Findings in the phase Ib KEYNOTE-013 and phase II KEYNOTE-170 trials, reported in the Journal of Clinical Oncology by Philippe Armand, MD, PhD, of DanaFarber Cancer Institute, and colleagues, indicate that pembrolizumab is active in relapsed or refractory primary mediastinal large B-cell lymphoma.1
Philippe Armand, MD, PhD
The KEYNOTE-170 trial supported the 2018 accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more prior lines of therapy.
As noted by the investigators, primary mediastinal large B-cell lymphoma is associated with frequent amplification or translocation events at 9p24.1 that result in tumor cell surface expression of programmed cell death ligands 1 and 2 (PD-L1, PD-L2). Thus, it was hypothesized that pembrolizumab would be active in the disease.
The analysis included 21 patients in KEYNOTE-013 and 53 patients in KEYNOTE-170 who received pembrolizumab at 200 mg every 3 weeks (10 mg/kg every 2 weeks in the first 10 patients in KEYNOTE-013). Treatment continued for a maximum of 35 cycles or 2 years or until disease progression, unacceptable toxicity, or patient withdrawal.
In the KEYNOTE-013 and KEYNOTE-170 populations, median age was 31 years (range = 22–62 years) and 33 years (range = 20–61 years); 67% and 57% were female; and all had an Eastern Cooperative Oncology Group performance status of 0 (48% and 43%) or 1. In addition, 62% and 74% had undergone no prior transplantation; the median number of prior lines of therapy was three in both studies; 5% and 30% had primary refractory disease; 71% and 32% had received prior radiation therapy; and all patients had received prior rituximab.
Objective response rates on central review using International Working Group 2007 criteria were 48% (complete responses in 7 patients, or 33%) among 21 patients in KEYNOTE-013 and 45% (complete responses in 7 patients, or 13%) among 53 patients in KEYNOTE-170. A complete response based on Lugano criteria was observed in 11 patients (21%) in KEYNOTE-170. Stable disease was observed in an additional 24% of patients in KEYNOTE-013 and 9% of patients in KEYNOTE-170.
After median follow-up of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. Durations of response were 1.9+ to 39.8+ months among responders in KEYNOTE-013, with 78% of responders having a response for at least 12 months, and 1.1+ to 22.0+ months in responders in KEYNOTE-170, with 76% of responders having a response for at least 12 months. At the time of analysis, no patient with a complete response had experienced disease progression, with two patients exhibiting a complete response for at least 1 year off therapy. The median time to response was 2.7 months (range = 1.4–3.4 months) in KEYNOTE-013 and 2.9 months (range = 2.4–8.5 months) in KEYNOTE-170.
The median progression-free survival was 10.4 months in KEYNOTE-013 and 5.5 months in KEYNOTE-170, with 12-month rates of 47% and 38%. The median overall survival was 31.4 months in KEYNOTE-013 and not reached in KEYNOTE-170, with 12-month rates of 65% and 58%. Among 40 patients evaluable for 9p24.1 gene abnormality status, amplification events were frequent, as was expression of PD-L1 on the tumor cell surface.
PD-L1 expression was measured by H score (the product of percentage of malignant tumor cells with membranous staining for PD-L1 and intensity of staining on a 0–3 scale). Among 42 evaluable patients, objective response rates were 25% in those with a PD-L1 H score of 0, 42% in those with a score of 1 to 99, and 64% in those with a score of ≥ 100 (P = .22). PD-L1 expression was significantly associated with progression-free survival.
Treatment-related events of any grade occurred in 71% of patients in KEYNOTE-013 and 57% of patients in KEYNOTE-170; grade 3 or 4 events occurred in 24% and 23%, with the most common being neutropenia in both trials (14% and 13%). One patient discontinued treatment due to treatment-related febrile neutropenia in KEYNOTE-013, and one discontinued treatment due to increased aspartate transaminase levels in KEYNOTE-170. Adverse events led to death in three patients in KEYNOTE-170 (1 patient each from Aspergillus infection, cardiac tamponade, and myocardial infarction), with none of the deaths being considered related to study treatment.
Immune-mediated adverse events occurred in 19% of patients in KEYNOTE-013 (including grade 3 myositis in 1 patient [5%]) and 11% in KEYNOTE-170 (including grade 4 pneumonitis in 1 patient [2%]). In KEYNOTE-013, grade 1 or 2 events consisted of hypothyroidism in two patients (9%) and colitis in one patient (5%). In KEYNOTE-170, grade 1 or 2 events consisted of hypothyroidism in four patients (8%), hyperthyroidism in two (4%), and thyroiditis in one (2%). No patients discontinued treatment due to immune-mediated adverse events, and no deaths were attributed to immune-mediated adverse events.
The investigators concluded: “Pembrolizumab is associated with a high response rate, durable activity, and a manageable safety profile in patients with [relapsed or refractory primary mediastinal large B-cell lymphoma].”
DISCLOSURE: Dr. Armand has had a consultant role with Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichy Sankyo, and Miltenyi; has received research funding (institutional) from Merck, BMS, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and has received honoraria from Merck and BMS. The studies were supported by Merck Sharp & Dohme, a subsidiary of Merck & Co, and others. For full disclosures of the study authors, visit ascopubs.org.
1. Armand P, Rodig S, Melnichenko V, et al: Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol 37:3291-3299, 2019.
Primary mediastinal B-cell lymphoma is an uncommon but distinct clinicopathologic variant of diffuse large B-cell lymphoma (DLBCL) that typically presents with an aggressive mediastinal mass and invasion of local structures. Most patients are young, typically in their 20s and 30s, and there is a...