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

Background:

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 1^st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL.

Methods:

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.

Results:

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.

Conclusion:

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.

Acknowledgements:

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.