Saiama N. Waqar

Clinical next-generation sequencing in patients with non-small cell lung cancer.

A clinical assay was implemented to perform next‐generation sequencing (NGS) of genes commonly mutated in multiple cancer types. This report describes the feasibility and diagnostic yield of this assay in 381 consecutive patients with non–small cell lung cancer (NSCLC).

Postoperative Radiotherapy for Pathologic N2 Non–Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: A Review of the National Cancer Data Base

PURPOSE To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non-small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. PATIENTS AND METHODS Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. RESULTS Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). CONCLUSION For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone.

Improving Survival for Stage IV Non-small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Survey from 1990 to 2005

Background: Although there has been a significant survival improvement for patients with metastatic NSCLC enrolled in randomized trials, it is not clear whether a similar benefit is seen in an unselected group of patients. Therefore, we conducted a study to evaluate for survival changes in a large national cancer registry database. Patients and Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients with NSCLC stage IV, aged 21 years or older, and diagnosed between 1990 and 2005. We analyzed four equally divided time periods between 1990 and 2005 (1990 to 1993 or period 1, 1994 to 1997 or period 2, 1998 to 2001 or period 3, and 2002 to 2005 or period 4) to determine changes in overall survival for all patients and according to histology. Results: We identified 129,337 patients meeting eligibility criteria. There was a significant improvement in overall survival since period 1. One-year and 2-year overall survival increased from 13.2 and 4.5%, respectively, in period 1 to 19.4% and 7.8%, respectively, in period 4. On multivariate analysis, survival for adenocarcinoma was increased compared with squamous cell carcinoma only in period 4 (p = 0.02). Conclusions: There has been a modest but statistically significant improvement in overall survival for stage IV NSCLC over the past 16 years. The recent differences in outcomes based on histology observed in period 4 may reflect the increased activity of epidermal growth factor receptor tyrosine kinase inhibitors in adenocarcinoma compared with squamous cell carcinoma.

Prognostic Impact of Malignant Pleural Effusion at Presentation in Patients with Metastatic Non–Small-Cell Lung Cancer

Background: Despite its common occurrence, the influence of malignant pleural effusion (MPE) on the outcomes of patients with advanced non–small-cell lung cancer (NSCLC) with distant metastasis (M1b) is unknown. We evaluated the clinical characteristics associated with MPE at presentation and the prognostic impact of MPE at presentation in patients with stage M1b NSCLC. Methods: We extracted data from the Surveillance Epidemiology and End Results (SEER) registry from patients with NSCLC diagnosed between 2004 and 2005. Odds-ratio estimates were calculated using logistic regression, and the Kaplan–Meier method was used to estimate the overall survival. Cox proportional hazard model was used to evaluate whether MPE was an independent risk for outcome. Results: Among the 57,685 patients, MPE was present in 9170 (15.9%), including 3944 out of 31,506 (12.5%) without distant metastases and 5226 (20.0%) out of 26,179 with M1b. The probability of MPE was higher in patients with larger tumors, mediastinal lymph node involvement, and adenocarcinoma, NSCLC not otherwise specified, or large-cell histology. In patients with stage M1b, median overall survival (3 months versus 5 months), estimated 1-year survival (12.6% versus 24.8%), and 2-year survival (5.4% versus 11.3%) were significantly lower in patients with MPE compared with those without MPE (hazards ratio 1.49, 95% confidence interval 1.44–1.54, p < 0.0001). MPE was also an independent factor for worse survival in multivariate analysis (hazards ratio 1.36, 95% confidence interval1.30–1.43, p < 0.001). Conclusions: MPE is a common complication in patients with NSCLC and is associated with decreased survival in patients with distant metastases. If these data are validated, subsequent studies in patients with advanced NSCLC may consider stratification according to the MPE status.

Prognostic Significance of Tumor Size in Patients with Stage III Non–Small-Cell Lung Cancer: A Surveillance, Epidemiology, and End Results (SEER) Survey from 1998 to 2003

Background: Increased tumor size is a known risk for poor outcomes in patients with stage I and II non–small cell lung cancer (NSCLC), who are treated with surgery or radiotherapy. However, there is limited information regarding the impact of tumor size on the outcomes of patients with mediastinal lymph node involvement. We conducted a Surveillance, Epidemiology, and End Results (SEER) database analysis to evaluate the prognostic significance of tumor size in patients with unresected stage III NSCLC. Methods: The SEER registry was queried for patients with unresected NSCLC stage III and no malignant pleural effusion, aged 21 years or older, and diagnosed between 1998 and 2003. Tumor size was defined as S1 (0.1–3cm), S2 (3.1–5cm), S3 (5.1–7cm), and S4 (7.1–20cm). Demographic variables included age, sex, race and histology. Overall survival (OS) and disease-specific survival (DSS) were estimated by the Kaplan–Meier method, and the Cox proportional hazard model was used to evaluate whether tumor size remained an independent risk factor in multivariable analysis. Results: A total of 12,315 patients met the eligibility criteria. Median age at diagnosis was 70 years and most patients were men (58.7%) and white (81.3%). Tumor size was an independent predictor for both OS (p < 0.0001) and DSS (p < 0.001) in all subgroups of patients. Conclusion: Tumor size is an independent predictor for OS and DSS in patients with unresected stage III NSCLC, and should be considered in the stratification of patients treated in this setting after validation of this finding in additional studies.

Barriers to enrollment in non-small cell lung cancer therapeutic clinical trials.

Introduction: Despite recent advances in treatment, lung cancer remains the leading cause of cancer-related mortality in the United States. Therefore, there is a strong need for developing clinical trials in lung cancer therapeutics. Only a small fraction of patients with lung cancer are enrolled in clinical trials. It is critical to understand the barriers to participation in lung cancer clinical trials. Methods: We reviewed the outpatient charts of consecutive patients with non-small cell lung cancer who presented for initial evaluation or consultation for further therapeutic management to the thoracic medical oncology group at the Alvin J. Siteman Cancer Center between January 1, 2006, and December 31, 2006. Available and appropriate clinical trials specific to the histologic subtype and stage were presented to the patients routinely, and reasons for nonenrollment were documented. We collected information on age, gender, ethnicity, histology, stage, performance status (PS), and insurance status. Results: During the study period, 263 patients with non-small cell lung cancer were identified for the study. After initial screening, 183 patients had clinical trials available, which were appropriate for their diagnosis and stage of disease. One hundred one patients (55.2%) were ineligible for enrollment in a clinical trial. The most common reasons for ineligibility were poor PS (18%), need for emergent radiation (12%), lack of adequate staging information (6%), and comorbid conditions (4.9%). Despite being eligible for participation, 57 patients (31.1%) did not enroll in a clinical trial. Patient refusal accounted for 8.7%. The problems with transportation and distance from the medical center were reasons given for nonparticipation by 7.1%. Eleven patients (6%) did not participate in a clinical trial because of insurance issues. Ultimately, 25 patients (13.7%) were enrolled in a clinical trial. Conclusions: Poor PS, the need for emergent radiation, and patient refusal were the most common reasons for not participating in a clinical trial.

Adjuvant Chemotherapy for Patients with T2N0M0 NSCLC

Background: Adjuvant chemotherapy improves survival in patients with completely resected stage II and III NSCLC. However, its role in patients with stage IB NSCLC disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large data set of patients with completely resected T2N0M0 NSCLC. Methods: Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection between 2004 and 2011 were identified from the National Cancer Data Base and classified into four groups based on tumor size: 3.1 to 3.9 cm, 4 to 4.9 cm, 5 to 5.9 cm, and 6 to 7 cm. Patients who died within 1 month after their operation were excluded. Survival curves were estimated by the Kaplan‐Meier product‐limit method and compared by log‐rank test. Results: Among the 25,267 patients who met the inclusion criteria, there were 4996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5‐year overall survival compared with observation for all tumor size groups. In patients with T2 tumors smaller than 4 cm, adjuvant chemotherapy was associated with improved median and 5‐year overall survival in univariate (101.6 versus 68.2 months [67% versus 55%], hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.61–0.72, p < 0.0001) and multivariable analysis (HR = 0.77, 95% CI: 0.70–0.83, p < 0.001) as well as propensity‐matched score (101.6 versus 78.9 months [68% versus 60%], HR = 0.75, 95% CI: 0.70–0.86; p < 0.0001). Conclusions: In patients with completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors smaller than 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials.

A Phase I Trial of Sunitinib and Rapamycin in Patients with Advanced Non-Small Cell Lung Cancer

Background: Sunitinib is an oral multitargeted tyrosine kinase inhibitor, with single-agent activity in non-small cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitor therapy is mediated by the mammalian target of rapamycin (mTOR) pathway, and may be reversed by using mTOR inhibitors. Methods: We performed a phase I study evaluating the combination of sunitinib and rapamycin in patients with advanced NSCLC. Results: Nineteen patients were enrolled in the study. The dose-limiting toxicities included infection, pneumonia, diarrhea/dehydration and treatment delay due to thrombocytopenia in 1 patient each. Sunitinib 25 mg orally daily and rapamycin 2 mg orally daily with 4 weeks on and 2 weeks off therapy were determined to be the maximum tolerated dose. No objective responses were noted, and 6 patients had stable disease as a best response. Conclusion: The combination of sunitinib and rapamycin is well-tolerated and warrants further investigation in the phase II setting.

The impact of smoking and tp53 mutations in lung adenocarcinoma patients with targetable mutations—the lung cancer mutation consortium (LCMC2)

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC. Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038–47. ©2017 AACR.

A phase I study of temsirolimus and thoracic radiation in non-small cell lung cancer

BACKGROUND The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation. PATIENTS AND METHODS This was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC. RESULTS Ten patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease. CONCLUSION The combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.