Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study.

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS

RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non–Small Cell Lung Cancer

Purpose: In E GFR-mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. Patients and Methods: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. Results: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. Conclusions: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types

Intra-examiner and inter-examiner reproducibility of paraspinal thermography.

OBJECTIVE: The objective of this study was to evaluate the intra-examiner and inter-examiner reproducibility of paraspinal thermography using an infrared scanner. MATERIALS AND METHODS: The thermal functions of a commercially available infrared scanner (Insight Subluxation Station®) were evaluated for clinical reliability. Two practicing clinicians conducted the measures on 100 subjects. Intra class correlation coefficients (ICCs) and concordance correlation coefficients (CCCs) were calculated from the collected data. RESULTS: Mean bilateral paraspinal skin temperature was 89.78° F and ranged from 88.77° F to 91.43° F. Intra class correlation coefficients (ICCs) for agreement and consistency ranged from 0.959 to 0.976. Concordance correlation coefficients (CCCs) ranged from 0.783 to 0.859 with tight confidence intervals indicating robust estimates of these quantities. CONCLUSION: This study revealed excellent intra-examiner and inter-examiner reproducibility of paraspinal thermography using a commercially available unit

Bland-Altman Plot for Examiner B (Trial 1) vs. Examiner B (Trial 2).

<p>Figure 5 corresponds to intra – examiner agreement and shows that only 4.6% of Examiner B's readings fell outside the 95% agreement limits.</p

Overall Inter-Examiner Variability Coefficients.

<p><b>a</b>– 95% CIs are based on 2000 bootstrap samples.</p><p>*The total inter-examiner variability between Left and Right readings is 1.56 times higher than one would expect if the two examiners were perfectly equivalent in their readings.</p><p>**The total inter-examiner variability between Trial -1 and Trial-2 readings is 1.32 times higher than one would expect if the two examiners were perfectly equivalent in their readings.</p><p>• <b><i>Definition of terms</i></b></p><p>○ CIV  =  Coefficient of Inter-Observer Variability.</p><p>○  =  Agreement Coefficient based on CIV.</p><p>○ CEOV  =  Coefficient of Excess Observer Variability.</p

Inter-examiner Reliability Statistics.

<p>*- CCC is adjusted for Left/Right difference and differences in Spinal Location.</p><p>@ - CCC is adjusted for Trial 1/Trial 2 difference and differences in Spinal Location.</p

Scatter Plot: Intra-examiner agreement (Examiner B).

<p>Figure 2 presents overall scatter of the data corresponding to the intra – examiner agreement for Examiner B. The plot shows a good distribution of data points around the 45° degree line, indicating a high degree of correlation between Examiner B's repeat measurements.</p

Scatter Plot: Intra-examiner agreement (Examiner A).

<p>Figure 1 presents overall scatter of the data corresponding to the intra – examiner agreement for Examiner A. The plot shows a good distribution of data points around the 45° degree line, indicating a high degree of correlation between Examiner A's repeat measurements.</p

Bland-Altman Plot for Examiner A vs. Examiner B.

<p> Figure 6 shows the Bland-Altman plot corresponding to the inter–examiner agreement between the two examiners. On the horizontal axis is the average of the 1^st and 2^nd temperature readings and on the vertical axis, the difference between the measurements of the two examiners. The plot shows the 95% agreement limits between the measurements of the two examiners with only 5.6% of readings falling outside the 95% agreement limits.</p