Decision regarding funding of pembrolizumab (Keytruda), nivolumab (Opdivo), posaconazole (Noxafil) and raltegravir (Isentress)

Medicines Decision

PHARMAC is pleased to announce the approval of an agreement with Merck Sharpe and Dohme (New Zealand) Limited (MSD) for the funding of pembrolizumab (Keytruda), posaconazole (Noxafil) and raltegravir (Isentress) and decisions to amend the Special Authority criteria applying to nivolumab and establish a “programmed cell death-1 (PD-1) inhibitors” therapeutic sub-group from 1 September 2016.

This was the subject of a consultation letter dated 28 June 2016, available on PHARMAC’s website. No changes were made to the proposal following consultation.

In summary, the effect of the decisions is that from 1 September 2016:

  • pembrolizumab (Keytruda) will be fully funded in DHB hospitals for the treatment of patients with unresectable or metastatic (advanced) melanoma, subject to the same clinical criteria as nivolumab.
  • a tablet form of the antifungal agent posaconazole (Noxafil) will be fully funded in DHB hospitals and the community, subject to certain clinical criteria being met.
  • the contractual terms of listing posaconazole oral liquid (Noxafil) and raltegravir (Isentress) will be amended, without changing the funding of these treatments.
  • the Special Authority criteria applying to nivolumab (Opdivo) will be amended so that it will also be funded for patients who experience early treatment intolerance on first-line pembrolizumab.
  • “programmed cell death-1 (PD-1) inhibitors” will be established as a therapeutic sub-group as defined in PHARMAC’s Operating Policies and Procedures.

Evolution of evidence of PD-1 inhibitors

The proposal to fund pembrolizumab is a result of evolving information and better commercial proposals over time. This has been summarised below, as a sequence of specific phases:

  • September 2015 – funding application to fund pembrolizumab was received.
    • PHARMAC’s clinical advisers gave this application a low funding priority – influenced by the early evidence base, uncertainty about the longer term benefits and risks, and the very high cost.
    • The application remained under review as PHARMAC continued discussions with the supplier over supply terms and pricing.
  • April 2016 – funding application to fund a competitor product, nivolumab, was received.
    • Clinical advice from the Pharmacology and Therapeutics Advisory Committee (PTAC) and the Cancer Treatments Subcommittee of PTAC (CaTSoP) was that the evidence for this treatment was, at the time, stronger than for pembrolizumab due to the clinical trial design.
    • PHARMAC continued discussions with the suppliers of both products over supply terms and pricing.
  • May 2016 – consulted on the funding of nivolumab
    • It was during this consultation that our view of the evidence base for the class of medicines pembrolizumab and nivolumab are a part of, known as PD-1 inhibitors, evolved. This occurred as a result of two key inputs:
      • a consensus statement from a number of medical oncologists who told PHARMAC that, in their view, nivolumab and pembrolizumab are considered clinically similar to the extent that they were comfortable switching patients from one treatment to the other; and
      • further advice from PTAC and CaTSoP was received. They noted that the currently available evidence is consistent with different PD-1 inhibitors (i.e. pembrolizumab and nivolumab) providing the same or similar therapeutic effect in the treatment of advanced melanoma.
  • June 2016 – decision made on the funding of nivolumab from 1 July 2016 and consulted on the funding of pembrolizumab
    • As a result of the evolution of evidence, PHARMAC was more confident in the clinical efficacy and long term benefits of pembrolizumab.
    • The commercial terms that PHARMAC was able to secure through negotiations with MSD were significantly better than in the original funding application.
  • July 2016 – decision made on the funding of pembrolizumab from 1 September 2016.

Throughout this whole process, PHARMAC has remained open-minded to funding pembrolizumab and has worked constructively with the supplier to reach a favourable commercial arrangement.

Details of the decision

Pembrolizumab (Keytruda)

  • Pembrolizumab will be listed in Section B and Part II of Section H of the Pharmaceutical Schedule from 1 September 2016 at the following prices and subsidies (ex-manufacturer, excluding GST): 
Chemical and presentation Brand Pack size Price and subsidy
Pembrolizumab inj 50 mg vial Keytruda 1 $2,340.00
Pembrolizumab inj 1 mg for ECP Baxter 1 mg $49.14
  • A confidential rebate will apply to Keytruda that will reduce its net price to the Funder.
  • Pembrolizumab will be listed in the Pharmaceutical Schedule as a Pharmaceutical Cancer Treatment only (PCT only – Specialist), meaning that only DHB hospitals will be able to claim for its use.
  • Pembrolizumab will be listed in Section B of the Pharmaceutical Schedule, for claiming purposes only, subject to the following Special Authority criteria:

Special Authority for Subsidy

Initial Application — (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 4 months for applications meeting the following criteria:

All of the following:

  1. Patient has metastatic or unresectable melanoma stage III or IV; and
  2. Patient has measurable disease as defined by the presence of at least one CT or MRI measurable lesion; and
  3. Either:
    1. Patient has not received funded nivolumab; or
    2. Both:
      1. Patient has received an initial Special Authority approval for nivolumab and has discontinued nivolumab within 12 weeks of starting treatment due to intolerance; and
      2. The cancer did not progress while the patient was on nivolumab; and
  4. Pembrolizumab is to be used at a maximum dose of 2 mg/kg every 3 weeks for a maximum of 12 weeks (4 cycles); and
  5. Baseline measurement of overall tumour burden is documented (see Note); and
  6. Documentation confirming that the patient has been informed and acknowledges that the initial funded treatment period of pembrolizumab will not be continued beyond 12 weeks (4 cycles) if their disease progresses during this time.

Renewal— (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 4 months for applications meeting the following criteria:

All of the following:

  1. Any of the following:
    1. Patient’s disease has had a complete response to treatment according to RECIST criteria (see Note); or
    2. Patient’s disease has had a partial response to treatment according to RECIST criteria (see Note); or
    3. Patient has stable disease according to RECIST criteria (see Note); and
  2. Response to treatment in target lesions has been determined by radiologic assessment (CT or MRI scan) following the most recent treatment period; and
  3. No evidence of progressive disease according to RECIST criteria (see Note); and
  4. The treatment remains clinically appropriate and the patient is benefitting from the treatment; and
  5. Pembrolizumab is to be used at a maximum dose of 2 mg/kg every 3 weeks for a maximum of 12 weeks (4 cycles).

Notes:

Disease responses to be assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47). Assessments of overall tumour burden and measurable disease to be undertaken on a minimum of one lesion and maximum of 5 target lesions (maximum two lesions per organ). Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, and suitable for reproducible repeated measurements. Target lesion measurements should be assessed using CT or MRI imaging with the same method of assessment and the same technique used to characterise each identified and reported lesion at baseline and every 12 weeks. Response definitions as follows:

  • Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
  • Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
  • Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.
  • The same restrictions will apply in Part II of Section H of the Pharmaceutical Schedule (the Hospital Medicines List; HML).
  • The Special Authority criteria applying to nivolumab will be amended from 1 September 2016 as follows (additions in bold):

Nivolumab (Opdivo)

Special Authority for Subsidy

Initial Application — (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 4 months for applications meeting the following criteria:

All of the following:

  1. Patient has metastatic or unresectable melanoma stage III or IV; and
  2. Patient has measurable disease as defined by the presence of at least one CT or MRI measurable lesion; and
  3. Either:
    1. Patient has not received funded pembrolizumab; or
    2. Both:
      1. Patient has received an initial Special Authority approval for pembrolizumab and has discontinued pembrolizumab within 12 weeks of starting treatment due to intolerance; and
      2. The cancer did not progress while the patient was on pembrolizumab; and
  4. Nivolumab is to be used at a maximum dose of 3 mg/kg every 2 weeks for a maximum of 12 weeks (6 cycles); and
  5. Baseline measurement of overall tumour burden is documented (see Note); and
  6. Documentation confirming that the patient has been informed and acknowledges that the initial funded treatment period of nivolumab will not be continued beyond 12 weeks (6 cycles) if their disease progresses during this time.

Renewal— (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 4 months for applications meeting the following criteria:

All of the following:

  1. Any of the following:
    1. Patient’s disease has had a complete response to treatment according to RECIST criteria (see Note); or
    2. Patient’s disease has had a partial response to treatment according to RECIST criteria (see Note); or
    3. Patient has stable disease according to RECIST criteria (see Note); and
  2. Response to treatment in target lesions has been determined by radiologic assessment (CT or MRI scan) following the most recent treatment period; and
  3. No evidence of progressive disease according to RECIST criteria (see Note); and
  4. The treatment remains clinically appropriate and the patient is benefitting from the treatment; and
  5. Nivolumab will be used at a maximum dose of 3 mg/kg every 2 weeks for a maximum of 12 weeks (6 cycles).

Notes:

Disease responses to be assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47). Assessments of overall tumour burden and measurable disease to be undertaken on a minimum of one lesion and maximum of 5 target lesions (maximum two lesions per organ). Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, and suitable for reproducible repeated measurements. Target lesion measurements should be assessed using CT or MRI imaging with the same method of assessment and the same technique used to characterise each identified and reported lesion at baseline and every 12 weeks. Response definitions as follows:

  • Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
  • Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
  • Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.
  • The same changes will be made to the restrictions in Part II of Section H of the Pharmaceutical Schedule from 1 September 2016.
  • From 1 September 2016, “programmed cell death-1 (PD-1) inhibitors” will be established as a therapeutic sub-group, as defined in PHARMAC’s Operating Policies and Procedures. A therapeutic sub-group is defined as “a set of pharmaceuticals that produce the same or similar therapeutic effect in treating the same or similar condition(s).”

Establishment of PD-1 inhibitors as a therapeutic sub-group

Posaconazole (Noxafil)

  • Posaconazole 100 mg modified-release tablets will be listed on the Pharmaceutical Schedule subject to the same Special Authority criteria and hospital restrictions that currently apply to posaconazole oral liquid 40 mg per ml (Noxafil).
  • A confidential rebate will apply to all funded formulations of Noxafil that will reduce their net price to the Funder.
  • All funded formulations of Noxafil will have protection from delisting and subsidy reduction until 30 June 2019.

Raltegravir (Isentress)

  • Raltegravir 400 mg tablets (Isentress) will have protection from delisting and subsidy reduction until 30 June 2019.

Feedback received

We appreciate all of the feedback that we received and acknowledge the time people took to respond. All consultation responses received by 15 July 2016 were considered in their entirety in making a decision on the proposed changes. Most responses were supportive of the proposal, and the following issues were raised in relation to specific aspects of the proposal:

Theme Comment
Several responders were supportive of pembrolizumab and nivolumab being considered clinically similar and the establishment of a PD-1 inhibitor therapeutic subgroup.  Noted.
Several responders raised concerns regarding resource implications for DHBs.  PHARMAC’s assessments and economic analysis take into account costs to the health system including costs associated with compounding, administration and monitoring; however we acknowledge that decisions will have financial and resourcing impacts on DHBs over and above the pharmaceutical costs which are funded by PHARMAC. The impact on DHB services was assessed as part of the decision to fund nivolumab. We consider that funding of pembrolizumab will reduce the impact on DHB infusion services, compared with nivolumab funding. 
Two responders noted the potential for patient confusion regarding the efficacy of pembrolizumab and nivolumab.  We acknowledge the potential for confusion that may have occurred over the timeframe of PHARMAC’s consideration of PD-1 inhibitor funding. Our views reflect the evolving information over time, which is detailed at the beginning of this notification. We will continue to monitor and review any new evidence for these treatments as it becomes available. 
One responder requested consideration of wastage for posaconazole modified-release tablets and raltegravir.  We consider that it is unnecessary to apply the wastage rule to these products.PHARMAC staff note that raltegravir is not a new listing and raltegrevir does not currently have wastage applied.We anticipate that clinicians would manage the supply of posaconazole tablets in the same manner as the currently funded oral liquid by prescribing to the original pack size.  
One responder raised concerns that the contractual extension for raltegravir may defer or delay possible funding of a once daily integrase strand transfer inhibitors.  The contractual terms that have been negotiated with the supplier of raltegravir would not restrict PHARMAC’s ability to list further integrase strand transfer inhibitors.

More information

If you have any questions about this decision, you can email us at enquiry@pharmac.govt.nz or call our toll free number (9 am to 5 pm, Monday to Friday) on 0800 66 00 50.