Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903)

Erin M. Bertino; Ryan D. Gentzler; Sarah Clifford; Jill Kolesar; Alona Muzikansky; Eric B. Haura; Zofia Piotrowska; D. Ross Camidge; Thomas E. Stinchcombe; Christine Hann; Jyoti Malhotra; Liza C. Villaruz; Cloud P. Paweletz; Christie L. Lau; Lynette Sholl; Naoko Takebe; Jeffrey A. Moscow; Geoffrey I. Shapiro; Pasi A. Janne; Geoffrey R. Oxnard

doi:10.1158/1078-0432.CCR-20-4084

Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903)

Erin M. Bertino, Ryan D. Gentzler, Sarah Clifford, Jill Kolesar, Alona Muzikansky, Eric B. Haura, Zofia Piotrowska, D. Ross Camidge, Thomas E. Stinchcombe, Christine Hann, Jyoti Malhotra, Liza C. Villaruz, Cloud P. Paweletz, Christie L. Lau, Lynette Sholl, Naoko Takebe, Jeffrey A. Moscow, Geoffrey I. Shapiro, Pasi A. Janne, Geoffrey R. Oxnard

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Purpose: Osimertinib is an effective therapy in EGFR-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 EGFRmutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: 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 EGFR-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. Results: A total of 27 patients were enrolled (18 in the doseescalation 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. Conclusions: 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.

Original language	English
Pages (from-to)	1604-1611
Number of pages	8
Journal	Clinical Cancer Research
Volume	27
Issue number	6
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4084
State	Published - Mar 2021

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.

Funding

This study was approved by the NCI-CTEP and funded by NCI grant UM1 CA186709 (to G.I. Shapiro), an NCI-CTEP UM1 CA 186709 Biomarker Supplement (to G.R. Oxnard and C.P. Paweletz), the Dana-Farber Cancer Institute-Brigham and Women's Hospital UM1 CA 186709 Biomarker/Molecular Characterization Hub (to L. Sholl), as well as NIH grant NIH R35 - R35CA220497 (to P.A. J€anne), and Damon Runyon Cancer Research Foundation grant CI-86–16 (to G.R. Oxnard). Additional funding in part from the Expect Miracles Foundation (to C.P. Paweletz) and the Robert and RenéBelfer Foundation (C.P. Paweletz). E.M. Bertino reports grants from NCI UM1 during the conduct of the study, as well as personal fees from Pfizer and nonfinancial support from Lilly, Merck, and Intellosphere outside the submitted work. R.D. Gentzler reports grants and nonfinancial support from NCI during the conduct of the study; grants from Pfizer, Merck, Bristol Myers Squibb, Takeda, Helsinn, and Jounce Therapeutics; personal fees and nonfinancial support from AstraZeneca, Pfizer, and Rockpointe CME; nonfinancial support from Syndax; personal fees from BluePrint Medicines, Targeted Oncology, and OncLive outside the submitted work. S. Clifford reports other from Foundation Medicine outside the submitted work. J. Kolesar reports grants from NCI during the conduct of the study, as well as grants from ArtemiFlow and nonfinancial support from ArtemiFlow and Helix Diagnostics outside the submitted work. E.B. Haura reports personal fees from Janssen and Amgen outside the submitted work. D.R. Camidge reports personal fees from Amgen, Anchiarno (SAB), Apollomics (SRC), AstraZeneca, Bio-Thera (DSMB), BMS, Daiichi-Sankyo (ILD adjudication committee), EMD Serono, Elevation (SRC), Eli Lilly, GSK, Helssin, Janssen, Onkure, Mersana, Pfizer, Qilu, Roche, Sanofi, Seattle Genetics, and Takeda outside the submitted work; and reports company sponsored trials at institution (PI roles), 2018–20: Abbvie, AstraZeneca, BMS, GSK, Hansoh, Inhibrx, Karyopharm, Lycera, Medimmune, Merck, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Symphogen, Takeda, and Tolero. T.E. Stinchcombe reports personal fees from AstraZeneca, Takeda, Genentech/Roche, Foundation Medicine, Pfizer, EMD Serono, Novartis, Daiichi Sankyo, Lilly, Medtronic, and Puma Biotechnology and grants from Genentech/Roche, Blueprint Medicines, AstraZeneca, Takeda, Advaxis, and Regeneron outside the submitted work. C. Hann reports grants and personal fees from AstraZeneca and AbbVie; grants from Amgen and GSK; personal fees from Ascentage;grants,personal fees, andotherfrom Genentech/RocheandBMS outside the submitted work. J. Malhotra reports personal fees from AstraZeneca and Blueprint and grants from Biohaven Pharma, Bristol Meyers Squibb, Beyond Spring Pharmaceuticals, and Celldex outside the submitted work. L. Sholl reports personal fees from EMD Serono, Foghorn Therapeutics, and AstraZeneca and grants from Genentech outside the submitted work. G.I. Shapiro reports grants and personal fees from Eli Lilly, Merck KGaA/EMD-Serono, Sierra Oncology, and Pfizer; grants from Merck & Co.; personal fees from G1 Therapeutics, Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Concarlo Holdings, Syros, Zentalis, and CytomX Therapeutics outside the submitted work; in addition, G.I. Shapiro has a patent for Dosage regimen for sapacitabine and seliciclib issued to Cyclacel Pharmaceuticals and has a patent for Compositions and methods for predicting response and resistance to CDK4/6 inhibition pending to Liam Cornell and Geoffrey Shapiro. P.A. J€anne reports grants and personal fees from AstraZeneca and personal fees from Abbvie during the conduct of the study; grants and personal fees from Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, and Takeda Oncology; personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Ignyta, Loxo Oncology, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi Oncology, Mirati Therapeutics, Transcenta, Silicon Therapeutics, and Syndax; grants from Revolution

Funders	Funder number
Biohaven Pharma
Dana-Farber Cancer Institute-Brigham
Expect Miracles Foundation
NCI-CTEP
RenéBelfer Foundation
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	UM1 CA186709, R35CA220497
National Childhood Cancer Registry – National Cancer Institute
Damon Runyon Cancer Research Foundation	CI-86–16
Damon Runyon Cancer Research Foundation
AMGen
Bristol-Myers Squibb
Eli Lilly and Company
Pfizer
AstraZeneca
GlaxoSmithKline
Merck
AbbVie
Takeda Pharmaceuticals U.S.A.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-20-4084

Cite this

Bertino, E. M., Gentzler, R. D., Clifford, S., Kolesar, J., Muzikansky, A., Haura, E. B., Piotrowska, Z., Ross Camidge, D., Stinchcombe, T. E., Hann, C., Malhotra, J., Villaruz, L. C., Paweletz, C. P., Lau, C. L., Sholl, L., Takebe, N., Moscow, J. A., Shapiro, G. I., Janne, P. A., & Oxnard, G. R. (2021). Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903). Clinical Cancer Research, 27(6), 1604-1611. https://doi.org/10.1158/1078-0432.CCR-20-4084

@article{ab76eeff4f874c97b015bd1fc5f92ae5,

title = "Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903)",

abstract = "Purpose: Osimertinib is an effective therapy in EGFR-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 EGFRmutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: 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 EGFR-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. Results: A total of 27 patients were enrolled (18 in the doseescalation 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. Conclusions: 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.",

author = "Bertino, {Erin M.} and Gentzler, {Ryan D.} and Sarah Clifford and Jill Kolesar and Alona Muzikansky and Haura, {Eric B.} and Zofia Piotrowska and {Ross Camidge}, D. and Stinchcombe, {Thomas E.} and Christine Hann and Jyoti Malhotra and Villaruz, {Liza C.} and Paweletz, {Cloud P.} and Lau, {Christie L.} and Lynette Sholl and Naoko Takebe and Moscow, {Jeffrey A.} and Shapiro, {Geoffrey I.} and Janne, {Pasi A.} and Oxnard, {Geoffrey R.}",

year = "2021",

month = mar,

doi = "10.1158/1078-0432.CCR-20-4084",

language = "English",

volume = "27",

pages = "1604--1611",

number = "6",

}

Bertino, EM, Gentzler, RD, Clifford, S, Kolesar, J, Muzikansky, A, Haura, EB, Piotrowska, Z, Ross Camidge, D, Stinchcombe, TE, Hann, C, Malhotra, J, Villaruz, LC, Paweletz, CP, Lau, CL, Sholl, L, Takebe, N, Moscow, JA, Shapiro, GI, Janne, PA & Oxnard, GR 2021, '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, no. 6, pp. 1604-1611. https://doi.org/10.1158/1078-0432.CCR-20-4084

TY - JOUR

T1 - Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903)

AU - Bertino, Erin M.

AU - Gentzler, Ryan D.

AU - Clifford, Sarah

AU - Kolesar, Jill

AU - Muzikansky, Alona

AU - Haura, Eric B.

AU - Piotrowska, Zofia

AU - Ross Camidge, D.

AU - Stinchcombe, Thomas E.

AU - Hann, Christine

AU - Malhotra, Jyoti

AU - Villaruz, Liza C.

AU - Paweletz, Cloud P.

AU - Lau, Christie L.

AU - Sholl, Lynette

AU - Takebe, Naoko

AU - Moscow, Jeffrey A.

AU - Shapiro, Geoffrey I.

AU - Janne, Pasi A.

AU - Oxnard, Geoffrey R.

PY - 2021/3

Y1 - 2021/3

N2 - Purpose: Osimertinib is an effective therapy in EGFR-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 EGFRmutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: 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 EGFR-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. Results: A total of 27 patients were enrolled (18 in the doseescalation 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. Conclusions: 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.

AB - Purpose: Osimertinib is an effective therapy in EGFR-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 EGFRmutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: 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 EGFR-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. Results: A total of 27 patients were enrolled (18 in the doseescalation 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. Conclusions: 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.

UR - http://www.scopus.com/inward/record.url?scp=85102356072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102356072&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-4084

DO - 10.1158/1078-0432.CCR-20-4084

M3 - Article

C2 - 33376097

AN - SCOPUS:85102356072

SN - 1078-0432

VL - 27

SP - 1604

EP - 1611

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 6

ER -

Phase IB study of osimertinib in combination with navitoclax in egfr-mutant nsclc following resistance to initial EGFR Therapy (ETCTN 9903)

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this