Journal article
Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR -mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903)
Clinical cancer research, Vol.27(6), pp.1604-1611
03/15/2021
DOI: 10.1158/1078-0432.CCR-20-4084
PMCID: PMC7976451
PMID: 33376097
Abstract
Osimertinib is an effective therapy in
-mutant non-small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of
-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance.
This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced
-mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily.
A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia.
Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.
Details
- Title: Subtitle
- Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR -mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903)
- Creators
- Erin M Bertino - The Ohio State UniversityRyan D Gentzler - University of VirginiaSarah Clifford - Dana-Farber Cancer InstituteJill Kolesar - University of KentuckyAlona Muzikansky - Massachusetts General HospitalEric B Haura - Moffitt Cancer CenterZofia Piotrowska - Massachusetts General HospitalD Ross Camidge - University of Colorado HospitalThomas E Stinchcombe - Duke Medical CenterChristine Hann - Sidney Kimmel Cancer CenterJyoti Malhotra - Rutgers, The State University of New JerseyLiza C Villaruz - UPMC Hillman Cancer CenterCloud P Paweletz - Dana-Farber Cancer InstituteChristie L Lau - Dana-Farber Cancer Institute, Boston, MassachusettsLynette Sholl - Brigham and Women's HospitalNaoko Takebe - National Cancer InstituteJeffrey A Moscow - National Cancer InstituteGeoffrey I Shapiro - Dana-Farber Cancer InstitutePasi A Jänne - Dana-Farber Cancer InstituteGeoffrey R Oxnard - Dana-Farber Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.27(6), pp.1604-1611
- DOI
- 10.1158/1078-0432.CCR-20-4084
- PMID
- 33376097
- PMCID
- PMC7976451
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- R35 CA220497 / NCI NIH HHS UM1 CA186709 / NCI NIH HHS UM1 CA186690 / NCI NIH HHS UM1 CA186712 / NCI NIH HHS
- Language
- English
- Date published
- 03/15/2021
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695795602771
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