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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. ispartof: JOURNAL OF GASTRIC CANCER vol:23 issue:2 pages:289-302 ispartof: location:Korea (South) status: published

Purpose:Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab.Patients and Methods:A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC).Results:A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non–small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug–drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64–8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression.Conclusions:Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.

Preclinical Data for Emibetuzumab and DC-101

Dose Adjustments

Progression-free Survival in Gastric Cancer population, MET +23

Exploratory Analysis of Different MET Expression Cut-offs in HCC Cohort

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Supplementary figures titles and legends are placed in this document

Trial Profile

Patient disposition

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles.Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

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

Supplementary Tables 1-3

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.

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.

This open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level enriched for EGFRmt could be overcome by emibetuzumab, an antibody against MET. Although some responses were seen, the trial did not meet its primary endpoint. 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. (C) 2022 Elsevier Inc. All rights reserved.

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

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 average1% 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 RS25. 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.

Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreatedPeriod 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreatedFrom 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).RELAY+ was found to have a favorable benefit-risk profile for RAM plus GEF in first-line treatment of East Asian patients with

Background: Combination treatments of CDK4 & 6 inhibitors (CDK4 & 6i) with endocrine therapy (ET) have improved outcomes in patients with HR-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Aside from estrogen receptor positivity (ER+), predictive biomarkers of clinical benefit from CDK4 & 6i in combination with ET remain elusive. We assessed clinical outcomes by genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients treated with abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI in the Phase 3 study MONARCH 3 (NCT02246621). Methods: MONARCH 3 randomized 493 postmenopausal women with HR+, HER2- ABC who had no prior systemic therapy in the advanced setting to treatment with abemaciclib plus NSAI or placebo plus NSAI. Biomarker analysis of baseline ctDNA was an exploratory objective; plasma was analyzed by the Guardant360 next-generation sequencing (NGS)-based assay to identify potential tumor-related (i.e., somatic) genomic alterations including point mutations (SNV), indels, amplifications, and fusions in over 70 cancer-related genes. Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including progression-free survival (PFS) and objective response rate (ORR). Results: Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring one or more detectable genomic alterations. Commonly altered genes of interest (% frequency) detected in baseline ctDNA included: PIK3CA (38%); TP53 (26%); EGFR (15%); FGFR1 (12%); NF1 (12%); MYC (9%); CCND1 (9%); ESR1 (5%).Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations, as shown in the Table (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]). Moreover, genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS Conclusions: In this exploratory subgroup analysis, the presence of detectable ctDNA genomic alterations was associated with shorter PFS with placebo plus NSAI. Consistently, abemaciclib added to NSAI improved outcomes for genomically identified subgroups. In contrast to prior studies, there was no subgroup (e.g., patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK4 & 6i in combination with ET. TableAbemaciclib + NSAIPlacebo + NSAIEvents, n/NMedian PFS (95% CI)Events, n/NMedian PFS (95% CI)Hazard Ratio (95% CI)OVERALLITT population170 / 32828.2 (23.7 - 33.9)123 / 16514.8 (11.2 - 19.2)0.52 (0.42 - 0.66)TR population93 / 20138.7 (31.1 - NR)71 / 9416.5 (11.7 - 23.1)0.45 (0.33 - 0.61)Any Gene AlterationDetected83 / 16634.1 (27.2 - 40.0)62 / 7914.9 (11.0 - 23.1)0.47 (0.34 - 0.66)Not detected10 / 35NR (36.4 - NR)9 / 1519.2 (9.40 - NR)0.31 (0.13 - 0.78)TP53Detected29 / 5327.0 (14.1 - NR)19 / 2315.4 (5.7 - 30.4)0.53 (0.30 - 0.95)Not detected64 / 14839.9 (34.1 - NR)52 / 7117.5 (11.7 - 24.2)0.42 (0.29 - 0.60)EGFRDetected10 / 26NR (32.4 - NR)16 / 1710.9 (2.1 - 24.7)0.20 (0.09 - 0.47)Not detected83 / 17536.4 (27.7 - NR)55 / 7717.6 (14.6 - 25.5)0.52 (0.37 - 0.73)FGFR1Detected15 / 2532.8 (10.1 - NR)10 / 117.6 (1.9 - 15.4)0.37 (0.16 - 0.85)Not detected78 / 17639.9 (31.1 - NR)61 / 8319.2 (14.6 - 26.5)0.45 (0.32 - 0.63)NF1Detected10 / 2435.9 (27 - NR)8 / 1014.6 (1.6 - 33.4)0.33 (0.13 - 0.84)Not detected83 / 17738.7 (30.8 - NR)63 / 8417.5 (11.7 - 24.2)0.47 (0.33 - 0.65)MYCDetected11 / 1720.1 (5.5 - NR)9 / 106.5 (1.2 - 15.7)0.33 (0.13 - 0.86)Not detected82 / 18438.9 (32.9 - NR)62 / 8419.2 (14.6 - 26.5)0.45 (0.32 - 0.63)CCND1Detected8 / 1632.8 (5.5 - NR)10 / 107.2 (3.6 - 9.0)0.28 (0.10 - 0.77)Not detected85 / 18538.7 (31.1 - NR)61 / 8417.6 (14.6 - 25.5)0.48 (0.34 - 0.67)n = number of patients with events; N = total number of patients in the corresponding population and treatment arm; NR = not reached. TR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained. Citation Format: Matthew P Goetz, J. Thaddeus Beck, Mario Campone, Sara Hurvitz, Seock-Ah Im, Stephen Johnston, Antonio Llombart-Cussac, Miguel Martin, Joohyuk Sohn, Masakazu Toi, Lacey M Litchfield, Hillary T Graham, Hong Wang, Sameera R Wijayawardana, Valerie M Jansen, Angelo Di Leo. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-06.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus 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/m 2 (60 mg/m 2 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

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.

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.

Background: Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- metastatic breast cancer (MBC) patients (pts) in combination with endocrine therapy or as monotherapy. Recent studies have demonstrated the potential for CDK4 & 6 inhibitors, including abemaciclib, to promote anti-tumor immunity. Schaer et al., (Cell Reports 2018) showed that abemaciclib monotherapy results in upregulation of antigen presentation on tumor cells and increases T-cell activation. These activities synergized with anti-PD-L1 therapy to further enhance immune activation leading to complete tumor rejection in murine tumor models (Schaer et al., Cell Reports 2018). In this exploratory analysis, we evaluated the early and late immune-modulating effects of abemaciclib in the neoadjuvant study neoMONARCH (NCT02441946). Methods: NeoMONARCH is a Phase II trial in women with stage I-IIIB HR+, HER2- BC evaluating neoadjuvant treatment with 2 weeks of abemaciclib, alone or in combination with anastrozole (abemaciclib+ANZ), or ANZ alone. All patients received 14 weeks of abemaciclib +ANZ after the first 2 weeks of treatment. Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early - after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor biopsies at each time point and subjected to whole transcriptome RNA sequencing. The curated data were subjected to statistical analysis using ANOVA tests followed by pathway analysis using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Results: Consistent with the known activity of abemaciclib to inhibit the cell cycle, we observed at the early and late time points a significant treatment induced downregulation of genes related to mitotic spindle organization, replication stress response, G2M checkpoint, and E2F targets. Abemaciclib treatment for 2 weeks, alone or in combination with ANZ, followed by 14 weeks of combination therapy was associated with upregulation of gene expression signatures related to T-cell immune response and antigen presentation. Importantly, this phenomenon was notobserved with 2 weeks of ANZ treatment alone followed by 14 weeks of combination therapy. Conclusion: These data lend support that continuous inhibition of CDK4 & 6 signaling by abemaciclib treatment leads to prolonged cell cycle arrest resulting in tumor cell apoptosis & senescence, which then leads to an enhanced immune activation. Citation Format: Hurvitz S, Martin M, Press M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-10.

Background: Combination treatments of endocrine therapy (ET) with CDK4 & 6 inhibitors have improved outcomes in patients with HR+ advanced breast cancer, both as initial therapy and after progression on ET. Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- MBC patients (pts), alone or in combination with ET. However, biomarkers that predict benefit from this class of agents remain elusive. We previously reported in the phase II neoadjuvant neoMONARCH study (NCT02441946), after 2 weeks of treatment, abemaciclib, alone or in combination with anastrozole (ANZ), led to a significantly higher rate of complete cell cycle arrest (CCCA, defined as Ki67 ≤2.7%) compared to ANZ alone in early stage HR+, HER2- breast cancer (Martin et al. SABCS 2017). As an exploratory aim of this trial, we evaluated the gene expression analyses in order to determine markers of sensitivity and resistance to therapy. Methods: Serial biopsies were collected at 3 time points: Baseline (BL) - prior to treatment, Early – after 2 weeks of therapy with abemaciclib, ANZ, or abemaciclib+ANZ, and Late – after 2 weeks of initial therapy followed by 14 weeks of abemaciclib+ANZ. RNA was extracted from FFPE tumor biopsies at each timepoint and subjected to a Cell Cycle Associated Gene (CCAG) expression panel using the Modaplex® platform and whole transcriptome RNA sequencing. Ki67 was measured at each time point by immunohistochemistry (IHC). Tumors were categorized by the post-treatment Ki67 expression as either sensitive (Ki67 ≤2.7) or resistant (Ki67 ≥7.4), based upon the IMPACT and POETIC studies. Additionally, tumors intrinsically resistant/sensitive to therapy were also identified. Results: ANZ-treated tumors that did not achieve CCCA at 2 weeks (N= 8) displayed higher expression of the cell cycle associated genes FOXM1, E2F1, TOPO2A, and RRM2. The addition of abemaciclib to ANZ decreased gene expression in a majority of the tumors (N=5, 62.5%). Tumors intrinsically resistant to treatment with abemaciclib+ANZ displayed persistently elevated levels of cell cycle associated genes compared to sensitive tumors. Finally, gene expression signature of Rb loss-of-function (Rbsig) and RB1 gene expression levels were associated with sensitivity to abemaciclib. Conclusion: On-treatment Ki67 indicated treatment sensitivity and correlated with cell cycle associated gene expression in sensitive and resistant tumors. These exploratory analyses suggest that gene expression analyses may identify genomic markers for abemaciclib and ET treatment sensitivity and may help inform in which tumors to use abemaciclib. Citation Format: Hurvitz S, Martin M, Wijayawardana S, Brahmachary M, Ebert PJ, Young S, Jansen V, Slamon D. Markers of response to CDK4 & 6 inhibition from neoMONARCH: A phase II neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-08.

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-positiveThis open-label, single-arm phase I study enrolled patients withTwenty-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 (Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial. ispartof: EUROPEAN JOURNAL OF CANCER vol:127 pages:150-157 ispartof: location:England status: published

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC.Patients and Methods: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed.Results: Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non–small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9–4.2] for SCC of the anus, 1.6 months (90% CI, 1.4–2.8) for SCCHN, and 3.0 months (90% CI, 1.4–3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress.Conclusions: Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m2 was confirmed as the recommended phase II dose. Clin Cancer Res; 24(14); 3263–72. ©2018 AACR.

Purpose Mesenchymal–epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling. Methods This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size. Results Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33–0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3–not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab’s pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated. Conclusion Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.

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, Eli Lilly and CompanyEli Lilly, This study was funded by Eli Lilly and Company.

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.

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.

BACKGROUND: Mutations (mt) in PIK3CA have been implicated in resistance to endocrine therapy (ET) in HR+ advanced breast cancer (ABC). In the MONARCH 2 study the addition of abemaciclib to fulvestrant (fulv) demonstrated a clinically meaningful and statistically significant median overall survival (OS) benefit of 9.4 months (mos) (HR 0.757, p=0.01), in addition to prolonging time to chemotherapy (TTC) (Sledge et al. JAMA Oncology 2019). We previously showed that abemaciclib plus fulv demonstrated improvement in progression-free survival (PFS) regardless of PIK3CA mt status, with a numerically larger magnitude of benefit for patients (pts) with PIK3CA mt in baseline circulating tumor DNA (ctDNA; Tolaney et al. AACR 2019). Here, we assessed the OS, TTC, and chemotherapy-free survival (CFS) in patients with and without PIK3CA mt in MONARCH 2. METHODS: MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib plus fulv or placebo plus fulv in pre-/perimenopausal (with ovarian suppression) and postmenopausal women with ET resistant HR+, HER2- ABC. Results of PIK3CA mt status (E542K; E545K; H1047L; H1047R) from baseline ctDNA were available for 238 patients. Exploratory analyses of OS, TTC, and CFS were assessed in pts with and without PIK3CA mt using the Cox Interaction Model including treatment, PIK3CA mt status and treatment by PIK3CA interaction term. RESULTS: Abemaciclib plus fulv demonstrated a similar OS benefit for pts with PIK3CA mt (HR: 0.57; 95% CI: 0.34, 0.96) and for pts with PIK3CA wild-type (HR: 0.56; 95% CI: 0.34, 0.91) compared with placebo plus fulv. Median TTC and CFS were longer in the abemaciclib plus fulv arm compared with the placebo plus fulv arm both in pts with detectable PIK3CA mt and in pts without PIK3CA mt, as shown in Table 1. Table 1.PIK3CA mutantPIK3CA wild-typeAbemaciclib +Fulvestrant (n=58)Placebo + Fulvestrant (n=38)Hazard Ratio (95% CI)Abemaciclib + Fulvestrant (n=91)Placebo + Fulvestrant (n=51)Hazard Ratio (95% CI)Interaction p-valueOverall Survival Median (95% CI)44.5 mos (31.0, NR)33.8 mos (24.2, 41.7)0.57 (0.34, 0.96)55.5 mos (47.7, 55.5)41.7 mos (29.4, 49.7)0.56 (0.34, 0.91)0.949Time to Chemotherapy Median (95% CI)39.2 mos (24.6, NR)19.2 mos (6.7, NR)0.65 (0.37, 1.18)NR (34.3, NR)19.2 mos (12.0, 31.1)0.50 (0.31, 0.78)0.463Chemotherapy-Free Survival Median (95% CI)25.8 mos (16.0, 42.1)12.8 mos (5.2, 33.2)0.63 (0.39, 1.03)36.9 mos (20.7, NR)19.2 mos (12.0, 29.4)0.53 (0.35, 0.80)0.588CI = confidence interval; NR = not reached; mos = months CONCLUSIONS: In this exploratory analysis of MONARCH 2, abemaciclib plus fulv demonstrated benefit in OS, TTC, and CFS in patients with and without PIK3CA mutations. Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Hatem Soliman, Lacey M. Litchfield, Hong Wang, Sameera R. Wijayawardana, Valerie M. Jansen, George W. Sledge. Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 766.

RELAY (NCT02411448) showed a superior progression free survival benefit with RAM+ERL versus (v) PBO+ ERL (mPFS 19.4 vs 12.4mo, HR 0.59, p-value TablePts (≥2 in either treatment group) with treatment emergent alterationsaPop1bPop2bGene NameRAM+ERL (n=36)PBO+ERL (n=60)p-valuecRAM+ERL (n=98)PBO+ERL (n=129)p-valuecEGFRd16 (44)33 (55).3227 (28)47 (36).16TP538 (22)7 (12).1717 (17)16 (12).30NF15 (14)1 (2).027 (7)3 (2).08APC4 (11)1 (2).055 (5)3 (2).26MET3 (8)5 (8)1.006 (6)7 (5).82KRAS2 (6)3 (5).917 (7)3 (2).08FGFR22 (6)2 (3).603 (3)3 (2).73GNAS2 (6)0.052(2)1 (1).41BRAF1 (3)6 (10).163 (3)6 (5).54PI3KA1 (3)4 (7).391 (1)7 (5).06BRCA203 (5).094 (4)6 (5).84ERBB21 (3)3 (5).594 (4)4 (3).69AR02 (3).171 (1)2 (2).73CDK61 (3)2 (3).881 (1)2 (2).73RB11 (3)1 (2).722 (2)3 (2).88CDK41 (3)1 (2).721 (1)2 (2).73SMAD41 (3)1 (2).721 (1)2 (2).73KIT1 (3)1 (2).723 (3)1 (1).19PTEN1 (3)2 (3).882 (2)2 (2).78ARID1A1 (3)1 (2).723 (3)3 (2).73FGFR11 (3)0.162 (2)1 (1).41MAP2K11 (3)0.162 (2)0.07MAPK31 (3)0.162 (2)0.07MTOR01 (2).332 (2)1 (1).41MYC1 (3)0.162 (2)2 (2).78RET00–2 (2)0.07ROS100–2 (2)0.07STK1100–1 (1)2 (2).73Evaluable baseline NGS results were obtained for 390 out of 449 ITT patients (87%).aPts are included in more than one row if alterations arose in more than one gene.bAnalysis population 1 (Pop1, N=96) had disease progression by the 30-day post treatment discontinuation follow-up and had detectable EGFR ex19del or ex21.L858R mutation in baseline and 30 day follow-up blood samples. There is a greater confidence that alterations related to mechanisms of resistance would be detectable in this population since the patients had all progressed by 30-day follow-up and since the EGFR ex19del and ex21.L858R were detectable as shed circulating tumor DNA in the blood. Analysis population 2 (Pop2, N=227) had discontinued study treatment for any reason by the 30-day post treatment discontinuation follow-up and had any alteration detectable at baseline and at 30 day follow-up. Pop2 is a larger population (includes all Pop1 pts) and offers the opportunity to detect less common TE alterations that may not be found in the smaller Pop1. Seven (19%) RAM+ERL v 19 (32%) PBO+ERL of Pop1 and 33 (34%) v 59 (46%) of Pop2 pts had not acquired any of the evaluated alterations.cFisher's exact testdIncludes T790M; the frequencies of TE T790M in RAM+ERL v PBO+ERL for Pop1 were 42% v 50%, respectively, and for Pop2, 19% v 25% Citation Format: Edward Garon, Martin Reck, Kazuto Nishio, John Victor Heymach, Makoto Nishio, Silvia Novello, Luis Paz-Ares, Sanjay Popat, Santiago Ponce Aix, Sameera Wijayawardana, Rebecca R. Hozak, Carla Visseren-Grul, Kazuhiko Nakagawa. RELAY, ramucirumab plus erlotinib (RAM+ERL) versus placebo plus erlotinib (PBO+ERL) in previously untreated EGFR mutation-positive metastatic NSCLC: Next generation sequencing (NGS) results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT215.

9527 Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p

Purpose: Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab. Patients and Methods: A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC). Results: A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non–small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug–drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64–8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression. Conclusions: Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.

Background RANGE previously reported positive progression-free survival1 and a trend towards improved overall survival (OS)2 in ramucirumab (RAM) treated patients. Exploratory biomarker analysis of efficacy by programmed death-ligand 1 (PD-L1) expression revealed a hazard ratio (HR) for OS of 0.519, p = 0.0048 in patients with a PD-L1 combined positive score (CPS)≥10 compared to HR of 0.999, p = 0.9955 in patients with a PD-L1 CPS Methods Archival tumour specimens that met assay stability requirements (238/530 ITT patients in RANGE) were analyzed with the 22C3 PD-L1 antibody with CPS based on tumour cell (TC) and immune cell (IC) staining. RNA expression analysis on archival tumour tissue (394/530 ITT patients) was done by GenomeDx (RNA microarray)3. PD-L1 groups, urothelial carcinoma molecular subtypes, and immune4 and stromal phenotypes5 were determined and analyzed for association with OS outcome. Results Overall, RAM had the greatest improvement in OS in patients with TC ≥ 1, IC ≥ 4 or CPS≥10 PD-L1 status. OS was also more improved in patients with basal subtypes, with considerable overlap noted between basal subtypes and TC ≥ 1, IC ≥ 4, or CPS ≥10 PD-L1 status. In the subgroup with both basal/basal claudin-low subtype and CPS≥10 PD-L1 status, median OS was 9.2 months with RAM and 6.0 months with placebo (stratified hazard ratio 0.47; 95% confidence interval: 0.27-0.84, p = 0.01, n = 79). Conclusions Our analysis suggested significant improvement in OS in RAM treated patients with platinum refractory urothelial carcinoma, and with both basal subtype and positive PD-L1 status. References: 1Petrylak et al, Lancet 2017; 390:2266-77; 2Petrylak et al, Ann Oncol 2018; 29:viii304-5; 3Seiler et al, Eur Urol 2017; 72:544-54; 4Charoentong et al, Cell Rep 2017; 18:248-62; 5Uhlik et al Cancer Res 2016; 76:2573-86. Clinical trial identification NCT02426125. Editorial acknowledgement Lisa Cossens and Antonia Baldo of Syneos Health, funded by Eli Lilly and Company. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure T.B. Powles: Research grant / Funding (self), Personal fees: Roche; Research grant / Funding (self), Personal fees: AZ; Licensing / Royalties, Personal fees: Merck; Licensing / Royalties, Personal fees: Eli Lilly and Company; Licensing / Royalties, Personal fees: BMS; Licensing / Royalties, Personal fees: Pfizer. D.P. Petrylak: Research grant / Funding (self): Eli Lilly and Company; Licensing / Royalties, Personal fees: Bayer; Research grant / Funding (self), Licensing / Royalties, Personal fees: Bellicum; Research grant / Funding (self), Licensing / Royalties, Personal fees: Dendreon; Research grant / Funding (self), Licensing / Royalties, Personal fees: Sanofi Aventis; Research grant / Funding (self), Licensing / Royalties, Personal fees: Johnson and Johnson; Licensing / Royalties, Personal fees: Exelixis; Licensing / Royalties, Personal fees: Ferring; Research grant / Funding (self), Licensing / Royalties, Personal fees: Millineum; Licensing / Royalties, Personal fees: Medivation; Licensing / Royalties, Personal fees: Pfizer; Research grant / Funding (self), Licensing / Royalties, Personal fees: Roche Laboratories; Research grant / Funding (self), Licensing / Royalties, Personal fees: Tyme Pharmaceuticals; Research grant / Funding (self): Oncogenix; Research grant / Funding (self): Progenics; Research grant / Funding (self): Merck; Research grant / Funding (self): Agensys. R. de Wit: Licensing / Royalties: Eli Lilly and Company; Licensing / Royalties: Merck; Licensing / Royalties: Roche; Licensing / Royalties: Sanofi. K.N. Chi: Research grant / Funding (institution): Eli Lilly and Company. A. Necchi: Research grant / Funding (self), Licensing / Royalties, Non-remunerated activity/ies: Roche; Licensing / Royalties: Merck; Licensing / Royalties: AstraZeneca; Licensing / Royalties: Seattle Genetics; Licensing / Royalties: Bayer. C.N. Sternberg: Licensing / Royalties: Eli Lilly and Company; Licensing / Royalties: BMS; Licensing / Royalties: Merck/Pfizer; Licensing / Royalties: Clovis. S.A. Hussain: Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS. A. Bamias: Licensing / Royalties: AstraZeneca; Licensing / Royalties: BMS; Research grant / Funding (self), Licensing / Royalties: Roche. M.S. Xia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. E. Rasmussen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company.A. Aggarwal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S.R. Wijayawardana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. K. Bell-McGuinn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. All other authors have declared no conflicts of interest.

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Background The RELAY (NCT02411448) phase III study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for ERL plus RAM (RAM+ERL) versus ERL plus PL (PL+ERL) in patients with previously untreated EGFR mutation (mut)-positive (EGFR exon 19 deletion or exon 21 mut (L858R)) mNSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p Methods Plasma samples were collected before and during treatment (Baseline, Cycle 4, 13 and every 6 cycles up to Cycle 53) as well as post-discontinuation (the 30-day follow-up). Isolated ctDNA of plasma were subjected to droplet digital PCR (ddPCR) to determine EGFR mut status. Statistical analyses for T790M were performed for the population of patients with disease progression who had valid results from baseline and 30 day follow-up. Results The ddPCR population included 42 patients and had a similar PFS HR (0.61, 95% CI 0.33-1.15) to the full ITT population. The rates of EGFR T790M mut positivity at the 30-day follow-up were not different between treatment groups: 26% (5 of 19) (95% CI 12-49%) in RAM+ERL and 30% (7 of 23) (95% CI, 16-51%) in PL+ERL (p = 1.0). When evaluating the cumulative post-progression T790M rates according to the number of cycles received prior to disease progression, the rates for patients who had progressed by Cycle 4, Cycle 12, or Cycle 53 were 0%, 17% and 26% for RAM+ERL, and 0%, 33%, and 30% for PL+ERL, suggesting that RAM+ERL potentially may delay the occurrence of resistance by the T790M mutation. Conclusions Treatment with RAM+ERL resulted in superior PFS, with similar T790M rates at progression as compared to PL+ERL, suggesting the potential for effective EGFR-directed therapy after progression on RAM+ERL. Clinical trial identification NCT02411448. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure K. Nishio: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly Japan K.K.; Research grant / Funding (institution): Ignyta,Inc.; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co.,Ltd.; Speaker Bureau / Expert testimony: Eisai Co., Ltd.; Speaker Bureau / Expert testimony: Pfizer Inc.; Speaker Bureau / Expert testimony: Novartis Pharma K.K.; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Company; Speaker Bureau / Expert testimony: SymBio Pharmaceuticals Limited. ; Speaker Bureau / Expert testimony: Life Technologies Japan Ltd.; Speaker Bureau / Expert testimony: Solasia Pharma K.K. ; Speaker Bureau / Expert testimony: Yakult Honsha Co., Ltd.; Speaker Bureau / Expert testimony: Roche Diagnostics K.K. K. Sakai: Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co.; Speaker Bureau / Expert testimony: Roche Diagnostics K.K.; Speaker Bureau / Expert testimony: SRL. T. Seto: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Research grant / Funding (institution): Pfizer Japan; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self): Thermo Fisher Scientific; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): LOXO Oncology; Research grant / Funding (institution): Kissei Pharmaceutical. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer-ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono. M. Reck: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche. E.B. Garon: Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Neon; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Mirati; Advisory / Consultancy: Dracen; Honoraria (self), Personal Fee for Steering Committee: EMD Serono. C.M. Visseren-Grul: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. R.R. Hozak: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. S.R. Wijayawardana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. S. Enatsu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly & Co. K. Nakagawa: Research grant / Funding (institution): MSD K.K., Icon Japan K.K., Takeda Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb Company, Taiho Pharmaceutical Co.,Ltd., Parexel International Corp., Ono Pharmaceutical Co.,Ltd., IQVIA., A2 Healthcare Corp., AbbVie Inc., ; Research grant / Funding (institution): Chugai Pharmaceutical Co.,Ltd., SymBio Pharmaceuticals Limited., Merck Serono Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., Novartis Pharma K.K., Quintiles Inc., CMIC Shift Zero K.K., Eisai Co., Ltd., Nippon Boehringer Ingelheim Co.,Ltd., ; Research grant / Funding (institution): Kissei Pharmaceutical Co.,Ltd., Pfizer Japan Inc., Kyowa Hakko Kirin Co.,Ltd., EPS Corporation., Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd. ; Honoraria (institution): Astellas Pharma Inc., AstraZeneca K.K. MSD K.K., Ono Pharmaceutical Co.,Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bristol-Myers Squibb Company, Kyorin Pharmaceutical Co.,Ltd., CareNet,Inc, Nichi-Iko Pharmaceutical Co., Ltd., ; Honoraria (institution): Hisamitsu Pharmaceutical Co.,Inc., Yodosha Co., LTD., Takeda Pharmaceutical Co.,Ltd., Chugai Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co.,Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Nikkei Business Publications, Inc., ; Honoraria (institution): Medicus Shuppan, Publishers Co., Ltd., Thermo Fisher Scientific K.K., Nanzando Co.,Ltd, Medical Review Co., Ltd., Yomiuri Telecasting Corporation; Advisory / Consultancy: Astellas Pharma Inc., Takeda Pharmaceutical Co.,Ltd. Linguistic correction

BACKGROUND: Mutations in PIK3CA and ESR1 have been implicated in resistance to endocrine therapy in HR+ metastatic breast cancer. Herein, we assessed the clinical significance of PIK3CA and ESR1 mutations from ctDNA and FFPE samples from patients treated with abemaciclib plus fulvestrant and placebo plus fulvestrant. METHODS: Baseline plasma samples (n = 334) and FFPE tumor samples (n = 434) from 669 patients enrolled in MONARCH 2 were analyzed. Extracted DNA was analyzed by droplet digital PCR for four hotspot mutations of PIK3CA (E542K; E545K; H1047L; H1047R) and ESR1 (D538G; Y537C; Y537N; Y537S). Samples that failed DNA QC or where mutation status could not be determined were excluded from analysis. RESULTS: PIK3CA mutations were detected in 96 (40.3%) of 238 plasma samples and 133 (39.9%) of 333 FFPE samples. H1047R was the most frequent mutation followed by E545K, E542K, and H1047L. The concordance of PIK3CA mutations in ctDNA and FFPE samples was 62.8%. ESR1 mutations were detected in 190 (64.4%) of 295 plasma samples and 15 (4.4%) of 344 FFPE samples. D538G was the most frequent mutation followed by Y537C, Y537N, and Y537S. The concordance of ESR1 mutations in ctDNA and FFPE samples was 37.1%; this rate of detection of ESR1 mutations in ctDNA and FFPE samples is explained in part by the site of the biopsy (primary vs metastatic). Co-mutations in PIK3CA and ESR1 were observed in 86 (36.1%) plasma and 5 (1.5%) FFPE samples. Finally, we examined the relationship of PIK3CA and ESR1 mutation status and benefit from abemaciclib therapy as shown in Table 1. CONCLUSIONS: PIK3CA and ESR1 mutations in ctDNA but not in archived FFPE samples correlated with response to abemaciclib, confirming the potential use of ctDNA analysis. The addition of abemaciclib to fulvestrant in MONARCH 2 demonstrated improvement in PFS regardless of PIK3CA or ESR1 status; however, the magnitude of benefit was numerically greater for patients with tumors harboring PIK3CA/ESR1 mutations. Table 1.Abemaciclib + FulvestrantPlacebo + FulvestrantMutation Status (Plasma)nMedian PFS (95% CI)nMedian PFS (95% CI)Hazard Ratio (95% CI)PIK3CA wild-type9120 (14, NA)5112.7 (7.9, NA)0.68 (0.42, 1.09)PIK3CA mutant5815 (9.4, NA)385.7 (3.8, 15)0.46 (0.27, 0.78)ESR1 wild-type7216.3 (12.4, 22.8)3311.6 (7.4, 23.1)0.69 (0.41, 1.18)ESR1 mutant11821.9 (15, NA)7210.3 (5.7, 15.6)0.49 (0.33, 0.73) Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Lacey M. Litchfield, Sameera Wijayawardana, Tammy Forrester, Valerie M. Jansen, George W. Sledge. Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4458.

9059Background: Abemaciclib is a potent and selective inhibitor of CDK4 & 6 approved for treatment of HR+, HER2- metastatic breast cancer. In a Phase 1 study, abemaciclib showed activity in pts wit...