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Proffered papers 3 - Best abstracts

LBA1 - 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)

Date

24 May 2020

Session

Proffered papers 3 - Best abstracts

Presenters

Komal Jhaveri

Citation

Annals of Oncology (2020) 31 (suppl_2): S62-S82. 10.1016/annonc/annonc122

Authors

K. Jhaveri1, D. Juric2, Y. Yap3, S. Cresta4, R.M. Layman5, F.P. Duhoux6, C. Terret7, S. De Vita8, N. Kundamal9, W. He8, A. Balbin8, Q. Sheng8, A. Crystal8, G. Curigliano10

Author affiliations

  • 1 Medicine Dept, Memorial Sloan Kettering Evelyn H. Lauder Breast Center, 10065 - New York/US
  • 2 Oncology/hematology, Massachusetts General Hospital, 02114 - Boston/US
  • 3 Medical Oncology, National Cancer Centre Singapore, 169610 - Singapore/SG
  • 4 Medical Oncology, Fondazione IRCCS – Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 5 Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 6 Medical Oncology, Cliniques Universitaires Saint-Luc, Brussels/BE
  • 7 Medical Oncology, Centre Léon Bérard, 69008 - Lyon/FR
  • 8 Clinical Research, Novartis Institutes for Biomedical Research, Massachusetts/US
  • 9 Clinical Research, Novartis Institutes for Biomedical Research, East Hanover/US
  • 10 Early Drug Development for Innovative Therapies Division, University Of Milano, Istituto Europeo di Oncologia, 20141 - Milan/IT
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Resources

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Abstract LBA1

Background

ET plus RIB (CDK4/6 inhibitor) or ALP (PI3Kα inhibitor) provides consistent improvement in progression-free survival (PFS) and/or overall survival compared to ET alone. LSZ102 (LSZ), an oral SERD, demonstrated synergistic activity with RIB and ALP in preclinical models of ER+ BC. Here, we describe the dose escalation data from phase 1/1b, open-label study of single agent LSZ (arm A), and LSZ+RIB (arm B) or LSZ+ALP (arm C).

Methods

Study enrolled pre/post-menopausal patients (pts) (≥18 yrs; ECOG PS ≤1) with histologically confirmed ER+ BC who had progressed after ET for advanced disease or had a recurrence while on, or within 12 months (mo) from the end of adjuvant therapy. Prior PI3K, mTOR or AKT inhibitors were not allowed in arm C. The primary objective was to characterize safety and tolerability of LSZ alone or in combination with RIB or ALP and identify recommended dose(s) for expansion (RDE). Secondary objectives included preliminary antitumor activity and PK/PD properties of LSZ alone and combinations.

Results

Safety data are shown in the table. The RDEs were determined to be: 450 mg QD LSZ ± 400 mg QD RIB and 300 mg LSZ QD with 250 mg QD ALP. Overall response rate [CR or PR] and median PFS were: 1.3% and 1.8 mo (1.7-2.0), 15.8% and 6.2 mo (4.4-6.4), 5.4% and 3.5 mo (1.8-5.5) for Arm A, B and C, respectively. Paired biopsies showed downregulation of ER upon treatment (tx) with LSZ or in combination. cfDNA analysis across all arms identified commonly observed genetic alterations, and longitudinal analysis showed that ESR1 Y537S mutations were not enriched after tx. Table: LBA1

Safety data

Arm A (LSZ, N=78) Arm B (LSZ+RIB, N=76) Arm C (LSZ+ALP, N=39)
Most common tx related grade 3 or 4 AEs, n (%)
    Diarrhoea 3 (3.9) 3 (3.9) 3 (7.7)
    Nausea 2 (2.6) 2 (2.6) 2 (5.1)
    Neutropenia - 10 (13.2) -
    Decreased white blood cell count/leukopenia - 5 (6.6) -
    Hyperglycemia - - 4 (10.3)
    Hypophosphatemia - 2 (2.6) 4 (10.3)
    Rash maculo-papular - - 4 (10.3)
Dose limiting toxicities, a n (%) 4 (5.6) 2 (2.8) 7 (20.6)
On-tx deaths, b  n (%)
    Due to underlying cancer 5 (6.5) 3 (3.9) 2 (5.1)
a

Arm A: diarrhea (2 pts), vomiting (1 pt), increased ALT/AST (1 pt), Arm B: febrile neutropenia/sepsis (1 pt), decreased appetite (1 pt); Arm C: diarrhea (1 pt), stomatitis (1 pt), hyperglycemia (2 pts), maculo-papular rash (3 pts).

b

All on-treatment deaths were due to underlying cancer.

Conclusions

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.

Clinical trial identification

NCT02734615.

Editorial acknowledgement

Avinash Yerramsetti (Novartis Healthcare Pvt. Ltd.) for medical editorial assistance with this abstract.

Legal entity responsible for the study

Novartis Pharmaceuticals

Funding

Novartis Pharmaceuticals

Disclosure

K. Jhaveri: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Spectrum pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): ADC Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Taiho Oncology; Advisory/Consultancy: Synthon; Advisory/Consultancy: Lily Pharmaceuticals; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Debio Pharmaceuticals; Research grant/Funding (institution): Zymeworks. D. Juric: Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy: Ipsen; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Placon Therapeutics; Research grant/Funding (institution): Syros; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Takeda. Y. Yap: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pfizer; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Astra Zeneca; Advisory/Consultancy: Roche. R.M. Layman: Research grant/Funding (institution): Novartis. F.P. Duhoux: Advisory/Consultancy, Research grant/Funding (institution), Consulting fees paid to my institution: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Pfizer; Advisory/Consultancy, Consulting fees paid to my institution: AstraZeneca; Advisory/Consultancy, Consulting fees paid to my institution: Lilly; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Amgen; Travel/Accommodation/Expenses: Teva. S. De Vita: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Kundamal: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. W. He: Full/Part-time employment: Novartis. A. Balbin: Full/Part-time employment: Novartis. Q. Sheng: Full/Part-time employment: Novartis. G. Curigliano: Advisory/Consultancy: Merck; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Astra Zeneca; Speaker Bureau/Expert testimony: Daichi Sankyo; Speaker Bureau/Expert testimony: Roche.

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