Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study

Elisabeth A Lasater; Dhara N Amin; Rajat Bannerji; Raghuveer Singh Mali; Kathy Barrett; Ryan N Rys; Jason Oeh; Eva Lin; Tim Sterne-Weiler; Ellen Rei Ingalla; MaryAnn Go; Shang-Fan Yu; Maxwell M Krem; Chris Arthur; Uwe Hahn; Anna Johnston; Vinit Karur; Nadia Khan; Paula Marlton; Tycel Phillips; Giuseppe Gritti; John F Seymour; Monica Tani; Sam Yuen; Scott Martin; Matthew T Chang; Christopher M Rose; Victoria C Pham; Andrew G Polson; YiMeng Chang; Claudia Wever; Nathalie A Johnson; Yanwen Jiang; Jamie Hirata; Deepak Sampath; Lisa Musick; Christopher R Flowers; Ingrid E Wertz

doi:10.1002/ajh.26809

Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study

Am J Hematol. 2023 Mar;98(3):449-463. doi: 10.1002/ajh.26809. Epub 2023 Jan 17.

Authors

Elisabeth A Lasater¹, Dhara N Amin^{2

3}, Rajat Bannerji⁴, Raghuveer Singh Mali¹, Kathy Barrett⁵, Ryan N Rys^{6

7}, Jason Oeh¹, Eva Lin², Tim Sterne-Weiler⁸, Ellen Rei Ingalla¹, MaryAnn Go¹, Shang-Fan Yu¹, Maxwell M Krem⁹, Chris Arthur¹⁰, Uwe Hahn¹¹, Anna Johnston¹², Vinit Karur¹³, Nadia Khan¹⁴, Paula Marlton¹⁵, Tycel Phillips¹⁶, Giuseppe Gritti¹⁷, John F Seymour¹⁸, Monica Tani¹⁹, Sam Yuen²⁰, Scott Martin², Matthew T Chang⁸, Christopher M Rose²¹, Victoria C Pham²¹, Andrew G Polson¹, YiMeng Chang²², Claudia Wever^{6

7}, Nathalie A Johnson^{6

7}, Yanwen Jiang⁵, Jamie Hirata²³, Deepak Sampath¹, Lisa Musick²³, Christopher R Flowers²⁴, Ingrid E Wertz^{2

3}

Affiliations

¹ Department of Translational Oncology, Genentech, Inc., South San Francisco, California, USA.
² Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.
³ Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California, USA.
⁴ Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
⁵ Department of Biomarker Development, Genentech, Inc., South San Francisco, California, USA.
⁶ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
⁷ Department of Medicine, McGill University, Montreal, Quebec, Canada.
⁸ Department of Oncology Bioinformatics, Genentech, Inc., South San Francisco, California, USA.
⁹ Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
¹⁰ Royal North Shore Hospital (RNSH), Sydney, New South Wales, Australia.
¹¹ The Queen Elizabeth Hospital (TQEH), Adelaide, South Australia, Australia.
¹² Royal Hobart Hospital (RHH), Hobart, Tasmania, Australia.
¹³ Baylor Scott & White Healthcare, Temple, Texas, USA.
¹⁴ Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
¹⁵ Princess Alexandra Hospital, and University of Queensland, Brisbane, Queensland, Australia.
¹⁶ University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
¹⁷ Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
¹⁸ Peter MacCallum Cancer Centre, Royal Melbourne Hospital, and University of Melbourne, Melbourne, Victoria, Australia.
¹⁹ Ospedale S. Maria delle Croci, Ravenna, Italy.
²⁰ Calvary Mater Newcastle, Waratah, New South Wales, Australia.
²¹ Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, California, USA.
²² Hoffmann-La Roche Ltd, Mississauga, Ontario, Canada.
²³ Product Development Oncology, Genentech, Inc., South San Francisco, California, USA.
²⁴ Department of Lymphoma and Myeloma, UT MD Anderson Cancer Center, Houston, Texas, USA.

PMID: 36594167
DOI: 10.1002/ajh.26809

Abstract

The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.

Publication types

Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / adverse effects
Humans
Immunoconjugates* / therapeutic use
Lymphoma, Non-Hodgkin* / drug therapy
Lymphoma, Non-Hodgkin* / pathology
Myeloid Cell Leukemia Sequence 1 Protein / therapeutic use
Rituximab / therapeutic use

Substances

polatuzumab vedotin
venetoclax
Myeloid Cell Leukemia Sequence 1 Protein
Rituximab
Immunoconjugates