Sergey Yurasov

Phase 2, randomized, open‐label study of ramucirumab in combination with first‐line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non–small cell lung cancer

Vascular endothelial growth factor (VEGF)–mediated angiogenesis plays an important role in non–small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first‐line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC.

A Randomized, Double-Blind, Phase III Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non–Small-Cell Lung Cancer After Disease Progression After 1 Previous Platinum-Based Therapy (REVEL): Treatment Rationale and Study Design

This article describes the treatment rationale and study-related procedures for the A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small-Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL) study (I4T-MC-JVBA; ClinicalTrials.govNCT01168973). This international, randomized, placebo-controlled, double-blinded phase III trial examines the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV non-small-cell lung cancer (NSCLC) whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point is overall survival; secondary end points include progression-free survival, objective response rate, disease control rate, patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment N = 1242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, noncompliance, or patients consent withdrawal. Efficacy and safety will be compared between the study arms and in patient subgroups including patients with nonsquamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves overall survival of patients with NSCLC with progressive disease after first-line therapy, and to advance our knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.

A Phase II, Open-Label Study of Ramucirumab in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Patients with Stage IIIB/IV Non–Small-Cell Lung Cancer

Introduction: The objective of this study was to determine whether the addition of ramucirumab to first-line paclitaxel–carboplatin chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) resulted in a 6-month progression-free survival (PFS) rate that compares favorably with the historic rate for bevacizumab combined with paclitaxel–carboplatin in this patient population. Methods: In this phase II, single-arm, open-label, multicenter study, 40 patients with advanced NSCLC received ramucirumab (10 mg/kg intravenous [IV]) followed by paclitaxel (200 mg/m2 IV) and carboplatin area under the curve = 6 on day 1 every 21 days as first-line therapy. Therapy continued for up to six cycles. Patients not experiencing withdrawal criteria may have continued ramucirumab monotherapy every 3 weeks. The primary endpoint was PFS at 6 months, with 80% power to detect a 6-month PFS rate of at least 55%. Results: The 6-month PFS rate was 59.0% and the objective response rate was 55.0%. The most common treatment-related adverse events were fatigue, peripheral neuropathy, nausea, epistaxis, and myalgia. Single-nucleotide polymorphism (SNP) rs2981582 on the FGFR-2gene had significant associations with improved overall survival, PFS, and best overall response (p values without multiplicity adjustment were 0.0059, 0.0429, and 0.0392, respectively). Conclusion: Ramucirumab in combination with paclitaxel–carboplatin resulted in a 6-month PFS rate and safety profile that compared favorably with the historical control. In addition, no deaths were associated with this treatment. Furthermore, we describe an association of SNP on FGFR-2 gene with survival and response. These findings warrant further clinical investigation in patients with NSCLC.

Quality of life results from the phase 3 REVEL randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-docetaxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy

OBJECTIVES REVEL demonstrated that ramucirumab+docetaxel (RAM+DTX) improved overall survival, progression-free survival, and objective response rate in patients with advanced/metastatic non-small cell lung cancer with progression after platinum-based chemotherapy. This analysis examined quality of life (QoL) as assessed by the Lung Cancer Symptom Scale (LCSS) and clinician-reported functional status. MATERIALS AND METHODS The LCSS includes 6 symptom and 3 global items measured on a 0-100-mm scale; higher scores represent greater symptom burden. LCSS and ECOG PS data were collected at baseline, every 3-week cycle, the summary visit, and at the 30-day follow-up. LCSS total score and Average Symptom Burden Index (ASBI) were calculated. The primary analysis compared time to deterioration (TtD) between treatment arms for all individual items and summary scores, defined as increase from baseline by ≥ 15 mm using the Kaplan-Meier method and Cox regression. TtD to ECOG PS ≥ 2 was analyzed. RESULTS There were 1253 patients randomized to receive RAM+DTX or placebo+docetaxel (PL+DTX). Across all assessments, LCSS compliance was approximately 75% and balanced across arms. The mean (SD) baseline LCSS total score was 27.3mm (17.08 mm) on RAM+DTX and 29.6mm (17.59 mm) on PL+DTX. At 30-day follow-up, mean (SD) LCSS total score was 32.0 (19.03) on RAM+DTX and 32.5 (19.87) on PL+DTX. The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR=0.99 (0.81, 1.22), p=0.932 and HR=0.93 (0.75, 1.15), p=0.514 with approximately 70% of patients censored. TtD to PS ≥ 2 was similar between treatment arms (HR=1.03 [95% CI: 0.85, 1.26], p=0.743) with approximately two-thirds of the patients censored. CONCLUSION In addition to improvement of clinical efficacy outcomes demonstrated in REVEL, these results suggest that adding ramucirumab to docetaxel did not impair patient QoL, symptoms, or functioning.

REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. METHODS Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). RESULTS Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). CONCLUSIONS REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. CLINICAL TRIAL INFORMATION NCT01168973.

EGFR Genotyping of Matched Urine, Plasma, and Tumor Tissue in Patients With Non–Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor

PurposeLiquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with rociletinib.MethodsTissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.ResultsPositive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) tha...

1266PQUALITY OF LIFE (QOL) RESULTS FROM THE PHASE 3 REVEL STUDY OF RAMUCIRUMAB + DOCETAXEL (RAM + DTX) VERSUS PLACEBO + DOCETAXEL (PL + DTX) IN ADVANCED/METASTATIC NSCLC PATIENTS (PTS) WITH PROGRESSION AFTER PLATINUM BASED CHEMOTHERAPY

ABSTRACT Aim: RAM + DTX significantly improved overall survival and progression-free survival in pts with locally advanced or metastatic NSCLC with progression after platinum based chemotherapy. QoL data was obtained. Methods: Lung cancer symptom scale (LCSS) includes 6 symptom questions (loss of appetite, fatigue, cough, dyspnea, hemoptysis, pain) and 3 global items (symptom distress, difficulties with daily activities, global QoL) measured on a 0-100 mm scale, with higher scores representing greater symptom burden. LCSS and ECOG performance status (PS) data were collected at baseline (BL), every cycle, and at 30-day follow up (FU). LCSS total score and average symptom burden index (ASBI) were calculated. The primary prespecified analysis was time to deterioration (TtD) of the LCSS defined as increase from BL by ≥15 mm using the Kaplan-Meier method. TtD to PS ≥ 2 was also analysed. Results: Of the 1253 pts randomized to receive RAM + DTX or PL + DTX, 66.6% were male, median age was 62, and 67.4% had PS1. Pt compliance with LCSS was approximately 75% and balanced across both arms. The mean BL LCSS total score was 27.3 (SD 17.08) and 29.6 (SD 17.59) on RAM + DTX and PL + DTX, respectively. During treatment, the symptom burden appeared similar between treatment arms. At 30-day FU, mean total LCSS score was 32.0 (SD 19.03) and 32.5 (SD 19.87) on RAM + DTX and PL + DTX, respectively, reflecting a similar increase in symptom burden for both arms (mean increase of 5.4 and 6.0 from BL, respectively). The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR = 0.99 (0.81, 1.22), p = 0.932 and HR = 0.93 (0.75, 1.15), p = 0.514 with approximately 70% of pts censored. TtD to PS ≥ 2 was similar between treatment arms (HR = 1.03; [95% CI: 0.85, 1.26], p = 0.742) with approximately two-thirds of the pts censored. Conclusions: In addition to the improvement of clinical outcomes demonstrated in REVEL, the primary QoL analyses suggest that there was no detriment in QoL and pt functioning by adding RAM to DTX second line chemotherapy. Disclosure: K. Park: Advisor - AVEO, Astellas, BI, Astra Zeneca, Clovis, Daiichi Sankyo, Eli Lilly, Roche; M. Thomas: I Receive speakers and AD-Board Honoraria from Lilly Roche BMS AD-Board Honoraria from AstraZeneca Novartis Pierre Fabre; S. Yurasov: I am a full time employee of Ely Lilly & Co. the Sponsor of this clinical study; A. Zimmermann: I am an employee of Eli Lilly and do own stock in Lilly; G. Cuyun Carter: Employee and stockholder of Eli Lilly and Company; M. Reck: Member of Adboard (compensated): Hoffmann-La Roche, Lilly, BMS, Pfizer, Novartis, Boehringer-Ingelheim, AstraZeneca Honoraria for lectures: Hoffmann-La Roche Lilly, BMS, Pfizer, Novartis, Boehringer-Ingelheim, AstraZeneca; M. Perol: Advisory Board for Roche. All other authors have declared no conflicts of interest.