Atezolizumab in Combination with Daratumumab with or without Lenalidomide or Pomalidomide: A Phase Ib Study in Patients with Multiple Myeloma
Authors: Cho Hearn Jay , Costa Luciano J , Davies Faith E. , Neparidze Natalia , Vij Ravi , Feng Yuning , Teterina Anastasia , Wassner Fritsch Elisabeth , Wenger Michael , Kaufman Jonathan L 
Published: October 2019

Abstract
Introduction: Atezolizumab (atezo) is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) approved for the treatment (tx) of urothelial carcinoma and non-small cell lung cancer. PD-L1 is expressed on myeloma cells and appears to be upregulated in patients (pts) with relapsed or refractory (R/R) multiple myeloma (MM). Daratumumab (dara) is an anti-CD38 mAb approved for the tx of R/R MM; tx options are limited for pts who progress on dara. Given the anti-myeloma activity and immunomodulatory properties of dara, combination with an immune checkpoint inhibitor such as atezo may lead to additive or synergistic activity. A Phase Ib study is investigating the safety and preliminary efficacy of atezo alone or with lenalidomide (len) and/or dara, or with dara and pomalidomide (pom), in R/R MM pts (NCT02431208). Atezo alone and with len demonstrated good tolerability, but little activity. Here we present early data from the dara-combination cohorts.
Methods: R/R MM pts were enrolled into three cohorts: Cohort D (atezo + dara: Cohort D1, 1-3L prior tx; Cohort D2, 2-3L prior tx, refractory to last tx; Cohort D3, ≥2L prior tx, progressed on anti-CD38 mAb tx, refractory to proteasome inhibitor and immunomodulatory agent [IMiD]), Cohort E1 (atezo + dara + len: 1-3L prior tx), and Cohort F1 (atezo + dara + pom: ≥4 prior tx, refractory to last tx). Pts received atezo 840mg IV (C1, d2 and d16; C2, d1 and d15) plus dara 16mg/kg IV; pts in Cohort E1 also received len 10mg or 15mg orally (PO) d1-d21; pts in Cohort F1 also received pom 2mg or 4mg PO d1-d21. Primary endpoints included safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival and duration of response (DoR).
Results: Data cut-off was March 6, 2018; 24 pts have been enrolled and treated: 6 in Cohort D1; 4 in D2; 1 in D3; 7 in E1; and 6 in F1. Nine pts have discontinued ≥1 tx: 1 (17%) in D1; 1 (25%) in D2; 5 (71%) in E1; and 2 (33%) in F1. Median duration of follow-up was 16.2 months (mo) in Cohort D1, 0.5 mo in D2, 0.7 mo in D3, 8.5 mo in E1, and 7.1 mo in F1. High-risk cytogenetic features were present in 2 (50%) pts in Cohort D2, 5 (71%) pts in E1, and 2 (33%) pts in F1, and were absent in pts from Cohorts D1 and D3. The median number of prior tx was 2 in Cohorts D1, D2, and E1, and 4 in Cohort F1; the pt in Cohort D3 had received 9 prior tx. All pts experienced ≥1 adverse event (AE); Grade 3-4 AEs occurred in 2/6 (33%) pts in Cohort D1, 3/4 (75%) pts in D2, 0/1 pt in D3, 6/7 (86%) pts in E1, and 6/6 (100%) pts in F1. Serious AEs occurred in 0 pts in Cohorts D1 and D3, 1 (25%) pt in Cohort D2, 3 (43%) pts in Cohort E1, and 2 (33%) pts in Cohort F1; the majority were Grade 3-4 (Table). Two deaths were reported: 1 in Cohort D2 (due to an AE of multiple organ dysfunction syndrome following an AE of sepsis and suspicion of progression and assessed by the investigator as related to the underlying disease) and 1 in Cohort E1 (due to disease progression). AEs leading to dose modification/interruption for any study drug occurred in 4/6 (67%) pts in Cohort D1, 2/4 (50%) pts in D2, 0/1 pt in D3, 5/7 (71%) pts in E1, and 4/6 (67%) pts in F1. Two pts were withdrawn from all study tx due to AEs: persistent Grade 4 thrombocytopenia (Cohort E1, 1 pt) and Grade 4 gastrointestinal hemorrhage (Cohort D2, 1 pt). ORR was 67% (4/6 pts) in Cohort D1, 57% (4/7) in E1, and 67% (4/6 pts) in F1; in Cohort D2, 1 pt had stable disease, 1 pt died before assessment, and 2 pts had not yet had a response assessment at data cut-off; the pt in Cohort D3 had not yet had a response assessment. A very good partial response or better was observed in 3 pts (50%) in Cohort D1, 3 pts (43%) in E1, and 4 (67%) in F1. Response and DoR data are presented in the Figure. A reduction in M-protein was reported in 6/6 pts in Cohort D1, 5/7 pts in E1, and 4/5 pts in F1.
Conclusions: Atezo plus dara and in combination with len or pom demonstrated acceptable tolerability; no new safety signals were identified. Some pts treated with either atezo plus dara or atezo plus dara and IMiD appeared to have deep and durable responses. The benefit-risk profile of atezo in combination with dara with/without pom in R/R MM pts is promising. These early data support continuation of the study.

Disclosures
Cho: Agenus Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; J & J: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Genentech Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:BMS: Research Funding; Sanofi: Honoraria; Abbvie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding. Davies:Abbvie: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria. Vij:Bristol Myer Squibb: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria. Feng:Genentech Inc: Employment. Teterina:Hoffmann-La Roche Ltd: Employment. Wassner Fritsch:F. Hoffmann-La Roche Ltd: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Kaufman:Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy.