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

Abstract

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 1st 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. 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.

Safety and efficacy of durvalumab with R-CHOP or R2-CHOP in untreated, high-risk DLBCL: a phase 2, open-label trial

“…When combining the anti-PD-1 antibody pembrolizumab with R-CHOP, among 30 evaluable patients, 23 (77%) achieved a CR and four (13%) achieved a PR at the end of six cycles of R-CHOP; at 24 months, PFS was 83% and OS was 84% [23]. Sequential treatment of previously untreated patients with stage II-IV DLBCL with avelumab, an anti-PD-L1 monoclonal antibody, plus rituximab induction followed by six cycles of R-CHOP and then avelumab maintenance resulted in a high CR rate (89%) and a manageable safety profile, further supporting the potential benefit of immune checkpoint inhibitors as a frontline treatment for high-risk DLBCL [24]. Multiple studies are evaluating the efficacy of nivolumab in combination with agents such as ipilimumab (NCT03305445), rituximab and chemotherapy (NCT03259529), varlilumab (anti-CD27; NCT03038672), epacadostat (indoleamine 2,3-dioxygenase inhibitor; NCT02327078), and lenalidomide (NCT03015896) in patients with DLBCL.…”

DLBCL 1L—What to Expect beyond R-CHOP?

“…In a pilot study, Avelumab and Rituximab were administered for two cycles prior to the start of R-CHOP. In this immunotherapy-only induction phase, a remarkably high ORR of 60% was detected, with PET-negative CR rates in 21% [113]. Although the data require verification, such a strategy might also be particularly interesting for patients who do not qualify for chemotherapy due to comorbidities.…”

“…Another promising approach might be the addition of a PD1 or PD-L1 immune checkpoint blocker, such as Pembrolizumab, Nivolumab or Avelumab. While earlier singleagent investigations of immune checkpoint inhibition (ICI) across lymphoma entities in the R/R setting were rather disappointing [109][110][111], 1L combinations of the PD1 blocker Pembrolizumab or the PD-L1 blocker Avelumab with R-CHOP produced encouraging PFS signals [112,113]. The PD-L1 immune checkpoint blocker Avelumab is particularly interesting, since it may not only act via T-cell derepression but also subjects PD-L1-positive lymphoma cells to ADCC.…”

“…Equally discouraging results were obtained regarding small compounds such as Lenalidomide in the "REMARC" trial or the mTOR inhibitor Everolimus, where no differences in OS were seen [87,[120][121][122]]. Short-term (i.e., six cycles) maintenance therapy with the PD-L1 blocker Avelumab in the previously described Avelumab-R-CHOP trial will provide preliminary data about the efficacy of ICI for long-term disease control in DLBCL [113]. However, for adequate interpretation of potential clinical benefits due to Avelumab maintenance therapy, additional prospective randomized trials are needed.…”

Antibody Therapies for Large B-Cell Lymphoma

“…With a median follow-up of 16 months, 1-year failure-free survival was 76% and OS 89%. 91 The side effects and optimal dosing of avelumab, utomilumab, rituximab, ibrutinib, and combination chemotherapy are also being evaluated in a phase I clinical trial for R/R aggressive B-NHL (aNHL), including DLBCL. 92…”