LSZ102 / Novartis - LARVOL DELTA

[VIRTUAL] Interim results of a phase I/Ib study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib (RIB) or alpelisib (ALP) in patients with ER+ breast cancer (BC) who had progressed after endocrine therapy (ET) (ESMO-BC-I 2020) - P1 | "LSZ plus RIB or ALP showed manageable safety and encouraging clinical activity in heavily pre-treated ER+ BC pts, regardless of ESR1 and PIK3CA mutations. This is the first report of an oral SERD in combination with both CDK4/6 and PI3Kα inhibitors.Legal entity responsible for the study: Novartis Pharmaceuticals Funding: Novartis Pharmaceuticals Clinical trial identification: NCT02734615."

Clinical • Combination therapy • Late-breaking abstract • P1 data • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PIK3CA

A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, With or Without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer. (PubMed, Clin Cancer Res) - P1 | "LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use."

Clinical • Journal • P1 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Gastrointestinal Disorder • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Comparative analysis of approved and undertrial SERDs in estrogen receptor-α (ERα): An in-silico approach (AACR 2022) - "Many non-steroidal SERDs such as Amcenestrant, Elacestrant, Camizestrant, Giredestrant, and LSZ102 are under various advanced development stages. The current study helps us to understand the binding mechanism, antagonism, and downregulation of multiple SERDs, among which Fulvestrant showed the highest binding affinity towards ERα (due to its highest shape similarity with E2) and can interact with and disrupt H12 (due to its long tail) which is a critical component of SERD. This knowledge could further be used to develop novel SERDs for ESR1 mutant and HR-positive breast cancer treatment."

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

Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability. (PubMed, J Med Chem) - "Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials."

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

Species-dependent hepatic and intestinal metabolism of selective estrogen receptor degrader LSZ102 by sulfation and glucuronidation. (PubMed, Xenobiotica) - "As LSZ102 is metabolized by a number of different sulfotransferases, drug-drug interactions resulting from the inhibition of one sulfotransferase are unlikely.5. Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulfate M5, glucuronide M4, and secondary glucuronide/sulfate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites."

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

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=199; Terminated; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Terminated; Sponsor's decision

Clinical • Combination therapy • Trial termination • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET) (SABCS 2019) - "This phase 1/1b, open-label study evaluates single-agent LSZ102 (Arm A) and LSZ102 in combination with ribociclib (Arm B) or alpelisib (Arm C) in pts with ER+ ABC who had progressed after ET. The combination of LSZ102 and ribociclib was well-tolerated and demonstrated antitumor activity in heavily pre-treated pts with ER+ ABC many of whom had progressed after fulvestrant and/or CDK4/6 inhibitor therapy."

Clinical • Combination therapy • P1 data • ER

Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor-positive (ER+) advanced breast cancer (ABC) with progression on endocrine therapy (ET) (SABCS 2018) - "...Median age was 60 years, 75% (n=43) of pts had an ECOG PS of 0, 56% (n=32) had received prior fulvestrant, and 58% (n=33) had received prior CDK4/6 inhibitors; median number of prior lines of therapy (all settings) was 6... In heavily pretreated pts, LSZ102 was well tolerated, demonstrated antitumor activity, and achieved effective exposure levels based on PK and pharmacodynamics. Food intake did not appear to significantly alter the PK profile of LSZ102. Dose escalation for LSZ102 in combination with ribociclib or alpelisib is ongoing and will be reported in a future analysis."

P1 data • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine therapy (ET) (SABCS 2018) - P1; "The present study is evaluating the safety and tolerability of LSZ102 plus alpelisib in patients with ER+, HER2– ABC with progression on ET.Trial Design: This phase 1/1b, open-label study is enrolling ~18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Recruitment for Arm C is ongoing. NCT02734615 "

Combination therapy • P1 data • Brain Cancer • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=200; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Oct 2020 ➔ Mar 2021; Trial primary completion date: Oct 2020 ➔ Mar 2021

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

[VIRTUAL] Interim results of a phase I/Ib study of LSZ102, an oral selective estrogen receptor degrader, in combination with ribociclib or alpelisib in patients with ER+ breast cancer who had progressed after endocrine therapy.2020 ESMO Breast Cancer Virtual Meeting. Abstract (YIR 2021) - No abstract available

Clinical • Combination therapy • P1 data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=198; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; N=420 ➔ 198

Clinical • Combination therapy • Enrollment change • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=420; Recruiting; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=420; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Molecular modeling studies of benzothiophene-containing derivatives as promising selective estrogen receptor downregulators: a combination of 3D-QSAR, molecular docking and molecular dynamics simulations. (PubMed, J Biomol Struct Dyn) - "Finally, ten novel compounds were designed based on above findings, where the predicted activity of compound D8 was equivalent to that of the compound LSZ102. 3D-QSAR, ADMET and bioavailability predictions indicated that all designed compounds with good predicted activity, good physicochemical and bioavailability could be potential candidates for SERDs. These results and combinations of computational methods provided guidance for the rational drug design of novel potential SERDs."

Journal • ER

Tumor ER protein modulation, molecular characterization and monitoring of cfDNA in phase 1 study of LSZ102 and LSZ102 + ribociclib in patients with ER+ MBC (SABCS 2019) - "This first-in-human study of LSZ102 is evaluating LSZ102 as a single agent (SA) and in combination with the CDK4/6 inhibitor ribociclib or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with locally advanced/metastatic ER-positive (ER+) breast cancer (BC). Consistent with being a SERD, LSZ102 treatment leads to the degradation of ER in tumor biopsies. The addition of ribociclib does not alter LSZ102-induced ER downregulation. The most common genetic alterations found in cfDNA collected from enrolled ER+ MBC patients before the study treatment were ESR1 and PIK3CA mutations."

Clinical • P1 data • ER • PIK3CA

Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers (clinicaltrials.gov) - P1; N=420; Recruiting; Sponsor: Novartis Pharmaceuticals; N=312 ➔ 420; Trial primary completion date: Oct 2019 ➔ Oct 2020

Clinical • Combination therapy • Enrollment change • Trial primary completion date