Purpose: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. Patients and Methods: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n ¼77) or with ribociclib (arm B; n ¼78) or alpelisib (arm C; n ¼43) in heavily pretreated adults with histologically con- firmed 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 (DLT) in the first 28-day treatment cycle, adverse events (AE), 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); and arm C, 19% (8/43). LSZ102 exposure was slightly greater thandoseproportional.On-treatmentbiopsyERreductionswereobser- ved, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0–7.0); arm B, 16.9% (9.3–27.1); and arm C, 7.0% (1.5–19.1), and clinical benefit rates 7.8% (2.9–16.2),35.1% (24.5–46.8),and20.9% (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.

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 / K. Jhaveri, D. Juric, Y. Yap, S. Cresta, R.M. Layman, F.P. Duhoux, C. Terret, S. Takahashi, J. Huober, N. Kundamal, Q. Sheng, A. Balbin, Y. Ji, W. He, A. Crystal, S. De Vita, G. Curigliano. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - (2021), pp. clincanres.1095.2021.1-clincanres.1095.2021.12. [Epub ahead of print] [10.1158/1078-0432.CCR-21-1095]

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

G. Curigliano
Ultimo
Conceptualization
2021

Abstract

Purpose: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. Patients and Methods: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n ¼77) or with ribociclib (arm B; n ¼78) or alpelisib (arm C; n ¼43) in heavily pretreated adults with histologically con- firmed 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 (DLT) in the first 28-day treatment cycle, adverse events (AE), 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); and arm C, 19% (8/43). LSZ102 exposure was slightly greater thandoseproportional.On-treatmentbiopsyERreductionswereobser- ved, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0–7.0); arm B, 16.9% (9.3–27.1); and arm C, 7.0% (1.5–19.1), and clinical benefit rates 7.8% (2.9–16.2),35.1% (24.5–46.8),and20.9% (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.
Settore MED/06 - Oncologia Medica
25-ago-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/864891
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