rintodestrant (G1T48)

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.

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.

P1, N=107, Completed, G1 Therapeutics, Inc. | Active, not recruiting --> Completed

P1, N=107, Active, not recruiting, G1 Therapeutics, Inc. | Trial completion date: Mar 2024 --> Sep 2022 | Trial primary completion date: May 2022 --> Sep 2022

P1, N=107, Active, not recruiting, G1 Therapeutics, Inc. | Trial primary completion date: Jan 2022 --> May 2022

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 improve the management, outcomes, and quality of life in HR-positive breast cancer.

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.

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.

P1, N=107, Active, not recruiting, G1 Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=184 --> 107

These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.

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).

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.

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, N=184, Recruiting, G1 Therapeutics, Inc. | Active, not recruiting --> Recruiting

P1, N=184, Active, not recruiting, 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