54O - Safety outcomes by UGT1A1 status in the phase III TROPiCS-02 study of sacituzumab govitecan (SG) in HR+/HER2– metastatic breast cancer (mBC)

Background

SG is a Trop-2–directed antibody-drug conjugate approved for metastatic triple-negative BC in multiple countries and pretreated HR+/HER2– mBC in the US. In TROPiCS-02, SG significantly improved progression-free survival (PFS; median, 5.5 vs 4.0 mo; HR, 0.66; P=0.0003) and overall survival (OS; median, 14.4 vs 11.2 mo; HR, 0.79; P=0.020) vs treatment of physician’s choice (TPC) in patients (pts) with pretreated, endocrine-resistant HR+/HER2– mBC, with a manageable safety profile (Rugo et al. ESMO 2022). In the ASCENT study, UGT1A1 polymorphisms were associated with neutropenia, anemia, and diarrhea in SG-treated pts (Rugo et al. npj Breast Cancer 2022). Here, we report TROPiCS-02 safety analyses by UGT1A1 status.

Methods

Pts with HR+/HER2– mBC who received prior taxane, endocrine therapy, CDK4/6 inhibitor, and 2-4 prior chemotherapies (CT) were randomized 1:1 to SG or TPC. The primary endpoint was PFS by central review per RECIST 1.1; secondary endpoints included OS and safety. A post-hoc safety analysis was performed by UGT1A1 status.

Results

Of 543 enrolled pts (median number of prior CT for mBC, 3; visceral metastases, 95%), 517 (SG, n=268; TPC, n=249) received ≥1 dose of study treatment. UGT1A1 status in SG pts was: *1/*1 (n=104; 38%; wild type), *1/*28 (n=119; 44%), and *28/*28 (n=25; 9%); the respective median relative dose intensity was 99%, 98% and 94%. In SG pts, grade ≥3 treatment-emergent adverse events (TEAEs) included neutropenia (52%), diarrhea (10%), anemia (8%), and febrile neutropenia (6%). In pts with UGT1A1 *1/*1, *1/*28, and *28/*28 genotypes, grade ≥3 TEAEs for SG included: neutropenia (45%, 57%, and 64%), diarrhea (6%, 13%, and 24%), anemia (6%, 8%, and 8%), and febrile neutropenia (6%, 7%, and 4%), respectively. Myeloid growth factors (initiated on/after first dose) were used to manage neutropenia in 54% of pts in the SG group (33%, *1/*1; 49%, *1/*28; 11%, *28/*28). TEAEs were managed similarly regardless of UGT1A1 status.

Conclusions

SG had a manageable safety profile consistent with previous reports and across UGT1A1 status. UGT1A1 testing is not required for SG use in pretreated, endocrine-resistant HR+/HER2– mBC.

Clinical trial identification

NCT03901339.

Editorial acknowledgement

Medical writing and editorial support was provided by Ben Labbe, PhD of Parexel.

Legal entity responsible for the study

The study is sponsored by Gilead Sciences, Inc.

Funding

Gilead Sciences, Inc.

Disclosure

V.Y.M. Heong: Financial Interests, Institutional, Advisory Board: DKSH, Novartis, AstraZeneca, MSD; Financial Interests, Institutional, Principal Investigator: Gilead. F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Seagen, Gilead/immunomedics, Eisai, PharmaMar, Genomic Health, Myriad; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca; Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Local PI: Roche, Novartis, Eisai, MSD, Vaccibody, GSK; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, Gilead/Immunomedics, German Breast Group, AGO Research GmbH; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support: PUMA, NAPO, Mylan, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Local PI: Novartis, Lilly, Pfizer, Daiichi, AstraZeneca, Gilead Sciences, Inc., GSK, Sermonix Pharmaceuticals Ins., Pionyr Immunotherapeutics, Taiho Oncology, Inc., Veru Inc; Financial Interests, Institutional, Coordinating PI: OBI Pharma, Astellas Pharma Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Merck; Financial Interests, Personal, Other, Travel support to academic meetings: Merck, AstraZeneca, Gilead; Non-Financial Interests, Personal, Advisory Role, I advise a number of companies without compensation: various. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: 4D Pharma, ARC Therapeutics, Daiichi Sankyo, Eisai, Genentech/Roche, Gilead, SeaGen, Novartis, Sanofi; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Infinity Therapeutics, Myovant, OncXerna, Umoja Biopharma, Zentalis, Zetagen; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma, Mersana Therapeutics; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory board/consulting: Jazz Pharma; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding: Odonate, Pfizer, Sanofi, SeaGen, Cyclacel, Exelixis, Bristol Myers Squibb, Eisai, Merck, Novartis; Financial Interests, Institutional, Funding, And steering committing: AstraZeneca; Financial Interests, Institutional, Funding, And steering committee: Eli Lilly; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX; Financial Interests, Institutional, Funding, and steering committee: Gilead, Genentech/Roche; Financial Interests, Institutional, Local PI: Stemline/Menarini. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Personal, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Gilead, Eisai, MSD, SeaGen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. All other authors have declared no conflicts of interest.