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Pembrolizumab (flat dosing)

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer using immunological agents. Before commencing immunotherapy treatment in any patient, clinicians should have an understanding of the immune-related adverse events (irAEs) associated with immunotherapy treatment and their management.

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

This protocol does not have a calculator.

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

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Cycle 1 and further cycles

Drug Dose Route Day
Pembrolizumab 200 mg IV infusion 1
Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity (total maximum of 35 doses or 24 months treatment)
Notes:

In the first few months after the start of immunotherapy, some patients can have a transient tumour flare (termed 'pseudo progression', an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient is believed to be deriving clinical benefit.

Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.

Drug status:

Pembrolizumab: (PBS authority)

Cost:
~ $7,730 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity (total maximum of 35 doses or 24 months treatment)

Cycle 1 and further cycles

Drug Dose Route Day
Pembrolizumab 200 mg IV infusion 1
Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity (total maximum of 35 doses or 24 months treatment)
Notes:

In the first few months after the start of immunotherapy, some patients can have a transient tumour flare (termed 'pseudo progression', an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient is believed to be deriving clinical benefit.

Radiation recall has been observed with PD1 inhibitors, consideration should be given to the timing when starting this treatment after a prolonged course of radiation therapy.

Drug status:

Pembrolizumab: (PBS authority)

Cost:
~ $7,730 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity (total maximum of 35 doses or 24 months treatment)

Indications:

Monotherapy for relapsed or refractory classical Hodgkin lymphoma following:

  • autologous stem cell transplant (ASCT), or
  • 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)
  • previous radiation to the lungs.

Indications:

Relapsed or refractory primary mediastinal large B-cell lymphoma following:

  • autologous stem cell transplant (ASCT), or 
  • at least one prior therapy when ASCT is not a treatment option, or 
  • two or more prior lines of therapy (one of which includes rituximab-based chemotherapy)

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)
  • previous radiation to the lungs.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Emetogenicity MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Complications of allogeneic HSCT

Patients who received allogeneic haematopoietic stem cell transplant (HSCT) following discontinuation of pembrolizumab therapy experienced immune-mediated complications (some fatal) including graft versus host disease (GVHD) and severe sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease) following reduced-intensity conditioning.

 Monitor closely for early signs/symptoms of transplant-related complications (e.g. hyper-acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-mediated adverse reactions) and manage promptly. 
Immune-related adverse events (irAEs)

Immune-related adverse events (irAEs) can occur early and escalate quickly in patients receiving immune checkpoint inhibitors. irAEs can also occur after discontinuation of treatment. Fatalities have been reported. Management of irAEs is largely based on expert opinion and consensus guidelines.

Examples of irAEs with high risk of mortality include:

  • cardiac toxicity: myocarditis
  • musculoskeletal toxicity: myositis
  • neurological toxicity: encephalitis, Guillain-Barré syndrome, myelitis, myasthenia gravis
  • pulmonary toxicity: pneumonitis
  • skin toxicity: Steven-Johnson syndrome, toxic epidermal necrolysis.

Examples of irAEs in order of frequency include:

  • Common
    • endocrinopathies: thyroid dysfunction
    • gastrointestinal toxicity: diarrhoea
    • musculoskeletal toxicity: arthralgia, myalgia
    • skin toxicity: rash, erythema, pruritus
  • Less common
    • endocrinopathies: hypophysitis, type I diabetes mellitus
    • gastrointestinal toxicity: colitis
    • musculoskeletal toxicity: inflammatory arthritis
    • ocular toxicity: dry eye
    • renal toxicity
    • skin toxicity: vitiligo
  • Rare
    • endocrinopathies: primary adrenal insufficiency
    • gastrointestinal toxicity: pancreatitis
    • haematological toxicity
    • musculoskeletal toxicity: vasculitis
    • ocular toxicity: uveitis, iritis.

Proactive monitoring, patient self-monitoring and early reporting of adverse events is critical. Treatment interruptions/discontinuation, consultation with specialist and administration of corticosteroids and/or supportive care is required to minimise the risk of death.

Read more about the management of immune-related adverse events (irAEs)
Baseline investigations

Consider ECG and troponin at baseline. There is no clear evidence regarding the efficacy/value of baseline ECG or troponin in patients receiving immune checkpoint inhibitor therapy. Some cancer specialists obtain baseline testing, and others continue this through the initial period of therapy. Consider urinalysis at baseline, particularly in patients with additional risk factors for developing immune-related acute kidney injury.
Blood tests

FBC, EUC, LFTs, serum cortisol, TFTs and BSL at baseline.

Repeat FBC, EUC, LFTs and BSL prior to each cycle and serum cortisol and TFTs alternate cycles. Check lipase and amylase if symptomatic of pancreatitis.

In the absence of suspicion of immune related adverse events less frequent monitoring may be applicable, according to institutional guidelines. Evidence for the frequency of routine blood testing with immunotherapies varies within published studies and guidelines.

Read more about immunotherapy blood test monitoring recommendations
Hepatitis and HIV

Hepatitis screening is recommended in all patients who are to receive immune checkpoint inhibitors.

Immunotherapy is associated with inflammatory adverse reactions resulting from increased or excessive immune activity and patients are at risk of developing autoimmune hepatitis. It should be used with caution in patients who have a history of chronic hepatic infections (hepatitis B and C), detectable human immunodeficiency virus (HIV) viral load or acquired immune deficiency syndrome (AIDS).
Vaccinations

The safety of having vaccinations during treatment is unknown. Patients in the clinical trials were typically allowed to receive inactivated and recombinant vaccines but not live vaccines.

Read more about COVID-19 vaccines and cancer.
Effects of cancer treatment on fertility

Studies to evaluate the effects of immune checkpoint inhibitor therapy on fertility have not been performed. Therefore, the effect on male and female fertility is unknown. Limited evidence supports that immune checkpoint inhibitor-related hypogonadism due to orchitis and hypophysitis can impact fertility. Immune checkpoint inhibitors can cause fetal harm when given to pregnant women. A pregnancy test should be considered in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. There is very limited evidence to provide guidance regarding contraception timelines. Some studies have demonstrated PD-1 receptor occupancy for greater than 9 months after anti-PD-1 therapy (Brahmer et al., 2010). As a result, some cancer specialists advise using contraception for at least six months or even as long as two years after treatment finishes.

Read more about the effect of cancer treatment on fertility

Link to Brahmer et al., 2010
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • dose reduction is not recommended
  • no dose adjustment is required in the elderly, mild or moderate renal impairment or mild hepatic impairment. Pembrolizumab has not been studied in patients with severe renal impairment or moderate to severe hepatic impairment.

Management of immune-related adverse events (irAEs)

Link to Management of immune-related adverse events (irAEs)

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

Pembrolizumab
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
  Interaction Clinical management
Immunosuppressants (inc. corticosteroids) Reduced efficacy of both immunosuppressants and pembrolizumab possible due to pharmacodynamic interaction

It is recommended that patients requiring corticosteroids prior to treatment receive the lowest possible dose (preferably no greater than 10 mg prednisolone or equivalent steroid per day). Once started on pembrolizumab the use of corticosteroids to treat immune related adverse events (irAEs) does not appear to impact the clinical response to pembrolizumab. In patients requiring ongoing corticosteroids post management of an irAE, the dose should be as low as possible.

Monitor for signs of organ rejection in transplant recipients.

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA website for further information.

Day 1

Approximate treatment time: 60 minutes

Immunotherapy patient assessment prior to each treatment.

Any toxicity may require delay of treatment and review by medical officer before commencing treatment.

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Administer antiemetics if required

Pembrolizumab

Administer pembrolizumab:
  • a low protein binding 0.2 micron to 5 micron in-line or add-on filter must be used
  • attach a second IV line via a luer lock connector as close as possible to the site of injection 
    • this may be required in case of a hypersensitivity reaction.
  • via IV infusion over 30 minutes
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%.
Mild or moderate infusion-related reaction:
  • decrease the rate of infusion and monitor closely 
  • give any further doses with close monitoring
  • premedication with paracetamol and an antihistamine should be considered for further doses.
Severe infusion reaction:
  • stop infusion immediately 
  • medical officer review
  • permanently discontinue pembrolizumab.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Discharge Information

Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

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.

Immune related adverse events
Cardiotoxicity

Cardiotoxicity is a rare but serious side effect, which may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, myocarditis, pericarditis, cardiac fibrosis, hypertension, cardiac ischaemia, congestive heart failure (CHF) and cardiac arrest.

Read more about Management of immune related adverse events.
Gastrointestinal toxicity

Colitis, diarrhoea or more bowel movements than usual; blood or mucous in stools; dark, tarry, sticky stools; abdominal pain or tenderness.

Read more about Management of immune related adverse events
Haematological toxicity

Autoimmune haemolytic anaemia (AIHA), acquired thrombotic thrombocytopenic purpura (TTP), aplastic anaemia (AA), immune thrombocytopenia (ITP), acquired haemophilia (AH), haemolytic uremic syndrome (HUS) and lymphopenia are rare but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Hepatotoxicity

Transaminase and total bilirubin elevation, jaundice, severe nausea or vomiting, pain on the right side of the abdomen, drowsiness, dark urine, bleeding or bruising more easily than normal, anorexia.

Read more about Management of immune related adverse events.
Musculoskeletal toxicity

Inflammatory arthritis, temporal arteritis, arthralgia, myalgia, synovitis, vasculitis, polymyalgia-like syndrome and myositis.

Read more about Management of immune related adverse events.
Neurological toxicity

Aseptic meningitis, myasthenia gravis, Guillain-Barre syndrome, encephalitis, meningeal symptoms, optic neuritis, neuropathy and acute inflammatory demyelinating polyneuropathy are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Ocular toxicity

Eye pain, blurred vision, Uveitis/iritis, episcleritis, blepharitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia. 

Read more about Management of immune related adverse events.
Other endocrinopathies

Type 1 diabetes mellitus, hypophysitis, hypopituitarism and adrenal insufficiency are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events
Pulmonary toxicity

Radiographic changes, dyspnoea, new or worsening cough, hypoxia, tachycardia, chest pain or fever.

Read more about Management of immune related adverse events.
Renal toxicity

Increase in serum creatinine, oliguria, haematuria, peripheral oedema and anorexia.

Read more about Management of immune related adverse events.
Skin toxicity

Rash including full thickness, pruritus, skin blisters, ulceration and necrosis. Radiation recall can occur at site of previous radiation therapy. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about Management of immune related adverse events
Thyroid toxicity

Thyroid toxicity is common with immune checkpoint inhibitors. Hypothyroidism is most frequent however hyperthyroidism can also occur.

Read more about Management of immune related adverse events

Non-immune related adverse events
Fatigue

Read more about fatigue
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting

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 autologous stem cell transplant (ASCT) and brentuximab vedotin (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-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 endpoint 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 BV to pembrolizumab in relapsed/refractory classical Hodgkin lymphoma is underway internationally (ClinicalTrials.gov, NCT02684292).

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Chen et al. 2017r Yes Yes - 
Phase Ib trials  Armand et al. 2016r Yes  N/A  pembrolizumab 10 mg/kg every 2 weeks. 
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V.4 2021 Yes N/A - 
BCCA N/A  N/A N/A - 
CCO July 2021 Yes  Yes  - 

Efficacy

After a median follow up of 8 months, the ORR across all cohorts was 69% (CI 62.3 – 75.2).  The CR rate (CRR) overall was 22.4% (CI 16.9 – 28.6).  Progressive disease (PD) occurred in 14.3% (CI 9.9 – 19.8).r 

© Journal of Clinical Oncology 2017

Interim analysis at 6 months showed OS of 99.5% and progression-free survival (PFS) of 72.4%.  An ad hoc analysis at 9 months (in December 2016), when 97 patients remained on pembrolizumab, showed OS of 97.5% and PFS of 63%.

Figure 1. Reduction in tumour burden from baseline (left) and Kaplan-Meier estimates of objective response duration (right) - A for all patients, B for Cohort 1, C for Cohort 2 and D for Cohort 3.

© Journal of Clinical Oncology 2017

Patients attaining a complete remission (CR) could consider stopping pembrolizumab after a minimum of 6 months of treatment with ≥ 2 doses received after documented CR.r

Updated patient-reported outcomes out to 24 weeks were published in 2019.r There was an improvement in health-related quality of life at each time point across all three cohorts (as measured by The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global health status/quality of life score and EuroQoL Five Dimensions Questionnaire).

Two year follow-up of KEYNOTE-087 was presented at the American Society of Haematology (ASH) meeting in 2018.r Median follow-up was 27.6 months, and 5 of the 210 patients were still receiving pembrolizumab therapy.  The ORR was 71.9% (95% CI, 65.3-77.9) and CRR 27.6% (95% CI, 21.7-34.2), response rate by cohort is seen in table below.r Median duration of response was 16.5 months, median PFS was 13.7 months and median OS was not reached.  OS at 2 years was 90.9% and PFS was 31.3%.

© Blood 2018

Toxicity

Median number of treatment doses was 13.  The most frequent grade 3 or 4 treatment-related toxicities were neutropenia (2%), diarrhoea (1%) and dyspnoea (1%).  4.3% of patients discontinued treatment due to adverse events.  At the time of data cut-off, two patients had died, one in each of cohort 1 and cohort 2.r 

© Journal of Clinical Oncology 2017

The toxicity data was updated at the two year follow-up of KEYNOTE-087 presented at ASH in 2018r.  Adverse events occurred in 72.9% of patients. Hypothyroidism (14.3%), pyrexia (11.4%), fatigue (11%) and rash (11%) were the most common toxicities.  Grade 3 or 4 treatment related toxicities were seen in 11.9% of patients, including neutropenia (2.4%) and diarrhoea (1.4%).  There were no treatment-related deaths.  Drug cessation due to a treatment related adverse event occurred in 6.7% of patients.

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

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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.

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.

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Version 4

Date Summary of changes
14/04/2022

Protocol updated based on the consensus gained at the immunotherapy reference committee meeting held on 4th of March 2022. The following changes have been made across all immune checkpoint inhibitor protocols:

  • Indications and patient populations- previous radiation to the lungs added to precautions.
  • Clinical information- general irAEs, hepatitis and HIV, and fertility blocks updated. Individual irAE-related blocks removed. New block (baseline investigations) added.
  • Patient information- pregnancy and breastfeeding block in general advice section updated.

Version number increased to V.4. 

Version 3

Date Summary of changes
22/10/2021

Protocol reviewed by Haematology reference committee. Indication and evidence for PMBCL updated. Version number increased to V.3, for review in 2 years.

Version 2

Date Summary of changes
18/11/2020

Protocol updated to align with ID 1993 Management of immune-related adverse events (irAEs) clinical resource which has been electronically reviewed and approved by the eviQ immunotherapy reference committee. The following changes have been made across all immune checkpoint inhibitor protocols:

  • Treatment schedule - additional note added: transient tumour flare and radiation recall.
  • Clinical information- cardiotoxicity, haematological toxicity, musculoskeletal toxicity and ocular toxicity added; rheumatological toxicity removed; immunotherapy clinical information changed to alphabetical order.
  • Side effects- haematological added; rheumatological replaced with musculoskeletal; immunotherapy side effects changed to alphabetical order.

Arthralgia and myalgia non-irAE side effect removed to align with other immune checkpoint inhibitor protocols.

Version number increased to V.2.

Version 1

Date Summary of changes
15/11/2019

New multi-indication protocol developed and presented at the Haematology Reference Committee meeting in September. 
Protocol combined ID 3419 Hodgkin lymphoma pembrolizumab and new indication primary mediastinal large B-cell lymphoma.
Approved and published on eviQ.
Review in 1 year.

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

ID 3419 Hodgkin lymphoma pembrolizumab version 1
Date Summary of changes
21/06/2018

New protocol developed and presented at the May Haematology Reference Committee meeting. Discussion continued over email and protocol approved for publication with a second yearly review period. 

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31 Mar 2023