Vokes, Everett E.

Background Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited‐stage small cell lung cancer (LS‐SCLC). Many patients with LS‐SCLC are elderly with comorbidities. Methods Individual patient data were collected from 11 phase 2 or 3 trials for LS‐SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression‐free survival (PFS), the rate of severe adverse events, and off‐treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients). Results Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18‐1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03‐1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently. Conclusions Elderly patients with LS‐SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies.

Abstract Purpose The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall’s tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. Results The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall’s tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma.

Abstract The treatment of patients with metastatic non–small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439–44. ©2015 AACR.

Abstract Background: Overexpression of COX-2 has been associated with worse outcome in NSCLC. In C30203, we found that administration of the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved outcome (progression free and overall survival, PFS, OS) in pts with moderate to high COX-2 expression by immunohistochemistry (IHC). C30801 was designed to prospectively confirm that finding. Patients and Methods: Pts with NSCLC (stage IIIb with pleural effusion, IV 6th ed) were pre-registered and biopsy specimens analyzed for COX-2 by IHC. Pts with COX-2 expression &gt; or = 2, PS 0-2 and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin (AUC = 6), pemetrexed (500 mg/m2) d 1, q21 days for pts with non-squamous NSCLC; carboplatin(AUC=5.5) d1, gemcitabine (1000 mg/m2) d 1,8 for pts with squamous histology. Randomization was to celecoxib (400 mg bid) (Arm A) or placebo (Arm B). The primary endpoint was to demonstrate improvement in PFS in patients with COX-2 index &gt;=4 with hazard ratio of 0.645. Results: The study was halted by the DSMB for futility after 312 of the planned 322 pts were randomized. The current analysis is based upon the first 300 pts. There were no significant differences between the groups (Table). There was a possible harmful effect for COX-2 inhibition in the COX-2 2-3 subset (OS HR = 1.75, p =.0977). Toxicity was similar for both arms. Subset analyses evaluating histology, chemotherapy regimen, incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Conclusions: 1. COX-2 expression by IHC failed to select pts who could benefit from selective COX-2 inhibition. 2. COX-2 inhibition did not significantly increase toxicity associated with chemotherapy or increase cardiovascular morbidity. 3. We will evaluate other possible determinants of toxicity and response to COX-2 inhibition. OutcomeArm AArm BCOX-2 2-3 (n=37)COX-2 &gt; or = 4 (n=111)COX-2 2-3 (n=46)COX-2 &gt; or = 4 (n=106)PFS (months)4.404.934.606.11OS (months)9.0310.5814.8512.68 Citation Format: Martin J. Edelman, Xiaofei Wang, Lydia Hodgson, Richard T. Cheney, Maria Baggstrom, Thomas Sachdev, Ajeet Gajra, Erin Bertino, Karen Reckamp, Julian Molina, Joan Schiller, Kisha Mitchell-Richards, Paula Friedman, Jon Ritter, Everett Vokes, Alliance for Clinical Trials in Oncology. Phase III randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2014-CT238