Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) permits rapid evaluation of new therapeutic strategies in cancer. However, RECIST does not capture the heterogeneity of response in highly active therapies. Depth of tumor response may provide a more granular view of response. We explored the association between, depth of response (DepOR), with overall survival (OS) and progression-free survival (PFS) for patients with NSCLC being treated with an ALK inhibitor (ALKi) or an anti-PD-1 antibody (Ab). METHODS: Experimental arms from two randomized controlled trials (RCTs) of an ALKi and two RCTs of an anti-PD-1 Ab were separately pooled. Patient responses were grouped into DepOR 'quartiles' by percentage of maximal tumor shrinkage (Q1 = 1%-25%, Q2 = 26%-50%, Q3 = 51%-75%, and Q4 = 76%-100%), Q0 had no shrinkage. We carried out a retrospective exploratory responder analysis to evaluate the association between DepOR and OS or PFS using hazard ratios (HR) generated by the Cox proportional hazards model. RESULTS: In the pooled ALK analysis there were 12, 39, 70, 144, and 40 patients in quartiles 0-4, respectively. The DepOR versus PFS/OS analyses HR were: 0.19/0.94 for Q1 0.11/0.56 for Q2, 0.05/0.28 for Q3, and 0.03/0.05 for Q4. In the PD-1 trials within quartiles 0-4 there were 168, 70, 44, 45, and 28 patients, respectively. The DepOR versus PFS/OS analyses HR were 0.3/0.52 for Q1, 0.22/0.47 for Q2, 0.09/0.07 for Q3, and 0.07/0.14 for Q4. CONCLUSIONS: Our analysis suggests a greater DepOR is associated with longer PFS and OS for patients receiving ALKi or anti-PD1 Ab. Overall, this suggests that DepOR may provide an additional outcome measure for clinical trials, and may allow better comparisons of treatment activity.

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Non-Small Cell Lung Cancer.

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic.

Mutant envelope residues confer a transactivation function onto N-terminal sequences of the v-Rel oncoprotein.

The retroviral oncoprotein v-Rel is a member of the Rel/ NF-kappaB family of transcription factors. v-Rel has multiple changes as compared to the proto-oncoprotein c-Rel, and these changes render v-Rel highly oncogenic in avian lymphoid cells. Previous results have shown that three mutant residues in the eleven helper virus-derived Envelope (Env) amino acids (aa) at the N-terminus of v-Rel are required for its full oncogenicity. In this report, we show that these mutant Env aa also enable sequences in the N-terminal half of v-Rel to activate transcription in yeast and chicken cells, under conditions where the analogous sequences from c-Rel either do not or only weakly activate transcription. Removal of the Env aa from v-Rel or site-directed mutations that revert the three mutant residues to the residues present in the Rev-A helper virus Env protein abolish this transactivation ability of v-Rel. Addition of mutant Env aa onto c-Rel is not sufficient to fully restore the transactivation function; other sequences in the N-terminal half of v-Rel are needed for full transactivating ability. A C terminally-truncated form of NF-kappaB p100 (p85), produced in HUT-78 human leukemic cells, also activates transcription in yeast, under conditions where the normal p52 and p100 proteins do not. Furthermore, transcriptional activation by p85 in yeast is likely to occur through N-terminal sequences. Taken together, these results are consistent with a model in which transactivation by N-terminal Rel Homology (RH) domain sequences in oncogenic Rel family proteins is influenced by sequences outside the RH domain.

Rapid diagnosis of Legionella pneumophila serogroup 1 infection with the Binax enzyme immunoassay urinary antigen test.

The Binax legionella urinary antigen (LUA) enzyme immunoassay (Binax, Portland, Maine) was evaluated in 159 patients with suspected or proven legionellosis and 209 controls. A positive LUA test was found in 37% of patients with suspected legionellosis overall and in 83% of those with proven Legionella pneumophila serogroup 1 infection. The sensitivity of the LUA test was significantly greater than that of the direct fluorescent-antigen test (83 versus 42%; P < 0.0001) but not significantly different from that of culture (85%) or serology (91%); specificity was at least 99.5%.

Legionellosis linked with a hotel car park--how many were infected?

An outbreak of legionellosis associated with a hotel in Sydney, Australia, and the subsequent epidemiological and environmental investigations are described. Four cases of Legionnaires' disease were notified to the Public Health Unit. A cross-sectional study of 184 people who attended a seminar at the hotel was carried out. Serological and questionnaire data were obtained for 152 (83%) of these. Twenty-eight (18%) respondents reported symptoms compatible with legionellosis. Thirty-three subjects (22%) had indirect fluorescent antibody (IFA) titres to Legionella pneumophila serogroup 1 (Lp-1) of 128 or higher. The only site which those with symptoms of legionellosis and IFA titre > or = 128 were more likely to have visited than controls was the hotel car park (adjusted odds ratio [OR] 14.7, 95% confidence interval [CI]: 1.8-123.1). Those with symptoms compatible with legionellosis, but whose IFA titres were < 128 were also more likely to have visited the hotel car park (adjusted OR 4.4, 95% CI: 1.5-12.9). Seroprevalence of Lp-1 antibodies was higher in those who attended the seminar than in a population sample of similar age. Findings suggested that the 4 cases represented a small fraction of all those infected, and highlighted difficulties in defining illness caused by Lp-1 and in interpreting serology.