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597 Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Incorporating novel agents and new adoptive cell therapy approaches
Hematology Disease Topics & Pathways:
Biological, therapy sequence, Diseases, Therapies, Combinations, Non-Hodgkin Lymphoma, checkpoint inhibitors, DLBCL, Lymphoid Malignancies
Monday, December 7, 2020: 9:00 AM

Eliza A Hawkes, FRACP, MD, MBBS1,2, Geoffrey Chong, MD2,3, Charmaine Smith4*, Sze-Ting Lee5,6,7*, Leonid Churilov8*, Joseph McKendrick9*, William Renwick10, Piers Blombery, MBBS11,12*, Niles Elizabeth Nelson, BSc, MBBS13*, Tineke Fancourt14*, Joanne Hawking15*, Wendi Lin16*, Andrew M Scott5,6,7*, Allison Barraclough16*, Joel Wight16,17,18, Andrew Grigg, MBBS, MD, FRACP, FRCPA16*, Colm Keane, MD19, Chun Yew Fong, MBBS, PhD, FRACP, FRCPA20,21 and Kate Manos, MBBS16,17

1Department of Medical Oncology and Haematology, Eastern Health, Box Hill, Australia
2Austin Health and Olivia Newton John Cancer Research Institute, Heidelberg, Australia
3Ballarat Regional Integrated Cancer Centre, Melbourne, VIC, Australia
4Cancer Clinical Trials Centre, Olivia Newton-John Cancer & Wellness Centre, Heidelberg, Australia
5School of Cancer Medicine, La Trobe University, Melbourne, Australia
6Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia
7Olivia Newton-John Cancer Research Institute, Melbourne, Australia
8Melbourne Brain Centre, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
9Department of Medical Oncology and Haematology, Eastern Health, Melbourne, Australia
10Department of Haematology, Western Health, Melbourne, Australia
11Department of Pathology, Peter MacCallum Cancer Center, East Melbourne, Australia
12Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
13Peter MacCallum Cancer Centre, Melbourne, Australia
14Department of Anatomical Pathology, Austin Health, Melbourne, VIC, Australia
15Austin Health, Heidelberg, Australia
16Department of Haematology, Austin Health, Melbourne, Australia
17University of Melbourne, Melbourne, Australia
18Townsville University Hospital, Douglas, Australia
19Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia
20Olivia Newton John Cancer Research Institute, Austin Health, Melbourne, VIC, Australia
21Department of Clinical Haematology, Austin Hospital, Melbourne, VIC, Australia


Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate <10%, Ansell JCO 2019), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes. Concurrent ICI with R-CHOP is safe (Smith BJH 2020) but corticosteroid-related immunosuppression may negate ICI efficacy. These factors, along with evidence that ICI sensitises non-Hodgkin lymphoma to subsequent chemotherapy (Carreau BJH 2020), support a sequential treatment strategy.

Avelumab (Av) is an anti-PDL1 monoclonal antibody with antibody dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab (R) in vitro. We report the results of a phase II single arm study assessing safety of 1st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL.


Patients aged ≥18 years, ECOG 0-2 with untreated stage II-IV DLBCL and no active autoimmune disease were treated with AvR induction x2 cycles q2-weekly (Av 10mg/kg IV + R 375mg/m2 IV), followed by R-CHOP21 x 6 cycles then Av 10mg/kg x 6 cycles q2-weekly if in complete metabolic response (CMR) post R-CHOP. The primary endpoint was the rate of grade 3/4 immune-related adverse events (irAE). Secondary endpoints included overall response rate (ORR), failure free survival (FFS), overall survival (OS) and overall toxicity. Response was determined centrally by PET-CT (Lugano 2014 criteria). CMR rates by PET-CT post AvR induction and post C2 R-CHOP were exploratory endpoints. Genomic analysis was performed including next generation sequencing (NGS) based sequence variant detection, copy number analysis and structural variant detection.


28 pts were enrolled from Dec 2017 to Oct 2019. Key baseline characteristics included median age 54 yrs (range 20-79); stage III/IV disease 68%; elevated LDH 61%; IPI ≥2 25%. Histology included 21 DLBCL NOS (75%; 14 GCB, 7 non-GCB by Hans algorithm), 6 primary mediastinal B-cell lymphoma (PMBCL; 21%) and 1 EBV positive DLBCL (4%).

The study met its pre-specified primary endpoint of G3/4 irAE <30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2). G1/2 irAEs occurred in 71% (20/28) as follows: rash 53%, liver dysfunction 26%, hyper/hypothyroidism 29% and diarrhoea 21%. 79% had G3/4 toxicity, predominantly haematological, related to RCHOP with febrile neutropenia/infection in 28% of pts.

ORR post R-CHOP was 89% (all CR) (Figure 1). The ORR to 2 cycles of induction AvR was 60%, including 6 CMR (21%) across all diagnostic/histologic subgroups (n=1 PMBCL, n=2 non-GCB DLBCL, n=3 GCB DLBCL; Figures 1 and 2). Six pts (21%) progressed during AvR induction (with 1 pt completing only 1 x AvR cycle); all subsequently responded to R-CHOP. With a median follow-up of 16 months, 1-year FFS was 76% and OS 89%.

Treatment was discontinued early in 5 pts; 2 during R-CHOP due to progressive disease and 3 during Av maintenance (n=1 immune hepatitis; n=1 pulmonary embolism initially reported as pneumonitis; n=1 progressive disease).

Alterations in the CD274/PDCDLG2 locus were identified by NGS in 3 of 27 evaluable pts (n=2 PMBCL, n=1 EBV+ DLBCL). Full genomic analysis to identify factors associated with response will be presented.


Sequential AvR induction, R-CHOP and Av maintenance in pts with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to AvR alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting. These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL.


Merck KgA for avelumab plus funding. Tour de Cure Scott Canning Early Career Grant (E Hawkes) and Wilson Centre for Lymphoma Genomics for biomarker testing.

Disclosures: Hawkes: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; takeda: Speakers Bureau; Merck KgA: Research Funding. Chong: Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding; Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding. Blombery: Novartis: Consultancy; Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria. Barraclough: Roche: Other: Conference sponsorship. Keane: Celgene: Honoraria, Other: Travel; BMS: Research Funding; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Fong: Pfizer: Honoraria; Astellas: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria. Manos: Bristol-Myers Squibb: Other: Conference sponsorship.

OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody. Inhibition of the PD1/PDL1 pathway stimulates anti-tumour immunity.

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