Nitin Roper

Adult Cancer Clinical Trials That Fail to Complete: An Epidemic?

The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.

The landscape of precision cancer medicine clinical trials in the United States.

PURPOSEnAdvances in tumor biology and multiplex genomic analysis have ushered in the era of precision cancer medicine. Little is currently known, however, about the landscape of prospective precision cancer medicine clinical trials in the U.S.nnnMETHODSnWe identified all adult interventional cancer trials registered on ClinicalTrials.gov between September 2005 and May 2013. Trials were classified as precision cancer medicine if a genomic alteration in a predefined set of 88 genes was required for enrollment. Baseline characteristics were ascertained for each trial.nnnRESULTSnOf the initial 18,797 trials identified, 9094 (48%) were eligible for inclusion: 684 (8%) were classified as precision cancer medicine trials and 8410 (92%) were non-precision cancer medicine trials. Compared with non-precision cancer medicine trials, precision cancer medicine trials were significantly more likely to be phase II [RR 1.19 (1.10-1.29), p<0.001], multi-center [RR 1.18 (1.11-1.26), p<0.001], open-label [RR 1.04 (1.02-1.07), p=0.005] and involve breast [RR 4.03 (3.49-4.52), p<0.001], colorectal [RR 1.62 (1.22-2.14), p=0.002] and skin [RR 1.98 (1.55-2.54), p<0.001] cancers. Precision medicine trials required 38 unique genomic alterations for enrollment. The proportion of precision cancer medicine trials compared to the total number of trials increased from 3% in 2006 to 16% in 2013.nnnCONCLUSIONnThe proportion of adult cancer clinical trials in the U.S. requiring a genomic alteration for enrollment has increased substantially over the past several years. However, such trials still represent a small minority of studies performed within the cancer clinical trials enterprise and include a small subset of putatively actionable alterations.

Industry Collaboration and Randomized Clinical Trial Design and Outcomes

Industry Collaboration and Randomized Clinical Trial Design and Outcomes Industry-funded clinical trials are more likely to have favorable, proindustry results compared with nonindustry funded trials,1 but few studies have distinguished between industry funding in the context of industry collaboration in the design, analysis, or reporting of trials.2,3 For a sample of clinical trials published in high-impact journals, our objective was to examine whether industry funding with collaboration was associated with certain trial design features and outcomes.

Industry Collaboration and Primary Guest Authorship of High-Impact Clinical Trials

T he Authors’ Reply— We thank Drs. Marchington and Hamilton and Mr. Gertel for their letter in response to our paper. They note that our study may not be fully comparable to previous studies on guest authorship because we did not include Brevising the manuscript critically for important intellectual content^ as part of our definition of guest authorship. We agree that our study is not entirely comparable with other studies in the literature. However, the aim of our study was different than that of previous studies. We set out not just to determine the overall prevalence of guest authorship (which includes all authors) as was performed in previous studies, but to determine whether primary guest authorship (only first and last authors) was more common in trials with industry collaboration in the design, analysis, or reporting of results than among other trials. We chose to study only primary authors given the prominent role that primary (first and last) authors have in clinical trials—generally as principal investigators—and past evidence of guest authorship primarily among first authors . Given that no previous study, guidance, journal or publisher, to our knowledge, has defined specific authorship criteria for primary authors, we developed a definition based on International Committee of Medical Journal Editors (ICMJE) criteria that best represents the role of the primary authors in a clinical trial, which we believe includes Bdrafting of the manuscript.^ It is certainly reasonable for Marchington and colleagues to disagree with this definition, but it is important to note that our definition was chosen a priori and was applied equally to all three groups studied: trials with industry funding with collaboration, trials with only industry funding and trials with neither industry funding nor collaboration. Our main conclusion was that primary guest authorship was generally uncommon, but significantly more prevalent among trials with industry funding with collaboration. We believe these results are novel and important for the medical and publishing community, although they may not be directly comparable to previous guest authorship studies.

Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V

Lung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed “Super-SILAC” and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12-G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites. Knockdown of CDK12 in lung adenocarcinoma cells results in increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.

Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

Elucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.