Pembrolizumab (flat dosing)

Indications:

• Monotherapy for relapsed or refractory classical Hodgkin lymphoma
  • following autologous stem cell transplant (ASCT) OR 
  • following at least two prior therapies when ASCT is not a treatment option 

Precautions: 

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

• significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
• organ transplantation
• previous history of viral hepatitis
• HIV/acquired immune deficiency syndrome (AIDS).

Indications:

• Refractory primary mediastinal large B-cell lymphoma, or who have relapsed after 2 or more prior lines of therapy

Precautions: 

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

• significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
• organ transplantation
• previous history of viral hepatitis
• HIV/acquired immune deficiency syndrome (AIDS).

The most common side effects with this treatment are immune-related adverse events (irAEs). irAEs can escalate quickly and close monitoring of the patient is required. Symptoms should improve promptly after the introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice. Refer to the Management of immune related adverse events document for further information.

The rationale for pembrolizumab, a humanised IgG4/k monoAb that blocks binding between PD-1 & its ligands, is due to the fact that malignant Reed-Sternberg cells in classical Hodgkin lymphoma frequently have 9p24.1 alterations, resulting in over-expression of PD-L1 and PD-L2.

The evidence supporting this protocol is provided almost exclusively by a single arm, open label phase II multicentre study (KEYNOTE-087) involving a total of 210 patients in three cohorts.^r 

Cohort 1 - Progression after ASCT and BV - N = 69
Cohort 2 - Progression after salvage chemo and BV - N = 81
Cohort 3 - Progression after ASCT, but no BV post ASCT (may have had 1st or later line)

Pembrolizumab at a flat dose of 200 mg every three weeks was administered without premedication.  These patients were either relapsed post Autologous stem cell transplant (ASCT), ineligible for ASCT and a minority (approximately 58% of cohort 3 (16.6% overall)) were naive to brentuximab vedotin. 

Across all cohorts, the median number of prior lines of therapy was 4 (range, 1 – 12), with 86.7% of patients having received at least three prior lines.

Between June 2015 and March 2016, 210 patients were treated with pembrolizumab 200 mg every 21 days, planned for up to 24 months treatment.  Data cut-off was in September 2016, giving a median duration of exposure of 8 months (0 – 15).  If patients achieved a PET complete response (CR), pembrolizumab cessation could be considered after a minimum of 6 months treatment, with ≥ 2 doses received after achieving CR.  

The primary end point was Overall Response Rate (ORR) by blinded, centralised assessment.  Secondary endpoints included Investigator assessed ORR, CR rate and Overall Survival (OS), however, the data cut-off was too short to enable this assessment.

Other references related to the utility and rationale for pembrolizumab are noted in the reference section below.  A randomised phase 3 trial comparing brentuximab to pembrolizumab in relapsed/refractory classical Hodgkin lymphoma is underway internationally (ClinicalTrials.gov, NCT02684292).

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.  

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Bibliography

Roemer, M. G., R. H. Advani, A. H. Ligon, et al. 2016. "PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome." J Clin Oncol 34(23):2690-2697.

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PURPOSE: Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined. METHODS: We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS). RESULTS: Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL. CONCLUSION: PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

Version 1

As ID 3671 Pembrolizumab replaces the ID 3419 Hodgkin lymphoma pembrolizumab protocol, this History section is  included below for consistency in documentation.