Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.
BACKGROUND
Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).


METHODS
In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549.


RESULTS
Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL.


CONCLUSIONS
Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL.


BACKGROUND
Genentech.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: cpalwes@uw.edu.
Maria Corinna A
MC
Palanca-Wessels
Roswell Park Cancer Institute, Buffalo, NY, USA.
Myron
M
Czuczman
Hospices Civils de Lyon, Université Lyon-1, Pierre Bénite, France.
Gilles
G
Salles
Jewish General Hospital, Montreal, QC, Canada.
Sarit
S
Assouline
BC Cancer Agency, Centre for Lymphoid Cancer, Vancouver, BC, Canada.
Laurie H
LH
Sehn
Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
Ian
I
Flinn
Sarah Cannon Research Institute and Florida Cancer Specialists, Sarasota, FL, USA.
Manish R
MR
Patel
Cross Cancer Institute, Edmonton, AB, Canada.
Randeep
R
Sangha
Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Anton
A
Hagenbeek
Stanford Cancer Center, Stanford, CA, USA.
Ranjana
R
Advani
Hematology, Centre Henri Becquerel, Université de Rouen, Rouen, France.
Herve
H
Tilly
Hematology, CHU Dijon, Dijon, France.
Olivier
O
Casasnovas
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Oliver W
OW
Press
Genentech, South San Francisco, CA, USA.
Sreeni
S
Yalamanchili
Genentech, South San Francisco, CA, USA.
Robert
R
Kahn
Genentech, South San Francisco, CA, USA.
Randall C
RC
Dere
Genentech, South San Francisco, CA, USA.
Dan
D
Lu
Genentech, South San Francisco, CA, USA.
Surai
S
Jones
Genentech, South San Francisco, CA, USA.
Cheryl
C
Jones
Genentech, South San Francisco, CA, USA.
Yu-Waye
YW
Chu
Hematology, Hôpital Claude Huriez, Unité GRITA, Université de Lille, Lille Cedex, France.
Franck
F
Morschhauser
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D051925:CD79 Antigens / Q000096:biosynthesis / Q000276:immunology*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051925:CD79 Antigens; C497883:CD79B protein, human; D018796:Immunoconjugates; D000069283:Rituximab; C000600736:polatuzumab vedotin