Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)

E.C. Dees, P.G. Aftimos, C. W. Menke, E.G.E. De Vries, P Neven, M.D. Pegram, R Iqbal, J. Boers, J. Xiao, C. Sipes, C. Li, J.A. Sorrentino, R Malik, A.P. Beelen

Research output: Contribution to journalMeeting AbstractAcademic

Abstract

Background
The SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC.

Methods
Postmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose.

Results
Currently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant).

Conclusions
The oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270).
Original languageEnglish
JournalAnnals of Oncology
Volume30
Issue numberSupplement 5
DOIs
Publication statusPublished - 1 Oct 2019

Cite this

Dees, E.C. ; Aftimos, P.G. ; Menke, C. W. ; De Vries, E.G.E. ; Neven, P ; Pegram, M.D. ; Iqbal, R ; Boers, J. ; Xiao, J. ; Sipes, C. ; Li, C. ; Sorrentino, J.A. ; Malik, R ; Beelen, A.P. / Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC). In: Annals of Oncology. 2019 ; Vol. 30, No. Supplement 5.
@article{d6a743f326784541891d1abe3e2ce957,
title = "Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)",
abstract = "BackgroundThe SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC.MethodsPostmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose.ResultsCurrently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45{\%}, fulvestrant in 91{\%}, and CDK4/6i in 54{\%} of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27{\%} each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70{\%} (200 mg) to 88{\%} (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant).ConclusionsThe oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270).",
author = "E.C. Dees and P.G. Aftimos and Menke, {C. W.} and {De Vries}, E.G.E. and P Neven and M.D. Pegram and R Iqbal and J. Boers and J. Xiao and C. Sipes and C. Li and J.A. Sorrentino and R Malik and A.P. Beelen",
year = "2019",
month = "10",
day = "1",
doi = "10.1093/annonc/mdz242",
language = "English",
volume = "30",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "Supplement 5",

}

Dees, EC, Aftimos, PG, Menke, CW, De Vries, EGE, Neven, P, Pegram, MD, Iqbal, R, Boers, J, Xiao, J, Sipes, C, Li, C, Sorrentino, JA, Malik, R & Beelen, AP 2019, 'Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)' Annals of Oncology, vol. 30, no. Supplement 5. https://doi.org/10.1093/annonc/mdz242

Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC). / Dees, E.C. ; Aftimos, P.G. ; Menke, C. W.; De Vries, E.G.E. ; Neven, P; Pegram, M.D.; Iqbal, R; Boers, J.; Xiao, J.; Sipes, C.; Li, C.; Sorrentino, J.A.; Malik, R; Beelen, A.P.

In: Annals of Oncology, Vol. 30, No. Supplement 5, 01.10.2019.

Research output: Contribution to journalMeeting AbstractAcademic

TY - JOUR

T1 - Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)

AU - Dees, E.C.

AU - Aftimos, P.G.

AU - Menke, C. W.

AU - De Vries, E.G.E.

AU - Neven, P

AU - Pegram, M.D.

AU - Iqbal, R

AU - Boers, J.

AU - Xiao, J.

AU - Sipes, C.

AU - Li, C.

AU - Sorrentino, J.A.

AU - Malik, R

AU - Beelen, A.P.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - BackgroundThe SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC.MethodsPostmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose.ResultsCurrently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant).ConclusionsThe oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270).

AB - BackgroundThe SERD fulvestrant is a well-established therapy for ER+/HER2- ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC.MethodsPostmenopausal women with ER+/HER2- ABC following progression on endocrine therapy are eligible for this 3 + 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES-PET, and anti-tumor efficacy, and to determine the recommended phase 2 dose.ResultsCurrently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200-800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45%, fulvestrant in 91%, and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48-related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48-related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg), and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES-PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg)) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1), 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD ≥ 24 weeks (200 mg, prior abemaciclib/fulvestrant).ConclusionsThe oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2- ABC. Early efficacy, safety, PK, and FES-PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti-tumor activity, and cfDNA data will be presented (NCT#03455270).

U2 - 10.1093/annonc/mdz242

DO - 10.1093/annonc/mdz242

M3 - Meeting Abstract

VL - 30

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - Supplement 5

ER -