Faculty Bibliography

Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naive and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the "inflamed phenotype" including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.

Background: Renal cell carcinoma (RCC) accounts for 3% of cancers diagnosed in the Department of Veterans Affairs (VA). Each year, 15% of the 1,600 Veterans diagnosed with RCC have advanced disease. Until a decade ago, there were few non-surgical treatments for advanced RCC. Approval of multitargeted tyrosine kinase inhibitors (TKIs), sorafenib, sunitinib, and pazopanib significantly improved outcomes for patients. However, several studies demonstrated increased risk of congestive heart failure, stroke, and thromboembolic events in patients treated with TKIs. Objectives: To understand whether Veterans, who have a high prevalence of comorbidities, have increased risk of cardiac events following TKI treatment. Methods: This was a retrospective study of patients diagnosed with advanced RCC from 2006 to 2015. The outcome variable was whether the patient had congestive heart failure, cardiomyopathy, acute myocardial infarction, stroke, or cardiovascular-related death after initiation of at least one TKI. Clinical, demographic, and pharmacy data came from the VA Central Cancer Registry and Corporate Data Warehouse. Patient characteristics across treatments were evaluated using Chi-square tests, T-tests, and ANOVAs, as appropriate. We used multivariate logistic regression to determine the likelihood of cardiac events in patients treated with TKIs. Results: We identified 3,510 patients eligible for treatment who did not have a prior cardiac event. Overall, 1,840 patients were treated with at least one TKI prior to any cardiac event: 953 (27.1%) were treated with only sunitinib, 179 (5.1%) with sorafenib, 289 (8.2%) with pazopanib, and 419 (11.9%) treated with a combination. There were 909 who had a cardiac event (25.9% of all patients). Only 259 (28.49%) were treated with a TKI. On multivariate analysis, statistically significant predictors of a cardiac event were having diagnoses of dyslipidemia (Odds ratio [OR] 2.1, 95% confidence interval [CI] 1.7-2.5) or diabetes (OR 1.5, 95% CI 1.3-1.8). Patients treated with TKIs had a lower likelihood of a cardiac event (OR 0.3, CI 0.2-0.3). Conclusions: Among veterans, treatment with TKIs does not pose as great a risk for cardiac events as underlying comorbid diagnoses

Background: Tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes of advanced renal cell carcinoma (RCC) patients, although complete remission is uncommon. Disease-specific survival in RCC varies by race/ethnicity, but race is not an independent predictor of survival within single-payer healthcare systems, pointing to the importance of access to treatment. Objectives: To analyze patient-level utilization of three TKIs (sunitinib, sorafenib, and pazopanib) among veterans with RCC. Methods: In this retrospective cohort study, we used data from Department of Veterans Affairs (VA) Corporate Data Warehouse to identify Veterans diagnosed with RCC from 2006 to 2015 and exposed to TKIs and to obtain their demographic and clinical information. The distribution of patients' characteristics across treatments was evaluated using Chi-square and T-tests. Results: Of 2,410 patients exposed to TKIs, 956 (40%) received more than one TKI. Sunitinib was prescribed to 1,761 (73%) patients, pazopanib to 766 (32%), and sorafenib to 600 (25%) patients. The use of sorafenib declined steadily over time, from 37% of patients diagnosed in 2006 to 2% of those diagnosed in 2015, while the use of pazopanib grew from 8% to 38%, respectively. The comparison group was unexposed patients in Stage IV RCC (N = 1,144). Patients exposed to targeted treatments were significantly younger at diagnosis than those with no exposure (mean [M] age 65 years, SD 9 vs. M = 70 years, SD 10; p < 001). There were no statistically significant racial/ethnic or gender differences between patients exposed and unexposed to TKIs. Exposed patients had significantly higher body mass index (BMI) than unexposed (M = 29.6, SD 6 vs M = 27.9, SD 6, respectively; p < 0.01). Receipt of TKI was positively correlated with both surgery and chemotherapy, and negatively correlated with Charlson comorbidity index (p < 0.01). Conclusions: We documented equal access to TKIs treatment within the VA among RCC patients of different ethnic backgrounds and gender. Treatment with TKIs was correlated with younger age and fewer comorbidities, but higher BMI. We observed trends in use of individual TKIs, with more recently approved pazopanib gradually replacing sorafenib and sunitinib

PURPOSE: In 2015, both ASCO and the European Society for Medical Oncology (ESMO) proposed frameworks to quantify the benefit of antineoplastic drugs in the face of rising costs. We applied these frameworks to drugs approved by the US Food and Drug Administration over the past 12 years and examined relationships between costs and benefits. METHODS: We searched FDA.gov for drugs that received initial approval for solid tumors from 2004 to 2015 and calculated the ASCO Net Health Benefit version 2016 (NHB16) and 2015 (NHB15) and the ESMO Magnitude of Clinical Benefit Scale scores for each drug. We calculated descriptive statistics and explored correlations and associations among benefit scores, cost, and independent variables. RESULTS: We identified 55 drug approvals supported by phase II (18.2%) and III (81.8%) trials, with primary outcomes of overall survival (36.4%), progression-free survival (43.6%), or response rate (20.0%). No significant association was found between NHB16 and year of approval ( P = .81), organ system ( P = .20), or trial comparator arm ( P = .17), but trials with progression-free survival outcomes were associated with higher scores ( P = .007). Both NHB15 and Magnitude of Clinical Benefit Scale scores were approximately normally distributed, but only a moderate correlation existed between them ( r = 0.40, P = .006). No correlation between benefit score and cost (NHB16, r = 0.19; ESMO, r = -0.07) was found. Before 2010, two (15.3%) of 13 approved drugs exceeded $500/NHB point x month compared with 10 (25.0%) of 40 drugs subsequently approved. CONCLUSION: Our analysis of the ASCO and ESMO value frameworks illuminates the heterogeneous benefit of new medications and highlights challenges in constructing a unified concept of drug value. Drug benefit does not correlate with cost, and the number of high cost/benefit outliers has increased.

BACKGROUND: The optimal timing of thoracic radiation therapy (RT) in relation to chemotherapy is unknown in the treatment of nonmetastatic small cell lung cancer (SCLC). We analyzed the National Cancer Data Base (NCDB) to assess the effect on overall survival (OS) of RT timing with chemotherapy for patients with SCLC. MATERIALS AND METHODS: The NCDB was queried for patients diagnosed with nonmetastatic SCLC from 1998 to 2011 who had undergone definitive chemoradiation. The patients were stratified into quartiles according to the interval between the start of chemotherapy and the start of RT. The first and second quartiles (RT started 0-20 days after chemotherapy) were classified as "early" RT and the third and fourth quartiles (RT started 21-126 days after chemotherapy) as "late" RT. Patients were included if they had received hyperfractionated 45 Gy in 30 fractions or standard fractionation of >/= 60 Gy in 1.8- to 2-Gy fractions. Kaplan-Meier analyses of OS were performed, and multivariable Cox regression analysis was conducted to assess the effect of the covariates on OS. RESULTS: A total of 8391 patients were included (50.5% had received early RT). Early RT was associated with significant improvement in survival (5-year OS, 21.9% vs. 19.1%; P = .01). On subgroup analysis, the survival advantage for early RT was significant for patients receiving hyperfractionated RT (5-year OS, 28.2% vs. 21.2%; P = .004) but not for those receiving standard fractionation (19.8% vs. 18.4%; P = .29). On multivariable Cox regression analysis, hyperfractionated RT was associated with reduced mortality (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.85-0.96; P = .001), but early RT was not (HR, 0.98; 95% CI, 0.94-1.04; P = .53). CONCLUSION: These data support the early initiation of hyperfractionated thoracic RT for nonmetastatic SCLC.

INTRODUCTION: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer-specific survival [LCSS] and overall survival) between AFs and non-Asian males (NAMs), an EGFR mutation-enriched and EGFR mutation-unenriched population, respectively, with a diagnosis in the pre-EGFR TKI (1998-2004) and EGFR TKI (2005-2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. RESULTS: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre-TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre-TKI era (median, 4 months; log-rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682-0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822-0.860). CONCLUSIONS: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials.