Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL), however, it is molecularly different from DLBCL and shares many common features with the classical Hodgkin lymphoma (cHL) subtype, nodular sclerosing Hodgkin lymphoma (nsHL).
Most patients with newly diagnosed PMBCL are cured from standard frontline therapy such as DA-R-EPOCH with an overall survival (OS) rate of 97%.r For patients with relapsed/refractory PMBCL (rrPMBCL), however, prognosis is poor with limited treatment options because conventional chemotherapy is often ineffective in this setting.r CD30 expression is observed in over 80% of PMBCL, although it is weaker and more heterogeneous than that observed in classical Hodgkin Lymphoma.r The anti-CD30 immunodrug conjugate brentuximab does not seem to have significant activityr and a phase II trial in patients with rrPMBCL was terminated prematurely due to an unexpectedly low ORR.r Historically, patients with rrPMBCL have been treated with salvage regimens commonly used for DLBCL such as DHAP, mini-BEAM, often followed by transplant, with a 2-year OS of only 15%.r Outcomes are especially poor for patients who are ineligible for or relapse after second-line autologous stem cell transplantation.r
Pembrolizumab is a humanized anti-PD-1 monoclonal antibody that blocks the interaction of PD-1 and its ligands PD-L1 and PD-L2. Pembrolizumab has shown efficacy in cHL and is approved for the treatment of rrHL.r The rationale for pembrolizumab in the treatment of rrPMBCL, is that PMBCL, like cHL, frequently exhibits 9p24.1 alterations (including chromosome amplification) and overexpresses PD-1 ligands.rr
Keynote-013 was a multicentre, international phase Ib study of pembrolizumab in patients with rrPMBCL, followed by a phase II trial (Keynote-170).r For Keynote-013, eligible patients included those with rrPMBCL who had either relapsed after, or were ineligible for autologous stem cell transplant (ASCT).r The first 10 patients received intravenous (IV) pembrolizumab at a dose of 10mg/kg every 2 weeks for the trial’s duration; however, after a study amendment, the subsequent 11 patients received an equivalent regimen with a fixed dose of pembrolizumab 200 mg every 3 weeks. Treatment continued up to 2 years until disease progression or unacceptable toxicity. Treatment response was assessed by PET CT at 6 and 12 weeks, and then every 9 weeks thereafter. For both Keynote-013 and Keynote-170, responses were assessed by a central review using International Working Group 2007 Criteria and Lugano Criteria.r Primary endpoints of Keynote-013 were safety and objective response rate (ORR) by investigator assessment. Secondary endpoints included complete response (CR), duration of response, and time to subsequent lymphoma therapy.
The preliminary efficacy and safety findings in the Keynote-013 trial indicated pembrolizumab has the potential to provide clinical benefit in patients with rrPMBCL and led to the development of the phase II trial (Keynote-170). Together these trials established the clinical benefit and safety of pembrolizumab in this patient population, with almost half of all patients in both studies having an objective and durable response.r
Keynote-170 was a multicentre, international phase II trial of pembrolizumab (MK- 3475) in 53 patients with rrPMBCL or relapsed/refractory Richter syndrome (rrRS). Eligible participants in the rrPMBCL cohort were those who had either failed ASCT or have failed two or more prior lines of therapy and were ineligible for ASCT.r Patients were also required to have an ECOG performance status of 0 or 1 and adequate organ function, and were excluded if they had active CNS involvement or any autoimmune disease with systemic treatment in the past 2 years. Baseline patient characteristics were similar between the 2 studies.r Patients were treated with pembrolizumab 200mg intravenously (IV) every 3 weeks for a maximum of 35 administrations (approximately 2 years) or until disease progression or unacceptable toxicity. Response was assessed by PET CT every 12 weeks. The primary endpoint was the ORR. Secondary endpoints included CR, ORR by investigator assessment, duration of response, OS, and safety/tolerability.
Based on the positive results of the interim data from the Keynote-170 trial,r in June 2018, pembrolizumab was granted accelerated approval by the United States Food and Drug Administration for use in rrPMBCL patients who have progressed after two or more lines of prior therapy. The full trial data was published in 2019.r
Other references related to the use and rationale for pembrolizumab are noted in the reference section below.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Armand et al. 2019r
|
Yes |
Yes |
Interim data published by Zinzani et al. 2017r |
Phase Ib trials |
Zinzani et al. 2016r |
Yes |
N/A |
- |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V.5 2021 |
Yes |
N/A |
- |
BCCA |
February 2019 |
Yes |
Yes |
- |
CCO |
July 2021 |
N/A |
Yes |
Approved for Hodgkin lymphoma |
Efficacy
Twenty-one patients were treated in the phase 1b multi-cohort trial assessing the safety and efficacy of pembrolizumab in patients with rrPMBCL (Keynote-013).r The median age of participants was 30 years, 72% female, with 61% of participants receiving a median of 3 prior lines of therapy and 33% having had prior ASCT.
Using the IWG 2007 criteria for response, the ORR was 48% (7 complete responses (CR), 33%, and 14% partial responses (PR)) among 21 patients. 24% had stable disease (SD), while 19% had progressive disease (PD). Median time to response was 2.7 months. The estimated progression-free survival (PFS) rate at 12 months was 47%, and median OS was 31.4 months.
The phase II study (Keynote-170) showed a total of 53 patients with a median age of 33 years, 55% female, who were heavily pre-treated, receiving a median of three prior lines of therapy.r The ORR was 45% , with 13% achieving a CR (according to the IWG 2007 criteria) and 28% achieving a PR. 9% had SD with 23% showing progressive disease and 23% had no assessment (i.e., discontinued or died prior to the 24 week imaging assessment). 11 patients (21%) had CR with assessment by Lugano criteria. 75% of 40 evaluable patients had an overall reduction from baseline in target lesion size. Median time to response was 2.8 months. Pembrolizumab was well-tolerated with 1-year OS of 62%r and the estimated PFS rate at 12 months was 38%. After a median follow up time of 12.5 months, the median duration of response was not reached. No patient with complete response (in either study, as determined by central review) experienced progression, including 2 patients with complete response for at least 1 year off therapy.
Overall these results showed that almost half of patients in both studies had an objective response. The responses also appeared to be durable, particularly in the patients who achieved complete response.
Toxicity
Overall, the results from the phase IB study (Keynote-013) and the phase II study (Keynote-170) showed that pembrolizumab was generally well-tolerated.r 15 patients (71%) in the Keynote-013 study and 30 patients (57%) in the Keynote-170 study experienced treatment-related adverse events (TRAEs) of any grade.r Grade 3 or 4 events occurred in 5 patients (24%) and 12 patients (23%) in Keynote-013 and Keynote-170 respectively – the most common being neutropenia which occurred in 13-14% and caused one patient in each study to discontinue treatment. There were no treatment-related deaths. Other grade 3/4 TRAEs included myositis in 1 patient and pneumonitis in 1 patient.r