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.

Study Details

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.

Responses

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.

Adverse Events

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.

REFERENCE

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.