Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients.

BACKGROUND: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. METHODS: This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. RESULTS: Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P < 0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs. 25.0%, P = 0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab. CONCLUSIONS: Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Mass spectrometry-based serum proteomic signature as a potential biomarker for survival in patients with non-small cell lung cancer receiving immunotherapy.

BACKGROUND: VeriStrat test is a serum assay which uses a mass spectrometry (MS)-based proteomic signature derived from machine learning. It is currently used as a prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy. However, little is known about its role for NSCLC patients receiving immune checkpoint inhibitors (ICIs). METHODS: This is a retrospective study that includes 47 patients with advanced stage NSCLC without an activating EGFR mutation, who underwent the VeriStrat test from 2016 to 2018. Spectra from blood samples were evaluated to assign patients into the VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) risk group. The clinical outcomes of 32 patients who received programmed cell death 1 (PD-1) inhibitors nivolumab or pembrolizumab were analyzed by VeriStrat status. RESULTS: The VS-G group demonstrated significantly higher progression-free survival (PFS) and overall survival (OS) compared to the VS-P group among overall NSCLC patients regardless of treatment (median PFS of 7.1 vs. 4.2 months, P=0.013, and median OS, not reached vs. 17.2 months, P=0.012). Among NSCLC patients treated with ICIs, VS-G classification was associated with significantly increased PFS in comparison to VS-P classification (median PFS of 6.2 vs. 3.0 months, P=0.012), while the differences in OS trended towards significance (median OS, not reached vs. 16.5 months P=0.076). Multivariate analysis showed that the VeriStrat status was significantly correlated with PFS and OS in NSCLC patients treated with ICIs (P=0.017, P=0.034, respectively). CONCLUSIONS: MS-based serum proteomic signature has potential as a biomarker for survival outcome in NSCLC patients receiving immunotherapy.

Prognostic performance of proteomic testing in advanced non-small cell lung cancer: a systematic literature review and meta-analysis.

OBJECTIVE: Timely assessment of patient-specific prognosis is critical to oncology care involving a shared decision-making approach, but clinical prognostic factors traditionally used in NSCLC have limitations. We examine a proteomic test to address these limitations. METHODS: This study examines the prognostic performance of the VeriStrat blood-based proteomic test that measures the inflammatory disease state of patients with advanced NSCLC. A systematic literature review (SLR) was performed, yielding cohorts in which the hazard ratio (HR) was reported for overall survival (OS) of patients with VeriStrat Poor (VSPoor) test results versus VeriStrat Good (VSGood). A study-level meta-analysis of OS HRs was performed in subgroups defined by lines of therapy and treatment regimens. RESULTS: Twenty-four cohorts met SLR criteria. Meta-analyses in five subgroups (first-line platinum-based chemotherapy, second-line single-agent chemotherapy, first-line EGFR-tyrosine kinase inhibitor (TKI) therapy, and second- and higher-line TKI therapy, and best supportive care) resulted in statistically significant (p ≤ .001) summary effect sizes for OS HRs of 0.42, 0.54, 0.41, 0.52, and 0.50, respectively, indicating increased OS by about two-fold for patients who test VSGood. No significant heterogeneity was seen in any subgroup (p > .05). CONCLUSIONS: Advanced NSCLC patients classified VSGood have significantly longer OS than those classified VSPoor. The summary effect size for OS HRs around 0.4-0.5 indicates that the expected median survival of those with a VSGood classification is approximately 2-2.5 times as long as those with VSPoor. The robust prognostic performance of the VeriStrat test across various lines of therapy and treatment regimens has clinical implications for treatment shared decision-making and potential for novel treatment strategies.

The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.

The serum-based VeriStrat® test is associated with proinflammatory reactants and clinical outcome in non-small cell lung cancer patients.

BACKGROUND: The VeriStrat test is a serum proteomic signature originally discovered in non-responders to second line gefitinib treatment and subsequently used to predict differential benefit from erlotinib versus chemotherapy in previously treated advanced non-small cell lung cancer (NSCLC). Multiple studies highlight the clinical utility of the VeriStrat test, however, the mechanistic connection between VeriStrat-poor classification and poor prognosis in untreated and previously treated patients is still an active area of research. The aim of this study was to correlate VeriStrat status with other circulating biomarkers in advanced NSCLC patients - each with respect to clinical outcomes. METHODS: Serum samples were prospectively collected from 57 patients receiving salvage chemotherapy and 70 non-EGFR mutated patients receiving erlotinib. Patients were classified as either VeriStrat good or poor based on the VeriStrat test. Luminex immunoassays were used to measure circulating levels of 102 distinct biomarkers implicated in tumor aggressiveness and treatment resistance. A Cox PH model was used to evaluate associations between biomarker levels and clinical outcome, whereas the association of VeriStrat classifications with biomarker levels was assessed via the Mann-Whitney Rank Sum test. RESULTS: VeriStrat was prognostic for outcome within the erlotinib treated patients (HR = 0.29, p < 0.0001) and predictive of differential treatment benefit between erlotinib and chemotherapy ((interaction HR = 0.25; interaction p = 0.0035). A total of 27 biomarkers out of 102 unique analytes were found to be significantly associated with OS (Cox PH p ≤ 0.05), whereas 16 biomarkers were found to be associated with PFS. Thrombospondin-2, C-reactive protein, TNF-receptor I, and placental growth factor were the analytes most highly associated with OS, all with Cox PH p-values ≤0.0001. VeriStrat status was found to be significantly associated with 23 circulating biomarkers (Mann-Whitney Rank Sum p ≤ 0.05), 6 of which had p < 0.001, including C-reactive protein, IL-6, serum amyloid A, CYFRA 21.1, IGF-II, osteopontin, and ferritin. CONCLUSIONS: Strong associations were observed between survival and VeriStrat classifications as well as select circulating biomarkers associated with fibrosis, inflammation, and acute phase reactants as part of this study. The associations between these biomarkers and VeriStrat classification might have therapeutic implications for poor prognosis NSCLC patients, particularly with new immunotherapeutic treatment options.

Prognostic role of the VeriStrat test in first line patients with non-small cell lung cancer treated with platinum-based chemotherapy.

OBJECTIVES: VeriStrat® is a blood-based test that utilizes matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry to assign a binary classification of VeriStrat Good or VeriStrat Poor that is associated with treatment outcomes in cancer patients. A number of other studies have shown an association between VeriStrat status and clinical outcomes in second and subsequent lines of therapy. The prognostic properties of VeriStrat were demonstrated in the placebo arms of two randomized studies in non-small cell lung cancer (NSCLC): TOPICAL and BR.21; the predictive properties of the test were shown in a prospective randomized phase III study PROSE in the second line treatment of NSCLC with erlotinib versus chemotherapy. Motivated by these observations, we sought to extend the clinical utility of VeriStrat to standard first line chemotherapy and evaluated the performance of the test in a number of clinical studies of patients treated with platinum-based regimens. MATERIALS AND METHODS: We examine the performance of VeriStrat in three independent clinical trials where the test classification was acquired for prospectively collected baseline samples from 481 patients treated with platinum-based chemotherapy in first line. RESULTS: Across these trials, 66-70% of patients were classified as VeriStrat Good; patients classified as VeriStrat Good had significantly longer progression-free survival and overall survival than VeriStrat Poor patients, with hazard ratios ranging from 0.36 to 0.72 and 0.26 to 0.51, respectively. These results demonstrated that VeriStrat is a strong prognostic test in NSCLC patients treated with platinum-based regimens in the first line. CONCLUSION: VeriStrat provides valuable clinical information that may be used to support patient-physician conversations regarding prognosis and treatment options, and to identify a subset of patients who might benefit from other treatment strategies, possibly in the framework of clinical trials.

Clinical decisions surrounding genomic and proteomic testing among United States veterans treated for lung cancer within the Veterans Health Administration.

BACKGROUND: Current clinical guidelines recommend epidermal growth factor receptor (EGFR) mutational testing in patients with metastatic non-small cell lung cancer (NSCLC) to predict the benefit of the tyrosine kinase inhibitor erlotinib as first-line treatment. Proteomic (VeriStrat) testing is recommended for patients with EGFR negative or unknown status when erlotinib is being considered. Departure from this clinical algorithm can increase costs and may result in worse outcomes. We examined EGFR and proteomic testing among patients with NSCLC within the Department of Veterans Affairs (VA). We explored adherence to guidelines and the impact of test results on treatment decisions and cost of care. METHODS: Proteomic and EGFR test results from 2013 to 2015 were merged with VA electronic health records and pharmacy data. Chart reviews were conducted. Cases were categorized based on the appropriateness of testing and treatment. RESULTS: Of the 69 patients with NSCLC who underwent proteomic testing, 33 (48%) were EGFR-negative and 36 (52%) did not have documented EGFR status. We analyzed 138 clinical decisions surrounding EGFR/proteomic testing and erlotinib treatment. Most decisions (105, or 76%) were concordant with clinical practice guidelines. However, for 24 (17%) decisions documentation of testing or justification of treatment was inadequate, and 9 (7%) decisions represented clear departures from guidelines. CONCLUSION: EGFR testing, the least expensive clinical intervention analyzed in this study, was significantly underutilized or undocumented. The records of more than half of the patients lacked information on EGFR status. Our analysis illustrated several clinical scenarios where the timing of proteomic testing and erlotinib diverged from the recommended algorithm, resulting in excessive costs of care with no documented improvements in health outcomes.

Evaluation of the VeriStrat® serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study.

OBJECTIVES: Identification of biomarkers associated with clinical benefit may be crucial in establishing optimal treatment choice for patients with squamous cell carcinoma (SCC) of the lung after first-line chemotherapy. In this study, the ability of the VeriStrat serum protein test to predict differential clinical benefit with afatinib versus erlotinib, and the association of VeriStrat status with clinical outcomes irrespective of EGFR-TKI used, was assessed in a retrospective analysis of the phase III LUX-Lung 8 trial. MATERIALS AND METHODS: Pretreatment plasma samples were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Spectra were evaluated to assign a VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) classification. Overall survival (OS), progression-free survival, and other endpoints were assessed with respect to pretreatment VeriStrat status; OS was the primary efficacy variable. Outcomes with other efficacy endpoints were similar. RESULTS: Of 795 patients randomized in LUX-Lung 8, 675 were classified (VS-G: 412; VS-P: 263). In the VS-G group, OS was significantly longer with afatinib versus erlotinib (HR 0.79 [95% CI: 0.63-0.98]). In the VS-P group, there was no significant difference in OS between afatinib and erlotinib (HR 0.90 [0.70-1.16]). However, there was no interaction between VeriStrat classification and treatment group for OS (pinteraction=0.5303). OS was significantly longer in VS-G versus VS-P patients, both in the overall VeriStrat-classified population (HR 0.41 [0.35-0.49]) and afatinib-treated patients (HR 0.40 [0.31-0.51]). Multivariate analysis showed that VeriStrat was an independent predictor of OS in afatinib-treated patients, regardless of ECOG PS or best response to first-line chemotherapy. CONCLUSION: VS-G classification is strongly associated with favorable survival outcomes with either afatinib or erlotinib compared with VS-P classification. In VS-G patients, survival outcomes with afatinib are superior to those with erlotinib. VeriStrat classification may guide treatment decisions in patients with SCC of the lung. ClinicalTrials.gov registration number: NCT01523587.

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

INTRODUCTION: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. METHODS: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. RESULTS: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. CONCLUSIONS: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).

A Randomized Phase 2 Study Comparing the Combination of Ficlatuzumab and Gefitinib with Gefitinib Alone in Asian Patients with Advanced Stage Pulmonary Adenocarcinoma.

INTRODUCTION: A randomized phase 2 study was designed to compare the combination of ficlatuzumab (AV-299), a humanized hepatocyte growth factor-neutralizing monoclonal antibody, plus gefitinib versus gefitinib monotherapy in a pulmonary adenocarcinoma population clinically enriched for EFGR tyrosine kinase inhibitor-sensitizing mutations. METHODS: A total of 188 patients were randomized 1:1 to receive either gefitinib or ficlatuzumab plus gefitinib treatment. Patients who demonstrated disease control in the single-agent gefitinib arm were allowed to cross over to ficlatuzumab plus gefitinib treatment upon disease progression. Molecular analyses included tumor EGFR mutation status and retrospective proteomic testing using VeriStrat, a multivariate test based on mass spectrometry. RESULTS: The addition of ficlatuzumab to gefitinib did not provide significant improvement over gefitinib monotherapy for the primary end point of overall response rate or the secondary end points of progression-free survival and overall survival. In the subgroup classified as VeriStrat poor, the addition of ficlatuzumab to gefitinib showed significant improvement in both progression-free survival and overall survival in both the intent-to-treat population and the subgroup with EGFR tyrosine kinase inhibitor-sensitizing mutations. For all patients, the most frequent adverse events were diarrhea, dermatitis acneiform, and paronychia. CONCLUSIONS: Although the trial showed no significant benefit from the addition of ficlatuzumab to gefitinib in the overall population of Asian patients with advanced-stage pulmonary adenocarcinoma, the biomarker data suggest that patients classified as VeriStrat poor may benefit from ficlatuzumab combination therapy.

Prognostic Value of Serum Proteomic Test and Comorbidity Index in Diversified Population with Lung Cancer.

BACKGROUND: The usefulness of serum proteomic test (VeriStrat) in African-Americans with non-small cell lung cancer (NSCLC) as well as the relationship between comorbidity and test performance have not been studied. MATERIALS AND METHODS: We reviewed records of patients with NSCLC in our practice for whom VeriStrat was performed to assist with the selection of therapy. We correlated survival with VeriStrat test classification, race, and comorbidity index using SAS software 9.4. RESULTS: We identified 49 qualified patients; 33 with VeriStrat Good (VSG), 16 with VeriStrat Poor (VSP). When stratified by VSG vs. VSP, overall survival (OS) did not differ between African-Americans and Whites [hazard ratio (HR)test (VSG/VSP)=0.78, 95% confidence interval (CI)=0.38-1.61; p=0.51]. OS adjusted for mean Charlson Comorbidity Index (CCI) was not different between erlotinib- and chemotherapy-treated groups in patients with non-squamous NSCLC (adjusted HR=0.91, 95% CI= 0.37-2.23; p=0.84), but was inferior in patients with squamous NSCLC treated with erlotinib (adjusted HR=10.6, 95% CI=1.28-87.8; p=0.029). Cox proportional hazard model for OS effect of VeriStrat test was estimated after adjusting for CCI. In both the VSG and VSP groups, a higher CCI value was associated with lower survival, and at any CCI value, the VSG group had better survival than the VSP group. CONCLUSION: Our study corroborates that race does not influence prognostic and predictive values of VeriStrat; however, comorbidities have a significant impact on survival in each proteomic stratum.

The value of proteomics in lung cancer.

Many studies have identified the prognostic and predictive value of proteins or peptides in lung cancer but most failed to provide strong evidence for their clinical applicability. The strongest predictive proteins seem to be fatty acid-binding protein heart (H-FABP), and the 8-peak mass spectrography signature of VeriStrat. When focusing on VeriStrat, a 'VeriStrat good' profile did not discriminate between chemotherapy and erlotinib. The 'VeriStrat poor' profile showed a better outcome to chemotherapy than to erlotinib. VeriStrat is a prognostic test and only the "poor profile" discriminates for the type of therapy that should be chosen. Whether it adds useful information in patients with advanced non-small cell lung cancer (NSCLC) and wild type EGFR mutations is still doubtful. The position of the VeriStrat test in clinical practice is still not clear and we are waiting for prospective studies where biomarker test are involved in clinical decision.

A comparison of individualized treatment guided by VeriStrat with standard of care treatment strategies in patients receiving second-line treatment for advanced non-small cell lung cancer: A cost-utility analysis.

OBJECTIVES: Two therapies are appropriate as 2nd-line treatment of non-small cell lung cancer (NSCLC) patients: chemotherapy and epidermal growth factor receptor (EGFR) inhibitor therapy. VeriStrat, a serum proteomic test, can be used to guide treatment decisions for NSCLC patients. The test classifies patients as likely to benefit from either of these two treatment options. The objective of this research was to model the anticipated survival and cost-effectiveness of four different treatment strategies: chemotherapy for all patients (C-all), EGFR inhibitor for all (E-all), a performance status guided selection strategy (PS-guided), and a strategy guided by VeriStrat test results (V-guided). MATERIALS AND METHODS: We developed a Markov model with the perspective of the U.S. health care system. Model inputs were taken from published literature for the base-case analysis. One-way and probabilistic sensitivity analyses were performed. RESULTS AND CONCLUSION: The C-all treatment strategy showed the best overall survival outcome (10.1 months), followed by V-guided (9.6 months), PS-guided (9.2 months), and E-all (8.2 months) strategies. The incremental cost-effectiveness ratio (ICER) of a V-guided treatment strategy was $91,111 (vs. E-all) and $8462 (vs. PS-guided) per quality-adjusted life year (QALY). The ICER for C-all compared to V-guided was $105,616. This cost-utility analysis indicates that a treatment strategy guided by the VeriStrat test in patients receiving second-line therapy for NSCLC may experience an overall survival benefit at an incremental cost-effectiveness ratio that is reasonable when compared with other practices, including cancer treatments, generally covered in the U.S. health care system. However, treating all patients with chemotherapy yielded the greatest expected survival.