TY - JOUR
T1 - Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma
T2 - a cohort of a multicentre, single-arm, phase 1b/2 study
AU - Diefenbach, Catherine
AU - Kahl, Brad S.
AU - McMillan, Andrew
AU - Briones, Javier
AU - Banerjee, Lalita
AU - Cordoba, Raul
AU - Miall, Fiona
AU - Burke, John M.
AU - Hirata, Jamie
AU - Jiang, Yanwen
AU - Paulson, Joseph N.
AU - Chang, Yi Meng
AU - Musick, Lisa
AU - Abrisqueta, Pau
N1 - Funding Information:
This study was funded by F Hoffmann-La Roche. We thank the participating patients and their families, and the research nurses, study coordinators, and operations staff. Investigators who enrolled patients include Hendrik-Tobias Arkenau, Mariana Bastos, Armando Lopez-Guillermo, Roger Lyons, Jose Maria Arguinano, Eva Gonzalez-Barca Roderick Johnson, Carlos Manuel Panizo, Radhakrishnan Ramchandren. Third-party editorial assistance, under the direction of the authors, was provided by Lucinda Sinclair, Ashfield MedComms, an Ashfield Health company, and funded by F Hoffmann-La Roche. This study was sponsored by Genentech and F Hoffmann-La Roche. CD was supported by funding from American Cancer Society grant MRSG-14-052-01-LIB.
Funding Information:
CD has received research funding from and held consultancy for Genentech/F Hoffmann-La Roche. BSK has held consultancy for and received research funding from F Hoffmann-La Roche, Celgene, and ADC Therapeutics; and has held consultancy for Genentech. AM reports honoraria for satellite symposia and advisory boards and financial support for attending international meeting from F Hoffmann-La Roche. JB reports honoraria, travel, accommodations, and expenses from F Hoffmann-La Roche, Takeda, Celgene and Gilead; and honoraria from Novartis; and has received travel, accommodations, and expenses from Janssen; and has held consultancy or advisory roles for Takeda, Janssen, Celgene and Gilead/Kite. LB reports honoraria from Takeda; and expenses for travel sponsorship, accommodations, and educational meetings from Takeda, AbbVie, Janssen, and Celgene. RC has held consultancy and participated in a speaker's bureau for and reports expenses for travel and accommodation from F Hoffmann-La Roche, AbbVie, Takeda, Janssen; consultancy for Celgene, Gilead/Kite, and Kyowa-Kirin; and expenses for travel and accommodation from, Gilead/Kite and Pfizer. FM reports honoraria for F Hoffmann-La Roche and Takeda. JMB has held consultancy for Genentech/F Hoffmann-La Roche, Adaptive Biotechnologies, AstraZeneca, Verastem, AbbVie, Bayer, Celgene/Juno, Gilead/Kite, Tempus Labs, and Seattle Genetics; and has participated in a speaker's bureau with Seattle Genetics. JH, YJ, JNP, and LM are employees of Genentech. YMC in an employee of F Hoffmann-La Roche. PA has held consultancy for and received honoraria from Janssen and F Hoffmann-La Roche; held consultancy for Celgene; received honoraria from Gilead and AbbVie.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/12
Y1 - 2021/12
N2 - Background: Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. Methods: This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1–21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1–21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at ClinicalTrials.gov, NCT02600897. Findings: Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2–31·3) the objective response rate was 76% (90% CI 64–86) and complete response rate was 63% (90 CI 50–75). After a median follow-up of 27·0 months (IQR 18·7–34·0), the most common grade 3–4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. Interpretation: Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. Funding: Genentech/F Hoffmann-La Roche.
AB - Background: Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. Methods: This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1–21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1–21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at ClinicalTrials.gov, NCT02600897. Findings: Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2–31·3) the objective response rate was 76% (90% CI 64–86) and complete response rate was 63% (90 CI 50–75). After a median follow-up of 27·0 months (IQR 18·7–34·0), the most common grade 3–4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. Interpretation: Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. Funding: Genentech/F Hoffmann-La Roche.
UR - http://www.scopus.com/inward/record.url?scp=85119527602&partnerID=8YFLogxK
U2 - 10.1016/S2352-3026(21)00311-2
DO - 10.1016/S2352-3026(21)00311-2
M3 - Article
C2 - 34826412
AN - SCOPUS:85119527602
SN - 2352-3026
VL - 8
SP - e891-e901
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 12
ER -