Avelumab Shows Clinical Activity in Relapsed/Refractory Extranodal Natural Killer/T-Cell Lymphoma

Avelumab is clinically active in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL), although researchers observed a lower-than-expected response rate, according to results from a phase II trial published in Blood. Investigators also found that high PD-L1 expression correlated with achievement of a complete response (CR), suggesting assessment of PD-L1 expression in this patient population could help stratify which patients may experience benefit with avelumab.

Patients with newly diagnosed ENKTL are often treated with non–anthracycline-based chemotherapy with L-asparaginase, study authors, led by Seok Jin Kim, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul, Korea, explained. Treatment options become limited once these patients become refractory to this therapy, however, indicating the need for more effective alternative therapies.

Avelumab is an anti–PD-L1 immunoglobulin G1 monoclonal antibody approved for metastatic Merkel cell carcinoma. Given the previously established association between PD-L1 expression and outcomes with pembrolizumab treatment in ENKTL, blockade of PD-L1 with avelumab may be an appropriate option for relapsed or refractory ENKTL.

In this phase II trial, 21 patients with relapsed or refractory ENKTL received intravenous avelumab 10 mg/kg on days one and 15 of a 28-day cycle. Treatment with single-agent avelumab continued until the incidence of an unacceptable adverse event (AE), disease progression, investigator decision, or withdrawal of consent.

In the overall cohort, the median age was 54 years and ranged between 24 and 78 years. The Eastern Cooperative Oncology Group performance status score in all but one patient was 0 or 1, and 17 patients had stage IV disease at the time of enrollment. Most patients (n=14) were treated with at least two prior therapies before study enrollment, including five whose disease relapsed following autologous hematopoietic cell transplant and 13 whose disease was refractory to the last therapy.

All participants started treatment with non–anthracycline-based chemotherapy.

The rate of CR (the study’s primary endpoint) was 24%, and the overall response rate was 38%. The study did not meet the primary endpoint, as the trial was terminated early before enrollment of the planned number of patients. Investigators noted that the trial ended early due to a lower-than-expected response rate.

According to the researchers, responses to avelumab were not associated with stage I/II versus III/IV, primary refractory disease versus relapsed disease, whole blood Epstein-Barr virus DNA titers, or the 5-variable PINK-E risk score.

Patients who did not initially respond to treatment had early disease progression, while five responders to therapy continue to receive avelumab and maintain their response. Over a median follow-up period of 15.7 months, the median progression-free survival was 2.7 months and the median overall survival was not reached.

Researchers also obtained and analyzed blood samples prior to and after treatment to assess cytokines and soluble PD1, PD-L1, and PD-L2. Patients were categorized as being “PD-L1 high” (n=11) and “PD-L1 low (n=10) based on their PD-L1 score. More responders to avelumab had high PD-L1 compared with low PD-L1 expression (p=0.001). Patients who achieved CR had significantly higher PD-L1 scores versus patients with progressive response and stable disease/progressive disease (p=0.001). No difference was found between responders and nonresponders in terms of tumor mutation burden (p=0.167).

“The response rate was remarkably durable … These results implied that avelumab could induce prolonged remission if patients respond to this drug.”

—Seok Jin Kim, MD, PhD

Treatment-related AEs were predominantly grade 1 or 2, the authors reported, and there were no grade 4 AEs. Grade 3 AEs included neutropenia (10%), thrombocytopenia (5%), fatigue (5%), infusion-related reaction (5%), and sore throat (5%). All events were considered manageable.

“Although the number of patients achieving CR was lower than expected, the response was remarkably durable, with the longest response duration being greater than 25 months,” they wrote. “These results implied that avelumab could induce prolonged remission if patients respond to this drug. Thus, the selection of patients with ENKTL who have a high probability of responding to avelumab might be important to improve the efficacy of avelumab.”

The study is limited by the small number of patients. Low enrollment was primarily caused by the early termination of the trial.

Study authors report relationships with Merck, which sponsored this trial.


Kim SJ, Lim JQ, Laurensia Y, et al. Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood. 2020 August 7. [Epub ahead of print]