Population-based estimate for the correlation of the Oncotype Dx Breast Recurrence Score® result and Ki-67 IHC MIB-1 pharmDx in HR+, HER2-, node-positive early breast cancer.

BACKGROUND: The United States Food and Drug Administration recently approved a Ki-67 immunohistochemistry (IHC) assay to identify patients with early breast cancer at high disease recurrence risk. The Oncotype Dx Breast Recurrence Score® assay has been validated in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) invasive breast cancer (IBC) to predict chemotherapy benefit and distant recurrence risk, regardless of nodal status. This study assessed the correlation between Recurrence Score® (RS) results and the Ki-67 IHC MIB-1 pharmDx assay. METHODS: HR+, HER2-, N1 IBC samples with RS results were examined by Ki-67 IHC; 311 specimens were collected, including 275 without regard to RS ("unselected RS") and 36 more with RS 26-100; 12 were lymph node negative upon pathology report review, and one had no Ki-67 score, leaving 262 unselected RS and 298 total samples. Spearman rank correlation was calculated using the unselected samples and a weighted rank correlation using all samples. A receiver operating characteristic (ROC) curve for predicting high RS (26-100) from Ki-67 was constructed. RESULTS: The Spearman rank correlation between Ki-67 and RS results was moderately positive (unselected RS samples: 0.396; 95% confidence interval [CI] 0.288-0.493; all samples: 0.394; 95% CI 0.294-0.486). While 71% of samples with RS 26-100 had Ki-67 ≥ 20%, 75% with RS 0-25 had Ki-67 < 20%. ROC area under the curve was 0.792 (95% CI 0.725-0.859). CONCLUSIONS: The moderately positive correlation is consistent with previous analyses suggesting the Oncotype Dx® assay and Ki-67 IHC MIB-1 assay should not be used interchangeably in clinical practice.

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.

BACKGROUND: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. FINDINGS: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5-13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3-4·8] vs 2·8 months [2·6-2·9]; HR 0·696 [95% CI 0·573-0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9-11·4) in the ramucirumab group versus 7·9 months (7·0-9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724-1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. INTERPRETATION: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. FUNDING: Eli Lilly and Company.

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.

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer.

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Immunohistochemical application of a highly sensitive and specific murine monoclonal antibody recognising the extracellular domain of the human hepatocyte growth factor receptor (MET).

AIMS: Development of novel targeted therapies directed against hepatocyte growth factor (HGF) or its receptor (MET) necessitates the availability of quality diagnostics to facilitate their safe and effective use. Limitations of some commercially available anti-MET antibodies have prompted development of the highly sensitive and specific clone A2H2-3. Here we report its analytical properties when applied by an automated immunohistochemistry method. METHODS AND RESULTS: Excellent antibody specificity was demonstrated by immunoblot, ELISA, and IHC evaluation of characterised cell lines including NIH3T3 overexpressing the related kinase MST1R (RON). Sensitivity was confirmed by measurements of MET in cell lines or characterised tissues. IHC correlated well with FISH and quantitative RT-PCR assessments of MET (P < 0.001). Good total agreement (89%) was observed with the anti-MET antibody clone SP44 using whole-tissue sections, but poor positive agreement (21-47%) was seen in tissue microarray cores. Multiple lots displayed appropriate reproducibility (R(2)  > 0.9). Prevalence of MET positivity by IHC was higher in non-squamous cell NSCLC, MET or EGFR amplified cases, and in tumours harbouring abnormalities in EGFR exon 19 or 21. CONCLUSIONS: The anti-MET antibody clone A2H2-3 displays excellent specificity and sensitivity. These properties make it suitable for clinical trial investigations and development as a potential companion diagnostic.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.

Two Instrument Comparison of Reagents From a US FDA-Approved Assay for the Assessment of Ki-67 in High-Risk Early Breast Cancer.

The objective of this study was to measure concordance of results obtained from the US Food and Drug Administration-approved Ki-67 immunohistochemistry MIB-1 pharmDx assay performed on the Dako Omnis automated staining instrument (Omnis) versus results produced from the assay reagents applied using an optimized protocol on the more widely available Autostainer Link 48 (ASL48) platform. Tissue sections obtained from 40 formalin-fixed paraffin-embedded breast carcinoma samples, with available Oncotype DX Breast Recurrence Score (RS) results, were stained. Three certified pathologists scored slides at 3 timepoints, totaling 360 observations for each instrument (N=720 total) using the approved scoring approach. Using the ≥20% cutoff, agreement was calculated with corresponding 2-sided 95% percentile bootstrap confidence intervals (CIs). Pairwise comparisons (N=360) from the interinstrument evaluation, performed with all observers, resulted in 325 (90.3%) concordant outcomes (244 negative and 81 positive) and 35 (9.7%) discordant outcomes. The overall agreement was 90.3% (95% confidence interval, 85.6% to 94.4%). No significant systematic differences were observed between instruments. Specimens scored from the Omnis were on average <1% higher than ASL48, with high correlation and little bias between the continuous Ki-67 scores (concordance correlation coefficient=0.916). Most specimens with a Ki-67 score ≥20% had a RS >25. This study demonstrated that good concordance can be achieved with the reagents run on the ASL48 instrument when using an optimized protocol and standardized scoring.

RELAY+: Exploratory Study of Ramucirumab Plus Gefitinib in Untreated Patients With EGFR-Mutated Metastatic NSCLC.

Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3-73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit-risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.

Clinical Significance of PIK3CA and ESR1 Mutations in Circulating Tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib plus Fulvestrant.

PURPOSE: PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2- advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2. PATIENTS AND METHODS: MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2- ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA. RESULTS: From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33-0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33-0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27-0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 0.37-0.79). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status. CONCLUSIONS: Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2- ABC that had progressed on ET.

A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib.

INTRODUCTION: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. PATIENT AND METHODS: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%). RESULTS: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). CONCLUSION: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.

Analytical Accuracy of RET Fusion Detection by Break-Apart Fluorescence In Situ Hybridization.

CONTEXT.­: RET gene fusions are oncogenic drivers in nonsmall cell lung cancer and nonmedullary thyroid cancer. Selpercatinib (RETEVMO), a targeted inhibitor of RET, was approved by the US Food and Drug Administration for the treatment of RET fusion-positive nonsmall cell lung cancer and nonmedullary thyroid cancer emphasizing the need for rapid and accurate diagnosis of RET fusions. Fluorescence in situ hybridization (FISH) has been used to detect gene rearrangements, but its performance detecting RET rearrangements is understudied. OBJECTIVE.­: To validate and describe the performance of Abbott Molecular RET break-apart FISH probes for detecting RET rearrangements. DESIGN.­: A training set with RET fusion-positive (13) and RET fusion-negative nonsmall cell lung cancer and nonmedullary thyroid cancer samples (12) was used to establish criteria for FISH scoring. The scoring criteria was then applied to a larger validation set of samples (96). RESULTS.­: A cutoff of 19% or more positive nuclei by FISH was established in the training set and determined by the mean ±3 SD. The validation set was tested using Abbott Molecular RET break-apart FISH compared with sequencing. With this cutoff, a sensitivity of 86% (12 of 14) and specificity of 99% (81 of 82) was achieved. Bootstrapping showed sensitivity could be optimized by using a greater than 13% cutoff with indeterminate samples of 13% to 18% abnormal nuclei requiring confirmation by an orthogonal method. Using this 3-tier scoring system sensitivity increased to 100% (14 of 14) and specificity was 96% (79 of 82). CONCLUSIONS.­: Abbott Molecular break-apart FISH probes can be used to detect RET fusions. Laboratories can optimize cutoffs and/or testing algorithms to maximize sensitivity and specificity to ensure appropriate patients receive effective, timely therapy.

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab.

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

PURPOSE: In EGFR-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.

Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non-small Cell Lung Cancer.

PURPOSE: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. RESULTS: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification. CONCLUSIONS: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.See related commentary by Garon, p. 905.

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated Metastatic EGFR-Mutated NSCLC: RELAY Japanese Subset.

INTRODUCTION: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. METHODS: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. RESULTS: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). CONCLUSIONS: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.

Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study.

BACKGROUND: Vascular endothelial growth factor (VEGF)-D was identified as a potential predictive biomarker for ramucirumab efficacy in second-line metastatic colorectal cancer using a research use only (RUO) assay. We describe results with a new assay for detecting VEGF-D in human plasma. METHODS: In RAISE (Clinical Trial Registration: NCT01183780), 1072 patients were randomized 1:1 to ramucirumab or placebo plus FOLFIRI. All patients were then randomized 1:2 to marker exploratory (ME) and marker confirmatory (MC) groups, and those with plasma samples were analyzed accordingly. A new assay validated for investigational use only (IUO) was used to measure VEGF-D levels in plasma, which were analyzed for correlation with overall and progression-free survival (OS/PFS). IUO assay data were compared with historical RUO assay data. RESULTS: ME subset analyses determined the optimal cutpoint of 5.4 ng/mL for defining high/low VEGF-D subgroups. In the combined ME/MC placebo arms, OS/PFS were numerically greater for patients with low vs high VEGF-D (OS: 12.8 vs 11.1 months; PFS: 5.6 vs 4.2 months). In patients with high VEGF-D, ramucirumab vs placebo demonstrated a numerically greater improvement in OS and PFS. Differential efficacy by VEGF-D level was statistically significant for PFS, but not OS. CONCLUSION: In patients with high VEGF-D, ramucirumab demonstrated a greater improvement in OS and PFS vs placebo; however, baseline VEGF-D level was not predictive of ramucirumab OS benefit using VEGF-D assay for IUO. The RAISE intent-to-treat results remain valid.

Renal arterial blood flow measurement by breath-held MRI: Accuracy in phantom scans and reproducibility in healthy subjects.

This study evaluates reliability of current technology for measurement of renal arterial blood flow by breath-held velocity-encoded MRI. Overall accuracy was determined by comparing MRI measurements with known flow in controlled-flow-loop phantom studies. Measurements using prospective and retrospective gating methods were compared in phantom studies with pulsatile flow, not revealing significant differences. Phantom study results showed good accuracy, with deviations from true flow consistently below 13% for vessel diameters 3mm and above. Reproducibility in human subjects was evaluated by repeated studies in six healthy control subjects, comparing immediate repetition of the scan, repetition of the scan plane scouting, and week-to-week variation in repeated studies. The standard deviation in the 4-week protocol of repeated in vivo measurements of single-kidney renal flow in normal subjects was 59.7 mL/min, corresponding with an average coefficient of variation of 10.55%. Comparison of renal arterial blood flow reproducibility with and without gadolinium contrast showed no significant differences in mean or standard deviation. A breakdown among error components showed corresponding marginal standard deviations (coefficients of variation) 23.8 mL/min (4.21%) for immediate repetition of the breath-held flow scan, 39.13 mL/min (6.90%) for repeated plane scouting, and 40.76 mL/min (7.20%) for weekly fluctuations in renal blood flow.

A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients.

INTRODUCTION: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC. METHODS: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. RESULTS: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]). CONCLUSIONS: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2- Breast Cancer.

PURPOSE: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. PATIENTS AND METHODS: Postmenopausal women with stage I-IIIB HR+/HER2- breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. RESULTS: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. CONCLUSIONS: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR+/HER2- early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

A Randomized Phase III Study of Abemaciclib Versus Erlotinib in Patients with Stage IV Non-small Cell Lung Cancer With a Detectable KRAS Mutation Who Failed Prior Platinum-Based Therapy: JUNIPER.

INTRODUCTION: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation. METHODS: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib. CONCLUSIONS: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT02152631.