Darrin Despain

Rociletinib in EGFR-mutated non-small-cell lung cancer.

BACKGROUND Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)

Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386–95. ©2016 AACR.

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

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

Abstract 927: Pretreatment and serial plasma assessments of EGFR mutations in NSCLC patients treated with rociletinib (CO-1686)

Background: EGFR mutation testing is required to identify patients who may respond to TKI therapy. However, tumor biopsies from NSCLC patients can pose challenges for molecular analyses due to inadequate sample material, the inability to biopsy patients due to poor health status or inaccessible lesions, and tumor heterogeneity. We examined the detection of EGFR mutations in circulating cell-free DNA (cfDNA) from plasma and the concordance of EGFR mutation status with contemporaneously matched tumor tissue in TIGER-X, a Phase 1/2 clinical study of rociletinib (CO-1686) in previously treated advanced NSCLC patients harboring EGFR mutations in their tumors. Rociletinib is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M, L858R and Del(19), while sparing wild-type EGFR. Methods: Pretreatment matched tumor tissue and plasma from 139 Stage IIIB/IV NSCLC patients enrolled in TIGER-X were evaluated for EGFR status. Tumor tissue was processed as FFPE and tested by allele-specific PCR. Plasma was tested as a two mL aliquot using BEAMing, a quantitative and sensitive detection technology based on digital PCR. Results: Using tissue as the reference, the positive percent agreement between tumor and BEAMing plasma test results was 86% (102/119) for activating mutations and 77% (78/101) for T790M. Four plasma samples of the 23 tumor T790M+/plasma T790M- cases were also tested by three independent plasma testing platforms with claimed analytical sensitivities of Conclusions: The BEAMing plasma test identified EGFR mutations detected in tumor with high sensitivity. In addition, plasma testing identified T790M+ patients that were determined T790M- by the tumor test, which may be in part explained by tumor heterogeneity and/or inadequate biopsy. These findings demonstrate that BEAMing can be a useful tool for the non-invasive assessment of EGFR mutations in NSCLC. Citation Format: Jonathan W. Goldman, Chris Karlovich, Elaina Mann, Lindsey Rolfe, Shannon Matheny, Darrin Despain, Philipp Angenendt, Claudia Stamm, Heather A. Wakelee, Jean-Charles Soria, Benjamin Solomon, D. R. Camidge, Rafal Dziadziuszko, Leora Horn, Shirish Gadgeel, Mitch Raponi, Andrew R. Allen, Lecia V. Sequist. Pretreatment and serial plasma assessments of EGFR mutations in NSCLC patients treated with rociletinib (CO-1686). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 927. doi:10.1158/1538-7445.AM2015-927

Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor

&NA; We profiled 77 non–small‐cell lung cancer patients with paired baseline and progression blood samples treated with the third‐generation EGFR tyrosine kinase inhibitor (TKI) rociletinib using a broad cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) gene panel. We demonstrated a utility of cfDNA NGS to detect EGFR T790M and predict response comparable to tissue‐based tests, even at low allele fractions, and we identified resistance mechanisms. Our findings highlight the genomic heterogeneity observed in disease after progression while receiving therapy with a third‐generation EGFR TKI. Introduction: The genomic alterations driving resistance to third‐generation EGFR tyrosine kinase inhibitors (TKIs) are not well established, and collecting tissue biopsy samples poses potential complications from invasive procedures. Cell‐free circulating DNA (cfDNA) testing provides a noninvasive approach to identify potentially targetable mechanisms of resistance. Here we utilized a 70‐gene cfDNA next‐generation sequencing test to interrogate pretreatment and progression samples from 77 EGFR‐mutated non‐small cell lung cancer (NSCLC) patients treated with a third‐generation EGFR TKI. Patients and Methods: Rociletinib was evaluated in advanced or metastatic (second line or higher) disease with EGFR T790M‐positive NSCLC in the TIGER‐X (NCT01526928) and TIGER‐2 (NCT02147990) studies. Plasma samples were collected at baseline and at the time of systemic progression while receiving rociletinib. The critical exons in 70 genes were sequenced in cfDNA isolated from plasma samples to elucidate a comprehensive genomic profile of alterations for each patient. Results: Plasma‐based cfDNA analysis identified 93% of the initial EGFR activating and 85% of the EGFR T790M resistance mutations in pretreatment samples with detectable tumor DNA. Profiling of progression samples revealed significant heterogeneity, with different variant types (eg, mutations, amplifications, and fusions) detected in multiple genes (EGFR, MET, RB1) that may be driving resistance in patients. Novel alterations not previously described in association with resistance to third‐generation TKIs were also detected, such as an NTRK1 fusion. Conclusion: cfDNA next‐generation sequencing identified initial EGFR activating and secondary T790M resistance mutations in NSCLC patients with high sensitivity, predicted treatment response equivalent to tissue analysis, and identified multiple novel and established resistance alterations.