OSPred Tool: A Digital Health Aid for Rapid Predictive Analysis of Correlations Between Early End Points and Overall Survival in Non-Small-Cell Lung Cancer Clinical Trials.

PURPOSE: Overall survival (OS) is the gold standard end point for establishing clinical benefits in phase III oncology trials. However, these trials are associated with low success rates, largely driven by failure to meet the primary end point. Surrogate end points such as progression-free survival (PFS) are increasingly being used as indicators of biologic drug activity and to inform early go/no-go decisions in oncology drug development. We developed OSPred, a digital health aid that combines actual clinical data and machine intelligence approaches to visualize correlation trends between early (PFS-based) and late (OS) end points and provide support for shared decision making in the drug development pipeline. METHODS: OSPred is based on a trial-level data set of 81 reports (35 anticancer drugs with various mechanisms of action; 156 observations) in non-small-cell lung cancer (NSCLC). OSPred was developed using R Shiny, with packages ggplot2, metafor, boot, dplyr, and mvtnorm, to analyze and visualize correlation results and predict OS hazard ratio (HR OS) on the basis of user-inputted PFS-based data, namely, HR PFS, or the odds ratio of PFS at 4 (OR PFS4) or 6 (OR PFS6) months. RESULTS: The three main features of the tool are as follows: prediction of HR OS on the basis of user-inputted early end point values; visualization of comparisons of the user's investigational drug with other drugs in the NSCLC setting, including by specific MoA; and creation of a probability density chart, providing point prediction and CIs for HR OS. A working version of the tool for download is linked. CONCLUSION: The OSPred tool offers interactive visualization of clinical trial end point correlations with reference to a large pool of historical NSCLC studies. Its focused capability has the potential to digitally transform and accelerate data-driven decision making as part of the drug development process.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II-IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy.

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

A phase II trial of gefitinib in patients with non-metastatic hormone-refractory prostate cancer.

OBJECTIVE: To investigate, in a phase II trial, the use of the epidermal growth factor receptor (EGFR) inhibitor gefitinib as monotherapy in patients with non-metastatic hormone refractory prostate cancer (HRPC), as current treatment options for this disease are limited, and agents which target the EGFR should be assessed because EGFR is highly expressed in prostate cancer and associated with a poor prognosis. PATIENTS AND METHODS: Patients with histologically or cytologically confirmed cancer of the prostate with no evidence of metastatic disease were enrolled into this open-label, multicentre study of monotherapy with gefitinib 500 mg/day. The primary endpoint of the study was biochemical response, defined as a >/=50% decrease in serum prostate-specific antigen (PSA) level. RESULTS: Fifty-eight men were enrolled across 10 centres in the USA; none of the 40 evaluable patients had a PSA response. Gefitinib was generally well tolerated, with diarrhoea being the most common treatment- related adverse event, in 71% of patients. There was treatment-related grade 3 diarrhoea in 5% of patients, with no grade 4 adverse events or deaths during the course of the study. CONCLUSIONS: Gefitinib has no single-agent activity in non-metastatic HRPC, as assessed by decreases in serum PSA level. This phase II study also confirmed the well-established favourable tolerability profile of gefitinib monotherapy.