Pembrolizumab Active in Relapsed Mediastinal Large B-Cell Lymphoma

Pier Luigi Zinzani, MD, PhD

Pembrolizumab (Keytruda) demonstrated antitumor activity in the majority of patients with recurrent/refractory primary mediastinal large B-cell lymphoma (rrPMBCL), according to an interim analysis of findings from the phase II KEYNOTE-170 trial.

The study’s primary endpoint, objective response rate (ORR) by blinded independent central review (BICR), was 41% based on 29 patients (95% CI, 24—61). Four patients (14%) showed complete response (CR) and 28% a partial response (PR). Stable disease was reported in 3 patients, 8 patients experienced progressive disease, and 6 patients were not assessed. Responses were ongoing in 10 patients at the time of data cutoff December 7, 2016.

“Although 80% of patients with PMBCL are cured with standard frontline rituximab therapy, those who are refractory to standard treatment have a poor prognosis and few treatment options,” noted Pier Luigi Zinzani MD, who presented the results at the 2017 International Conference on Malignant Lymphoma (ICML) biennial meeting in Lugano, Switzerland. “With only about 200 patients are diagnosed in the US yearly, the ability to conduct clinical trials to discover new treatment options is limited by small patient numbers.”

PMBCL frequently harbors genetic abnormalities at the 9p24 locus leading to the overexpression of PD-L1 and PD-L2, which may contribute to an immune evasion mechanism, according to Zinzani. “This may be targeted by PD-1 blockade with the anti-PD-1 antibody, pembrolizumab, which may restore tumor immune surveillance in PMBCL.”

Zinzani, an associate professor at the Institute of Hematology, University of Bologna, presented data from a preliminary analysis of 49 patients in the rrPMBCL cohort of the KEYNOTE-170 study. The planned enrollment is 53 patients for this cohort, who are required to have Richter syndrome and to have failed or have been ineligible for autologous stem cell transplant (auto SCT) and have ECOG performance status of 0-1.

Additionally, no patients undergoing allogenic SCT within 5 years or with autoimmune disease are allowed. The patients were a median age of 33 years (range, 20— 61) and had received a median 3 lines of prior therapy (range, 2–8), including 31% with prior radiation. All patients on the study had received prior rituximab therapy.

Pembrolizumab at 200 mg IV every 3 weeks is administered in the ongoing trial until disease progression, unacceptable toxicity, or completion of 35 treatment cycles. ORR by BICR is key secondary endpoints, including ORR by investigator assessment and adverse events (AEs), are assessed every 12 weeks. Patients achieving CR are allowed to discontinue treatment after ≥24 weeks.

At median follow-up of 6.6 months (range, 0.1—13.6), 73% of patients demonstrated reduction of target lesions >50% from baseline. The median duration of response was not reached (range, 1.1–8.2+ months) and the median time to response was 2.9 months (range, 2.4–8.5).

The ORR with pembrolizumab was strongest (60%) in the subgroup of patients who had failed auto SCT; 3 (30%) patients in this group each achieved CR and PR, respectively, compared with the auto SCT—ineligible subgroup where the ORR was 32%, with 1 patient achieving CR and 5 patients showing PR.

“In a cohort of patients with rrPMBCL, many of whom were heavily pretreated, pembrolizumab showed promising antitumor activity together with a manageable safety profile,” Zinzani said.

The safety population included 49 patients. One patient discontinued treatment due to an AE. Treatment-related AEs were reported in 53% of patients including neutropenia (18%), and 6% of patients each had asthenia, and pyrexia. Immune-related AEs included hypothyroidism and hyperthyroidism (both grade 2) in 6% of patients each, and grade 2 pneumonitis and grade 1 thyroiditis each occurred in 2% of patients. No treatment-related deaths were reported.

The KEYNOTE-170 trial (NCT02576990) is ongoing and recruiting participants. Pembrolizumab received an accelerated FDA approval in March 2017 for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after 3 or more prior lines of therapy.

Zinzani P, Thieblemont C, Melnichenko V, et al. Efficacy and safety of pembrolizumab in relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL): interim analysis of the KEYNOTE-170 phase 2 trial. Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. doi: 10.1002/hon.2437_49.