TY - JOUR
T1 - Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma
AU - Stewart, A. Keith
AU - Krishnan, Amrita Y.
AU - Singhal, Seema
AU - Boccia, Ralph V.
AU - Patel, Manish R.
AU - Niesvizky, Ruben
AU - Chanan-Khan, Asher A.
AU - Ailawadhi, Sikander
AU - Brumm, Jochen
AU - Mundt, Kirsten E.
AU - Hong, Kyu
AU - McBride, Jacqueline
AU - Shon-Nguyen, Quyen
AU - Xiao, Yuanyuan
AU - Ramakrishnan, Vanitha
AU - Polson, Andrew G.
AU - Samineni, Divya
AU - Leipold, Douglas
AU - Humke, Eric W.
AU - McClellan, James Scott
AU - Berdeja, Jesus G.
N1 - Funding Information:
A.K.S.: Consulting roles at Celgene, Amgen, Janssen, BMS, and Roche. S.S.: Speakers’ bureau for Celgene and Millennium Pharmaceuticals. R.V.B.: Speaker’s bureau for Celgene, Takeda, BMS, and Amgen. M.R.P.: Speaker’s bureau for Celgene, Exelixis, and Genentech. J.B., K.E.M., K.H., J.M., Q.S.N., Y.X., A.G.P., D.S., D. L., E.W.H., and J.S.M.: Employee of Genentech, Inc. and shareholders of F. Hoffmann La Roche, Ltd. V.R.: Former employee of Genentech, Inc. and shareholders of F. Hoffmann La Roche, Ltd. Current employee of BeiGene, USA. J.G.B.: Research funding from Genentech, Abbvie, Amgen, Bluebird, BMS, Celgene, Constellation, Curis, Janssen, Novartis, Takeda, and Teva. A.Y.K., R.N., A. A.C.K., and S.A. declare that they have no conflict of interest.
Funding Information:
The authors wish to thank the patients and their families, and the investigators who participated in this study. Writing assistance was provided by Genentech, Inc. This work was supported by Genentech, Inc., South San Francisco, California, USA.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/2/1
Y1 - 2019/2/1
N2 - FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
AB - FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
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U2 - 10.1038/s41408-019-0178-8
DO - 10.1038/s41408-019-0178-8
M3 - Article
C2 - 30718503
AN - SCOPUS:85061037366
SN - 2044-5385
VL - 9
JO - Blood cancer journal
JF - Blood cancer journal
IS - 2
M1 - 17
ER -