Avelumab in relapsed/refractory classical Hodgkin lymphoma: phase 1b results from the JAVELIN Hodgkins trial

Abstract

The 9p24.1 chromosomal alteration in classical Hodgkin lymphoma (cHL) is associated with increased expression of programmed death ligand 1 (PD-L1)/PD-L2 and an immunosuppressive tumor microenvironment. Blockade of PD-L1/PD-1 interactions with avelumab (anti-PD-L1) is hypothesized to restore antitumor immunity. JAVELIN Hodgkins was a phase 1b, multiple-dose, open-label, randomized, parallel-arm trial of avelumab in patients with relapsed/refractory (R/R) cHL. Primary end points included avelumab target occupancy by dose/schedule in peripheral blood immune cells and pharmacokinetic parameters. Secondary end points included safety and antitumor activity. Four dose levels and 2 dosing schedules were investigated: 70, 350, and 500 mg administered every 2 weeks; 500 mg every 3 weeks; and 10 mg/kg every 2 weeks. Thirty-one patients with R/R cHL were randomized; 9 (29.0%) and 20 (64.5%) had received 3 or ≥4 prior anticancer treatments, respectively. Target occupancy of >90% was observed across all treatment arms, throughout the dosing interval. Avelumab pharmacokinetic data were similar to those previously reported. The most common treatment-related adverse events of any grade were infusion-related reaction (30.0%), nausea (20.0%), increased alanine aminotransferase and rash (16.7% each), and fatigue (13.3%). The objective response rate (ORR) in all randomized patients was 41.9%, with a complete response rate of 19.4%; ORR in those with prior allogeneic hematopoietic stem cell transplant (allo-HSCT) was 55.6%. Due to decreased use of allo-HSCT in patients with R/R cHL, the expansion phase enrolling post-allo-HSCT patients was terminated. Avelumab was tolerable and demonstrated antitumor activity in heavily pretreated patients with cHL, suggesting that PD-L1 blockade may be sufficient for therapeutic benefit in cHL. This trial was registered at www.clinicaltrials.gov as #NCT02603419.

Conflict of interest statement

Conflict-of-interest disclosure: A.F.H. reports a consultancy/advisory role for Bristol Myers Squibb, Merck & Co, Karyopharm, and Seattle Genetics; and research funding from Bristol Myers Squibb, Genentech, Merck & Co, Pharmacyclics LLC, an AbbVie Company, Kite Pharma, Seattle Genetics, Immune Design, and AstraZeneca. J.R. reports a consultancy/advisory role for Takeda, Bristol Myers Squibb, ADC Therapeutics, and Novartis; owns stock in AstraZeneca and ADC Therapeutics; reports honoraria from Takeda, ADC Therapeutics, and Bristol Myers Squibb; provides speaker/expert testimony for Takeda and ADC Therapeutics; and reports research funding from Takeda. F.M. has received honoraria fees from Takeda and Roche. W.T. has received honoraria and consultancy fees from Roche and Gilead. A.S. reports a consultancy/advisory role for Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme (MSD), Sanofi, and ArQule; and speakers’ bureau work for Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, ArQule, Eli Lilly, Sandoz, Novartis, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD. P.L.Z. reports a consultancy/advisory role for Verastem, Gilead, Janssen-Cilag, Bristol Myers Squibb, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; and speakers’ bureau work for Verastem, Gilead, Janssen-Cilag, Bristol Myers Squibb, Servier, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, and Kyowa Kirin. C.F., S.B., B.H., and A.T. are employees of Pfizer and report stock ownership in Pfizer. G.P.C. has received honoraria for advisory work and research funding from Pfizer; honoraria for advisory and speakers’ bureau work from Roche, Takeda, Gilead, Bristol Myers Squibb, MSD, Celleron, ADC Therapeutics, and BeiGene; and research funding from Bristol Myers Squibb, MSD, Celleron, Amgen, and Celgene. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

PK and pharmacodynamic analyses. (A) Median serum concentration starting on cycle 1 day 1. (B) Median TO on CD14+ monocytes. (C) Median TO on CD3+ T cells. C, cycle; D, day; EOT, end of treatment; Q2W, every 2 weeks; Q3W, every 3 weeks.

Figure 2.

Clinical responses to avelumab. (A) Time to and duration of response among patients with an objective response across treatment groups per investigator assessment. (B) Percentage change in tumor burden per investigator assessment. (C) Best percentage change in tumor burden per investigator assessment. (B-C) Only patients with the largest dominant masses at baseline and ≥1 postbaseline assessment are included. The last measurement prior to the randomization date served as the baseline measurement. Patients missing from this summary were included in the full analysis set but were excluded here due to missing data: no baseline measurements within the 28-day window (n = 2); no appropriate postbaseline measurements (n = 3). Q2W, every 2 weeks; Q3W, every 3 weeks.