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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

Komal Jhaveri, Dejan Juric, Yoon-Sim Yap, Sara Cresta, Rachel M Layman, Francois P Duhoux, Catherine Terret, Shunji Takahashi, Jens Huober, Nicole Kundamal, Qing Sheng, Alejandro Balbin, Yan Ji, Wei He, Adam Crystal, Serena De Vita & Giuseppe Curigliano

abstract

PURPOSE
Data are sparse for oral selective estrogen receptor (ER) degraders (SERDs) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study.

MATERIALS AND METHODS
A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n=77) or with ribociclib (arm B; n=78) or alpelisib (arm C; n=43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLTs) in the first 28-day treatment cycle, adverse events (AEs), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1).

RESULTS
The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C (10/43 [23%]). DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose-proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose-response. Objective response rates (95% CI) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively.

CONCLUSIONS
LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.
   
citation Jhaveri K, Juric D, Yap Y S, Cresta S, Layman R M, Duhoux F P, Terret C, Takahashi S, Huober J, Kundamal N, Sheng Q, Balbin A, Ji Y, He W, Crystal A, De Vita S, Curigliano G. 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. Clin Cancer Res 2021;.
   
type journal paper/review (English)
date of publishing 25-08-2021
journal title Clin Cancer Res
ISSN electronic 1557-3265
PubMed 34433648
DOI 10.1158/1078-0432.CCR-21-1095