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. Historically, patients with rrPMBCL have been treated with salvage regimens commonly used for DLBCL such as DHAP, mini-BEAM, transplant, with a 2-year OS of only 15%.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 and overexpresses PD-1 ligands.r
In an ongoing multicentre, international phase Ib study of pembrolizumab in patients with rrPMBCL, eligible patients were those with rrPMBCL who had either relapsed after, or were ineligible for autologous stem cell transplant (ASCT) (Keynote-013).r The first 11 of 19 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 8 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. Primary endpoints 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).
The evidence supporting this protocol is provided by an ongoing multicentre, international phase II trial of pembrolizumab (MK-3475) in patients with rrPMBCL or relapsed/refractory Richter syndrome (rrRS) (Keynote-170; NCT02576990). Eligible participants in the rrPMBCL cohort were those who have either failed ASCT or have failed two or more prior lines of therapy and were ineligible for ASCT.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 assessed by a blinded independent central review using the International Working Group (IWG) response criteria.r Secondary end points 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.
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 |
Zinzani et al 2017r |
Yes |
Yes |
- |
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.2 2018 |
Yes |
N/A |
- |
BCCA |
February 2019 |
Yes |
Yes |
- |
CCO |
January 2018 |
N/A |
Yes |
Approved for Hodgkin lymphoma |
Efficacy
At the analysis cut off date (27 May 2016) of the ongoing phase 1b multi-cohort trial assessing the safety and efficacy of pembrolizumab in patients with rrPMBCL (Keynote-013), 19 patients had been enrolled and treated, with 17 patients included in the efficacy analyses (1 patient withdrew prior to receiving any doses and 1 patient did not receive the primary response assessment by time of data cut off).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.
The ORR was 41% (7/17). Two patients (11.8%) achieved CR, 5 patients (29.4%) achieved PR and 6 patients (35.3%) had SD with 81% of patients attaining an overall decrease in target lesions.
Similar to the phase I study, interim results from the phase II study (Keynote-170) showed a total of 49 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 also 41% by blinded independent central review, with 14% achieving a CR, 28% achieved a PR, 10% had SD with 28% showing progressive disease and 21% had no assessment (i.e., discontinued or died prior to the 24 week imaging assessment).r Pembrolizumab was well-tolerated with 1 year OS of 62%.r
Toxicity
Overall, the interim results from the phase II study (Keynote-170) showed that pembrolizumab was generally well-tolerated. 35% of patients experienced serious adverse effects and 53% experienced treatment-related adverse events (TRAEs).r
TRAEs ≥ Grade 3 included neutropenia (n=5), increased hepatic enzymes (n=2), Clostridium difficile infection (n=1), tumour flare (n=1), asthenia (n=1), and pneumonia (n=1). One patient experienced grade 4 neutropenia. There were no treatment-related deaths.r