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E.B. Garon
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O03 - NSCLC - Targeted Therapies I (ID 113)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Ross, J.C. Yang
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
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O03.06 - First-In-Human Evaluation of CO-1686, an Irreversible, Highly, Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) (ID 1354)
11:25 - 11:35 | Author(s): E.B. Garon
- Abstract
- Presentation
Background
Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.Methods
This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.Results
As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1Conclusion
CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)
- Event: WCLC 2013
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:M. Boyer, K. Fong
- Coordinates: 10/29/2013, 08:15 - 09:45, Plenary Hall, Ground Level
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PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)
09:21 - 09:33 | Author(s): E.B. Garon
- Abstract
Background
Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.Methods
Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.Results
Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).Conclusion
Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.
