rintodestrant (G1T48) / University of Illinois - LARVOL DELTA

Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review. (PubMed, Cancer Treat Rev) - "Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies."

Journal • Review • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer. (PubMed, Pharmacol Res) - P1 | "In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways...This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

[18F]FDG and [18F]FES PET/CT Imaging as a Biomarker for Therapy Effect in Patients with Metastatic ER+ Breast Cancer Undergoing Treatment with Rintodestrant. (PubMed, Clin Cancer Res) - P1 | "Absence of ER expression on [18F]FES PET is a predictor for no response to rintodestrant. [18F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs."

Biomarker • Journal • Metastases • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=107 | Completed | Sponsor: G1 Therapeutics, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=107 | Active, not recruiting | Sponsor: G1 Therapeutics, Inc. | Trial completion date: Mar 2024 ➔ Sep 2022 | Trial primary completion date: May 2022 ➔ Sep 2022

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1; N=107; Active, not recruiting; Sponsor: G1 Therapeutics, Inc.; Trial primary completion date: Jan 2022 ➔ May 2022

Clinical • Combination therapy • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer. (PubMed, Expert Opin Investig Drugs) - "Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties...Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant...Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further..."

Journal • Breast Cancer • Endocrine Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

[VIRTUAL] Rintodestrant (G1T48), an oral selective estrogen receptor degrader, in combination with palbociclib for ER+/HER2– advanced breast cancer: Phase 1 results. (ASCO 2021) - P1 | "Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%) . Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants."

Combination therapy • P1 data • Anemia • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • ER • HER-2

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) (ESMO 2019) - P1; "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). 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)."

Clinical

[VIRTUAL] Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection (SABCS 2020) - P1 | "Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Conclusions : Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270)."

P1 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

[VIRTUAL] Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer (SABCS 2020) - P1 | " The present analyses include data from two studies: (1) G1T48-01, a Phase 1 first-in-human study of rintodestrant monotherapy (200-1000 mg once daily [QD]) in women with ER+/HER2- ABC after progression on endocrine therapy (NCT03455270), and (2) G1T48-10, a study in healthy volunteers investigating potential drug-drug interactions between rintodestrant (200 mg QD) and palbociclib (125 mg QD). A population PK model was developed and Ex/Re relationship analyses were performed to support the development of rintodestrant for the treatment of patients with ER+ breast cancer. Initial results identified an Ex/Re relationship with target ER engagement via FES-PET analysis."

Clinical • PK/PD data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CTCs • ER • HER-2 • TMB

[VIRTUAL] Pharmacodynamic analysis from a Phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer (SABCS 2020) - P1 | "Conclusions : Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270)."

P1 data • PK/PD data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ER • HER-2 • PIK3CA • PTPRC • TP53

Biodistribution of F-FES in patients with metastatic ER+ breast cancer undergoing treatment with Rintodestrant (G1T48), a novel selective estrogen receptor degrader. (PubMed, J Nucl Med) - "This indicates that rintodestrant alters the kinetics of the tracer which could affect interpretation and quantification of F-FES uptake. Of note, ≥6 days after ending treatment with rintodestrant, the biodistribution returned to baseline values, consistent with recovery of ER availability after wash-out of the drug."

Clinical • Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

G1 Therapeutics Presents Phase 1 Data at ASCO Describing Favorable Safety Profile and Evidence of Antitumor Activity of Rintodestrant Combined with Palbociclib in Patients with ER+/HER2- Advanced Breast Cancer (GlobeNewswire) - P1, N=107; NCT03455270; Sponsor: G1 Therapeutics, Inc.; "G1 Therapeutics, Inc...presented results from its Phase 1 study...rintodestrant, demonstrating the drug was very well tolerated and did not result in additional or more severe toxicities when added to palbociclib for the treatment of ER+/HER2- advanced breast cancer. In addition, encouraging antitumor activity was observed in the study...from 30 percent with rintodestrant monotherapy to 60 percent with the combination of rintodestrant and palbociclib. This effect included patients with tumors harboring ESR1 variants, which are known to modulate breast cancer severity and resistance to hormone therapy."

P1 data • Breast Cancer • HER2 Negative Breast Cancer • Oncology

G1 Therapeutics Announces Upcoming Data at the American Society of Clinical Oncology (ASCO) Virtual 2021 Annual Meeting (GlobeNewswire) - “G1 Therapeutics, Inc…announced upcoming data presentations at the American Society of Clinical Oncology (ASCO) annual meeting, being held virtually June 4th through 8th. The presentations will describe results from the Company’s study of its oral selective estrogen receptor degrader (SERD), rintodestrant, in combination with palbociclib for the treatment of ER+/HER2- advanced breast cancer as well as data describing the effects of COSELA™ (trilaciclib) on T-cell activation and clonal expansion in patients with newly diagnosed extensive-stage small cell lung cancer. A copy of the posters will be made available on the G1 corporate website on June 4, 2021.”

Clinical data • Breast Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Triple Negative Breast Cancer

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1; N=107; Active, not recruiting; Sponsor: G1 Therapeutics, Inc.; Recruiting ➔ Active, not recruiting; N=184 ➔ 107

Clinical • Combination therapy • Enrollment change • Enrollment closed • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

G1 Therapeutics Provides Third Quarter 2020 Corporate and Financial Update (G1 Therapeutics Press Release) - "Key Anticipated 2020/2021 Milestones: Initiation of Phase 3 trilaciclib metastatic colorectal cancer clinical trial in November/December 2020. Presentation of additional Phase 2 data of trilaciclib in triple-negative breast cancer at the San Antonio Breast Cancer Summit (SABCS) in December 2020. Presentation of additional rintodestrant monotherapy data at SABCS in December 2020. Pending FDA approval, commercial launch of trilaciclib in SCLC in 1Q21. Presentation of rintodestrant/palbociclib Phase 2 data in 2Q21."

Clinical data • Enrollment status • Launch • P2 data • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer

G1 Therapeutics to Present Clinical Data on Trilaciclib and Rintodestrant at 2020 San Antonio Breast Cancer Symposium (SABCS) (GlobeNewswire) - “G1 Therapeutics, Inc…announced that final overall survival (OS) data from its randomized Phase 2 trial of trilaciclib in metastatic triple-negative breast cancer (mTNBC) were consistent with preliminary findings announced last year, and showed that trilaciclib significantly improved median OS for patients treated with trilaciclib in combination with a chemotherapy regimen of gemcitabine/carboplatin. These data will be presented in a Spotlight Poster Session at the 2020 San Antonio Breast Cancer Symposium (SABCS) on Wednesday, December 9…clinical trial of rintodestrant, a potential best-in-class oral selective estrogen receptor degrader (SERD) in development for treatment of ER+, HER2- breast cancer…‘We expect to initiate a pivotal trial of trilaciclib in metastatic TNBC in 2021 with overall survival as the primary endpoint, and will provide additional details on the trial during the 2020 SABCS.’”

P1 data • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology • Triple Negative Breast Cancer

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1; N=184; Recruiting; Sponsor: G1 Therapeutics, Inc.; Active, not recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

G1 Therapeutics provides first quarter 2020 corporate and financial update (G1 Therapeutics Press Release) - "NDA submission for trilaciclib in small cell lung cancer (SCLC) expected in 2Q20....Pivotal trial of trilaciclib in colorectal cancer expected to begin in 4Q20....I-SPY 2 neoadjuvant breast cancer trial including trilaciclib on track for 2Q20 initiation....Initiation of rintodestrant and Ibrance combination trial on track for 2Q20."

Enrollment status • NDA • New P3 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. (PubMed, Breast Cancer Res Treat) - "These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer."

Journal • Preclinical • ER

G1 Therapeutics provides fourth quarter and full-year 2019 corporate and financial update (GlobeNewswire) - “New Drug Application (NDA) submission for trilaciclib in small cell lung cancer on track for 2Q20; Rintodestrant (G1T48) combination trial with palbociclib expected to initiate in 2Q20 [as a treatment for ER+, HER2- breast cancer]; Reported additional data from Phase 1b/2a clinical trial of lerociclib in combination with fulvestrant for the treatment of ER+, HER2- breast cancer: Additional safety and efficacy data are expected in the third quarter of 2020.”

NDA • P1/2 data • Trial status

G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer (clinicaltrials.gov) - P1; N=184; Active, not recruiting; Sponsor: G1 Therapeutics, Inc.; Recruiting ➔ Active, not recruiting; N=104 ➔ 184; Trial completion date: May 2022 ➔ Mar 2024; Trial primary completion date: Mar 2020 ➔ Jan 2022

Clinical • Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • HER-2

G1 Therapeutics provides third quarter 2019 corporate and financial update (G1 Therapeutics Press Release) - "Begin rolling NDA submission for trilaciclib in SCLC in 4Q19, which the company expects to complete in 2Q20; submit Marketing Authorization Application to the European Medicines Agency in 2H20. Initiate clinical trials of trilaciclib in colorectal cancer and TNBC in 2020. Present additional data from the Phase 1b/2a clinical trial of lerociclib + Faslodex® (fulvestrant) at the 2019 San Antonio Breast Cancer Symposium (SABCS) on December 11, 2019. Identify dose and schedule of lerociclib and G1T48 for pivotal trials in ER+, HER2- breast cancer."

European regulatory • NDA • New trial • P1/2 data

G1 Therapeutics presents first clinical data on oral SERD G1T48 demonstrating safety and tolerability in patients with advanced breast cancer at ESMO 2019 (G1 Therapeutics Press Release) - P1/2a, N=104; NCT03455270; Sponsor: G1 Therapeutics, Inc; “G1T48 was well tolerated with no dose-limiting toxicities (DLTs) reported at any of the five dose levels (200 mg, 400 mg, 600 mg, 800 mg and 1,000 mg) studied; maximum tolerated dose (MTD) was not reached. No patient experienced a serious adverse event (SAE) related to G1T48….Of 19 patients with RECIST measurable tumors: The clinical benefit rate (complete response + partial response + stable disease for at least 24 weeks) across all doses was 15.8% (three out of 19 patients)….The company plans to initiate a first-line Phase 3 trial of G1T48 in combination with an oral CDK4/6 inhibitor for the treatment of ER+, HER2- breast cancer in 2020.”

New P3 trial • P1/2 data