Proposal relating to pembrolizumab (Keytruda), nivolumab (Opdivo), posaconazole (Noxafil) and raltegravir (Isentress)

Medicines Consultation Closed

PHARMAC recently announced a decision to fund nivolumab (Opdivo) for patients with unresectable or metastatic (stage III or IV) melanoma (advanced melanoma) from 1 July 2016.

PHARMAC has now reached a commercially favourable provisional agreement with Merck Sharpe and Dohme (New Zealand) Limited (MSD) for the supply of pembrolizumab (Keytruda) and is seeking feedback on a proposal to:

  • fund pembrolizumab for patients with advanced melanoma, subject to Special Authority criteria.
  • fund a tablet form of the antifungal agent posaconazole (Noxafil).
  • amend the contractual terms of listing of posaconazole oral liquid (Noxafil) and raltegravir (Isentress), without changing the funding of these treatments.

Separate to the provisional agreement with MSD we are also seeking feedback on a proposal to:

  • amend the Special Authority criteria applying to nivolumab so that it would also be funded for patients who experience treatment intolerance on first-line funded pembrolizumab and their cancer has not progressed while taking funded pembrolizumab.
  • establish “programmed cell death-1 (PD-1) inhibitors” as a therapeutic sub-group as defined in PHARMAC’s Operating Policies and Procedures.

All the above changes are proposed for implementation from 1 September 2016.

This proposal to fund pembrolizumab would result in a second PD-1 inhibitor being funded for patients with advanced melanoma. We are not aware of any evidence to support the use of pembrolizumab after nivolumab treatment failure, or vice versa, but the two agents may have different side effect profiles; therefore, they may be useful alternatives to each other in patients who experience early treatment-limiting toxicity. Under this proposal, switching between the two funded PD-1 inhibitor treatments would be permitted within the first 12 weeks of starting funded treatment if the first treatment choice is not tolerated and the patient’s cancer did not progress while on their first treatment.

Feedback sought

PHARMAC welcomes feedback on this proposal. To provide feedback, please submit it in writing by 4 pm on Monday, 11 July 2016 to:

Geraldine MacGibbon
Senior Therapeutic Group Manager / Team Leader
PHARMAC

Email: consult@pharmac.govt.nz

Fax:     04 460 4995
Post:     PO Box 10 254, Wellington 6143

All feedback received before the closing date will be considered by PHARMAC’s Board (or its delegate) prior to making a decision on this proposal.

Feedback we receive is subject to the Official Information Act 1982 (OIA) and we will consider any request to have information withheld in accordance with our obligations under the OIA. Anyone providing feedback, whether on their own account or on behalf of an organisation, and whether in a personal or professional capacity, should be aware that the content of their feedback and their identity may need to be disclosed in response to an OIA request.

We are not able to treat any part of your feedback as confidential unless you specifically request that we do, and then only to the extent permissible under the OIA and other relevant laws and requirements. If you would like us to withhold any commercially sensitive, confidential proprietary, or personal information included in your submission, please clearly state this in your submission and identify the relevant sections of your submission that you would like it withheld. PHARMAC will give due consideration to any such request

Details of the proposal

Pembrolizumab (Keytruda)

  • Pembrolizumab (Keytruda) would 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):

Presentation

Pack size

Price and subsidy

Inj 50 mg vial

1

$2,340.00

Inj 1 mg for ECP

1 mg

$49.14

*The proposed price and subsidy for the 1 mg for ECP presentation assumes 5% wastage based on the expected average dose, dosing schedule and number of patients treated.

  • A confidential rebate would apply to Keytruda which would reduce its net price to the Funder.
  • Pembrolizumab would be listed in the Pharmaceutical Schedule as a Pharmaceutical Cancer Treatment only (PCT only – Specialist), meaning that only DHB hospitals would be able to claim for its use.
  • Pembrolizumab would 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);
  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 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. 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 would apply in Part II of Section H of the Pharmaceutical Schedule (the Hospital Medicines List; HML).

Nivolumab (Opdivo)

  • The Special Authority criteria applying to nivolumab would be amended from 1 September 2016 as follows (additions in bold):

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 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. 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 would be made to the restrictions in Part II of Section H of the Pharmaceutical Schedule from 1 September 2016.

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

  • From 1 September 2016, “programmed cell death-1 (PD-1) inhibitors” would 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).”
  • See the Background section of this consultation letter for more information.

Posaconazole (Noxafil)

  • Posaconazole 100 mg modified-release tablets (Noxafil) would be listed in Section B and Part II of Section H of the Pharmaceutical from 1 September 2016 at a price and subsidy of $869.86 per pack of 24 tablets (ex-manufacturer, excluding GST).
  • Posaconazole 100 mg modified-release tablets would 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 would apply to all funded formulations of Noxafil which would reduce their net price to the Funder.
  • All funded formulations of Noxafil would have protection from delisting and subsidy reduction until 30 June 2019.
  • No other changes to the current listing of posaconazole oral liquid 40 mg per ml are proposed.

Raltegravir (Isentress)

  • Raltegravir 400 mg tablets (Isentress) would have protection from delisting and subsidy reduction until 30 June 2019.
  • No other changes to the current listing of raltegravir 400 mg tablets, or the current rebate arrangement, are proposed.

Background

Pembrolizumab

Pembrolizumab is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults. The recommended dose of pembrolizumab is 2 mg/kg administered intravenously over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Pembrolizumab is a monoclonal antibody in a class of treatment known as “PD-1 inhibitors”. PD-1 inhibitors block the interaction between the PD-1 receptor, located on T-cells, and its ligands PD-L1 and PD-L2, expressed by antigen-presenting or tumour cells. PD-1 down-regulates the immune system; therefore, PD-1 inhibitors work by activating the patient’s own immune system to attack the cancer cells.

Other treatments in this class include nivolumab (Opdivo), atezolizumab (MPDL3280A) and durvalumab (MEDI4736) – the latter two of which are currently in clinical trials and are not yet registered in New Zealand or overseas for advanced melanoma.

PHARMAC recently announced a decision to fund nivolumab for patients with advanced melanoma from 1 July 2016. Nivolumab is also registered as monotherapy for the treatment of unresectable or metastatic melanoma. The recommended dose of nivolumab is 3 mg/kg administered intravenously over 60 minutes every 2 weeks.

PHARMAC has now reached a commercially favourable agreement with MSD for the supply of pembrolizumab from 1 September 2016.

This proposal to fund pembrolizumab would result in a second PD-1 inhibitor being funded for patients with advanced melanoma. We are not aware of any evidence to support the use of pembrolizumab after nivolumab treatment failure, or vice versa, but the two agents may have different side effect profiles; therefore, they may be useful alternatives to each other in patients who experience early treatment-limiting toxicity. Under this proposal, switching between the two funded PD-1 inhibitor treatments would be permitted within the first 12 weeks of starting funded treatment if the first treatment choice is not tolerated and the patient’s cancer did not progress while on their first treatment.

Clinical advice

As previously advised, PHARMAC has been carefully assessing the funding of PD-1 inhibitors for advanced melanoma. The pembrolizumab (Keytruda) funding application was assessed by PHARMAC’s Cancer Treatments Subcommittee (CaTSoP) in September 2015. In November 2015 our Pharmacology and Therapeutics Advisory Committee (PTAC) reviewed the funding application and CaTSoP’s advice.

Both committees recommended that pembrolizumab be funded for the treatment of advanced melanoma with a low priority. They noted that the low priority rating was influenced by the early evidence base, and consequent uncertainty about pembrolizumab's longer term benefits and potential risks, as well as its very high cost (see here).

Establishment of PD-1 inhibitors as a therapeutic subgroup

Recent advice from PTAC (May 2016) is that, although there are no head-to-head studies, the currently available evidence is consistent with different PD-1 inhibitors (ie pembrolizumab and nivolumab) having similar efficacy. This view is supported by oncologist feedback we received in response to consultation on the proposal to fund nivolumab.

Oncologists told us 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.

Despite PHARMAC’s favourable negotiations with the suppliers for reduced pricing, PD-1 inhibitors remain expensive treatments that are also likely to be registered to treat other types of cancer in the future. Given current and future competition in this market, PHARMAC considers that it is important to be able to create opportunities for future savings.

Establishing a “PD-1 inhibitors” therapeutic sub-group would enable reference pricing to be applied to this therapeutic sub-group in the future. Reference pricing means that all pharmaceuticals in any given therapeutic sub-group would be subsidised at the level of the lowest priced pharmaceutical in that sub-group.

PHARMAC is not bound to apply reference pricing in every situation, or in the same way in every situation, where pharmaceuticals have been classified into a therapeutic sub-group. PHARMAC may also exempt certain pharmaceuticals from reference pricing, or groups of pharmaceuticals or to groups of patients, provided that PHARMAC consults on any proposed exemption before making its decision. PHARMAC would consult before making any decisions about reference pricing in this therapeutic sub-group.

See PHARMAC’s Operating Policies and Procedures for more information on the creation of therapeutic sub-groups and reference pricing.

Posaconazole

Posaconazole (Noxafil) modified-release tablets and oral liquid are indicated for use in the treatment of invasive fungal infections in patients 18 years of age or older.

Posaconazole oral liquid 40 mg per ml is currently funded subject to Special Authority criteria for patients with acute myeloid leukaemia treated with high-dose chemotherapy and for patients with a stem cell transplant and graft versus host disease on significant immunosuppressive therapy.

This proposal would see a tablet form of the same treatment available for the same patient group.

Clinical advice

In November 2015 the Anti-infective Subcommittee of PTAC advised that there are a number of issues related to the use of posaconazole liquid, including palatability and the requirement that it is taken with a high-fat meal. PTAC considered that a number of these issues could be overcome with the introduction of a modified-release tablet.

Raltegravir

Raltegravir (Istentress) tablets are indicated, in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus (HIV-1) infection. Raltegravir tablets are funded subject to the same Special Authority criteria that apply to other HIV treatments.

PHARMAC is not proposing any changes to the funding of raltegravir. The only change would be to the terms of the contractual arrangement with MSD for the supply of raltegravir; specifically, only for the time period of subsidy and delisting protection.