by log-rank test. RESULTS: This analysis employed data from 143,548 patients by sex (58% male, 42% female), cancer stage (35% stage IIIB, 65% stage IV), and age (12% 20-64 years, 22% 65-69 years, 45% 70-79 years, 22% 80 years and older). There was temporal improvement in survival for patients treated with newly approved chemotherapy (1-year survival rates: 32.41% in 1988-1994, 32.95% in 1995-1998, 37.40% in 1999-2003, and 39.55% in 2004-2005). Patients treated with a newly approved drug during the relevant treatment era had a significant reduction in the risk of death when compared with patients treated with chemotherapy other than the newly approved agent (hazard ratios [95% confidence interval] were 0.76 [0.71-0.81] for platinum, 0.73 [0.70-0.75] for docetaxel, 0.40 [0.37-0.44] for pemetrexed, and 0.33 [0.27-0.40] for bevacizumab; p < .001). Propensity score adjustment did not significantly alter these results. CONCLUSIONS: Currently approved drugs for the treatment of advanced NSCLC are associated with improved survival in the U.S. Medicare patient population. Our findings support the effectiveness of these agents in the real-world oncology practice.

Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database.

PURPOSE: To study the burden and outcome of lung cancer in the elderly, particularly for patients aged 80 years and older. PATIENTS AND METHODS: The national Surveillance, Epidemiology, and End Results database was analyzed for lung cancer outcomes during the period 1988 to 2003. A comparison was carried out between patients with lung cancer 80 years and older, 70 to 79 years, and younger than 70 years for demographics; stage distribution; 5-year relative survival; and survival based on histology, sex, race, stage, and treatment. The temporal trends in survival during the years 1988 to 1997 and 1998 to 2003 were also analyzed. RESULTS: Of 316,682 patients eligible for the analysis, 45,912 (14%) were 80 years or older (ie, very elderly); 103,963 (33%) were 70 to 79 years; and 166,807 (53%) were younger than 70 years. The distribution by stage and histology was comparable for all the three groups. Overall survival rate at 5 years was lower in the very elderly (7.4% v 12.3% v 15.5%; P < .0001) across sex, histologic subtypes, stages, and racial categories. Patients aged 80 years or older were less likely to receive local therapy (no surgery or radiation) than younger patients (47% v 28% and 19% for the age subgroups >/= 80 years, 70 to 79 years, and < 70 years, respectively). Overall outcomes for patients who underwent surgical therapy or radiation were comparable across the three age groups. In general, survival outcomes for the subgroup aged 70 to 79 years were similar to those of the subgroup aged 80 years and older who received single modality local therapy. CONCLUSION: Patients 80 years or older account for 14% (70 years or older accounted for 47%) of all lung cancers, are less likely to be subjected to surgery or radiation, and have inferior outcomes when compared with younger patients.