Primary Analysis of the Tegar Study: A Phase II Study Exploring the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab or Rituximab in Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), or Waldenstrom Macroglobulinemia (WM)
Authors: Panayiotidis Panayiotis , Tumyan Gayane , Thieblemont Catherine , Ptushkin Vadim V , Marin Niebla Ana , Garcia-Sanz Ramon , Zaritskey Andrey , Le Gouill Steven , Buske Christian , Van Hoef Marlies , Perretti Thomas , Tomiczek Monique S , Stathis Anastasios 
Published: November 2020

Introduction:Treatment options for R/R MCL, MZL and WM are limited. New combinations are in development. A previous Phase Ib study evaluating atezolizumab (A) in combination with obinutuzumab (O) in patients (pts) with R/R NHL reported no new safety signals and overall response rates of 57% and 16% in follicular lymphoma and diffuse large B-cell lymphoma pts, respectively (Palomba, et al. ICML 2017). The Phase II TEGAR study (EudraCT: 2016-003579-22) evaluated the safety and efficacy of A in combination with O or rituximab (R) in pts with R/R MCL, MZL or WM.
Methods:R/R MCL or WM pts received eight 21-day (D) cycles (C) of A 1200mg in combination with O 1000mg as induction. O was given by IV infusion on D1 of each C and optionally as a split dose on D1 (100mg) and D2 (900mg) of C1. O 1000mg was also given on D8 and D15 of C1. A was given after O on D1 of each C unless split dosing was pursued, in which case A was initiated on D2 C1 after the D2 O dose. R/R MZL pts received A 1200mg in combination with R 375mg/m2 by IV infusion on D1 C1 and A 1200mg by IV infusion and R 1400mg by SC injection on D1 C2-8 as induction. A was always given after R. In all pts, A 1200mg was continued from C9 for 10 Cs. Anti-CD20 premedication was given per protocol. The primary endpoint in the MCL and MZL cohorts was end of induction (EOI) response; in the WM cohort it was best overall response (BOR). Data cut-off was December 17, 2019, and the primary analysis presents results at EOI.
Results:A total of 30 MCL, 21 MZL (3 nodal [N], 10 extra nodal [including 7 non-gastric (EN) and 3 gastric (G)] and 8 splenic [S]) and 4 WM pts were enrolled (median age: 67 years [range: 47-87]; 56.4% male). The majority of MCL (80%) and MZL (67%) pts had Ann Arbor stage IV disease. Refractory disease was present in 36.7% of MCL, 23.8% of MZL and 25.0% (1/4) of WM pts. Median prior systemic treatments was 2 in the MCL (range: 1-8) and MZL (1-7) groups and 3.5 (1-4) in the WM group; 14/30 pts (46.7%) in the MCL group had received prior ibrutinib.
In the MCL, MZL and WM groups, respectively, 50.0%, 71.4% and 75.0% (3/4) of pts completed O or R treatment, 23.3%, 38.1% and 25.0% (1/4) completed A induction, and 10.0%, 9.5% and 0% had ongoing treatment at cut-off. Median numbers of O/A infusions were 9.5/8 (range: 2-10/1-18) (MCL group) and 10/9.5 (2-10/1-18) (WM group); in MZL, median numbers of R/A administrations were 8/15 (2-8/2-18). Median observation times were 9.99 (range: 0.9-23.4), 15.77 (2.7-22.3) and 8.43 (1.3-15.3) months in MCL, MZL and WM pts, respectively.
Treatment-emergent adverse events (TEAEs) occurred in 93.3% of MCL, 95.2% of MZL and 100% (4/4) of WM pts. Overall, the most frequent TEAEs were anemia, neutropenia and thrombocytopenia (18.2% each), and the most frequent serious TEAEs were pneumonia (5.5%) and sepsis (3.6%). The most frequent Grade (Gr) 3-4 AEs were neutropenia (16.4%), thrombocytopenia (9.1%) and pneumonia (9.1%), and Gr 3-4 AEs occurred in 53.3%, 47.6% and 100% (4/4) of MCL, MZL and WM pts, respectively. Serious AEs occurred in 30.0%, 23.8% and 0% of MCL, MZL and WM pts, respectively. AEs of special interest occurred in 33.3% of MCL, 33.3% of MZL and 50.0% (2/4) of WM pts, with the most frequent being peripheral edema (10.0% MCL, 4.8% MZL). TEAEs leading to discontinuation occurred in 10.0%, 19.0% and 0% of MCL, MZL and WM pts, respectively. One fatal TEAE (pneumonia) occurred in each of the MCL and MZL groups.
Objective response rates (ORR) at EOI were 16.7%, 42.9% and 0% (complete response in 3.3%, 14.3% and 0%) and BOR rates were 33.3%, 52.4% and 0% in MCL, MZL and WM pts, respectively. For MZL subtypes, ORRs were 66.7% N, 57.1% EN, 66.7% G and 12.5% S; BOR rates were 66.7%, 71.4%, 66.7% and 25.0%, respectively. Three MCL pts, 1 MZL patient and 1 WM patient discontinued before the first post-baseline assessment and were considered non-responders. Median duration of response was 6.8 (range: 0.0-14.2) months for MCL and not reached (NR) for MZL. Median progression free survival was 10.1 months (95% CI: 3.4, 14.0) for MCL, NR for MZL and 6.7 months (95% CI: 6.2, 7.2) for WM. Median overall survival was 23.4 months (95% CI: 12.3, 23.4) for MCL and NR for MZL or WM. Median time to next treatment was 10.5 months (95% CI: 6.7, 23.4) for MCL, 22.3 months (95% CI: 14.3, 22.3) for MZL and NR for WM.
Conclusions:A in combination with O or R has an acceptable safety profile in R/R MCL and MZL pts and no new safety signals were identified. A promising response rate was observed in MZL pts. WM data were inconclusive due to the small sample size.

Disclosures
Panayiotidis: AbbVie:Honoraria, Research Funding;Roche:Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Genesis:Honoraria, Research Funding;Janssen:Honoraria;Gilead:Honoraria;Takeda:Honoraria;Phizer:Honoraria;ASH:Honoraria.Thieblemont:Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Hospira:Research Funding;Kyte:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Cellectis:Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen:Honoraria;University Employement:Current Employment;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.Ptushkin:Alexion Pharmaceuticals Inc.:Honoraria.Marin Niebla:Janssen:Membership on an entity's Board of Directors or advisory committees, Other: Participation in advisory committees, continuing Medical Education for companies' staff members, Speakers Bureau;Takeda:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche:Other: Continuing Medical Education for companies' staff members, Speakers Bureau;Celgene:Speakers Bureau;Abbvie:Speakers Bureau;Gilead:Membership on an entity's Board of Directors or advisory committees, Other: Participation in advisory committees, continuing Medical Education for companies' staff members;Kiowa Kirin:Membership on an entity's Board of Directors or advisory committees, Other: Participation in advisory committees, continuing Medical Education for companies' staff members;BeiGene:Membership on an entity's Board of Directors or advisory committees.Garcia-Sanz:Novartis:Honoraria;Janssen:Honoraria, Research Funding;Incyte:Research Funding;Gilead:Honoraria, Research Funding;BMS:Honoraria;Amgen:Membership on an entity's Board of Directors or advisory committees;Pharmacyclics:Honoraria;Takeda:Consultancy, Research Funding.Zaritskey:Janssen:Research Funding;Celgene:Research Funding;Almazov centre:Current Employment.Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier:Honoraria;Loxo Oncology at Lilly:Consultancy.Buske:Morphosys:Membership on an entity's Board of Directors or advisory committees;Roche, Janssen, Bayer, MSD:Research Funding;Roche, Janssen, AbbVie, Pfizer, Celltrion:Honoraria, Speakers Bureau.Van Hoef:Lipomed AG:Ended employment in the past 24 months;Roche AG:Current Employment.Perretti:F. Hoffmann-La Roche Ltd:Current Employment.Tomiczek:F. Hoffmann-La Roche Ltd, Basel, Switzerland:Current Employment.Stathis:ADC Therapeutcis:Other, Research Funding;Merck:Other, Research Funding;Pfizer:Other, Research Funding;Loxo:Honoraria, Other, Research Funding;PharmaMar:Other: Travel Grant;Bayer:Other, Research Funding;MEI Pharma:Other, Research Funding;Novartis:Other, Research Funding;Cellestia:Research Funding;Roche:Other, Research Funding;Member of the steering committee of the trial of this abstract:Other;Abbvie:Other: Travel Grant.

OffLabel Disclosure:
GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of pts with previously untreated CLL; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of pts with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemo followed by GAZYVA monotherapy in pts achieving at least a partial remission, for the treatment of adult pts with previously untreated stage II bulky, III or IV FL. RITUXAN (rituximab) is a CD20-directed cytolytic antibody indicated for the treatment of adult pts with: R/R, low grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemo and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy; non-progressing (including SD), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo; previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CD20-positive CLL in combination with FC. RITUXAN HYCELA is a combination of rituximab, a CD20-directed cytolytic antibody, and hyaluronidase human, an endoglycosidase, indicated for the treatment of adult pts with: R/R FL as a single agent; previously untreated FL in combination with first line chemo and, in pts achieving a CR or PR to rituximab in combination with chemo, as single agent maintenance therapy; non-progressing (including SD), FL as a single agent after first-line CVP chemotherapy; previously untreated DLBCL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CLL. TECENTRIQ is a programmed death-ligand 1 (PD-L1) blocking antibody indicated: for the treatment of adult pts with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemo and whose tumors express PD-L1* or are not eligible for any platinum-containing chemo regardless of PD-L1 status, or have PD during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo; for the first-line treatment of adult pts with metastatic NSCLC whose tumors have high PD-L1 expression* with no EGFR or ALK genomic tumor aberrations; in combination with bevacizumab (bev), paclitaxel, and carboplatin, for the first-line treatment of adult pts with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations; in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult pts with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations; for the treatment of adult pts with metastatic NSCLC who have PD during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adult pts with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1*; in combination with carboplatin and etoposide, for the first-line treatment of adult pts with ES-SCLC; in combination with bev for the treatment of pts with unresectable or metastatic HCC who have not received prior systemic therapy. *As determined by an FDA-approved test