Proposal to list nivolumab (Opdivo) for advanced melanoma

Medicines Consultation Closed

New Zealand has a very high incidence of advanced melanoma (metastatic or unresectable Stage III and IV melanoma) for which there is an unmet health need for effective treatment options.

Following PHARMAC’s careful assessment of the available evidence for relevant treatments, we are seeking feedback on a proposal to list nivolumab (Opdivo) on the Pharmaceutical Schedule through a provisional agreement with Bristol-Myers Squibb from 1 July 2016 for patients with unresectable or metastatic (advanced) melanoma.

In summary, this proposal would mean that from 1 July 2016 nivolumab would be fully funded, subject to certain clinical criteria being met, for patients with metastatic or unresectable (advanced) melanoma.

Context

PHARMAC has been carefully assessing the funding of PD-1 inhibitors for advanced melanoma since Medsafe consent was granted for pembrolizumab in September 2015. We have reviewed all the evidence about these treatments that has been submitted and, having received advice from our specialist advisors, it is our current view that nivolumab (Opdivo) has better quality clinical trials with data showing a more certain survival impact. We were also able to negotiate better commercial terms with the supplier Bristol-Myers Squibb.

Being an area of unmet health need, PHARMAC has been keen for its independent expert clinical advisors to carefully review the available evidence for such treatments as quickly as they can. A summary of that assessment process is set out in the Background section below.

For the avoidance of doubt, the funding application for pembrolizumab (Keytruda) remains open and PHARMAC will continue talking with its supplier, Merck Sharpe & Dohme. We remain open minded about future funding opportunities.

Feedback sought

PHARMAC welcomes feedback on this proposal. To provide feedback, please submit it in writing by Wednesday, 25 May 2016 to:

Danae Staples-Moon
Therapeutic Group Manager
PHARMAC
PO Box 10254
Wellington 6143

Email: danae.staples-moon@pharmac.govt.nz
Fax: 04 460 4995

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

  • Nivolumab (Opdivo) would be listed in Section B and Part II of Section H of the Pharmaceutical Schedule from 1 July 2016 at the following prices and subsidies (ex-manufacturer, excluding GST):
    Presentation Pack size Price and subsidy
    Inj 10 mg per ml, 4 ml 1 $1,051.98
    Inj 10 mg per ml, 10 ml 1 $2,629.96
    Inj 1 mg for ECP 1 mg $27.62*

    *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 Opdivo which would reduce its net price to the Funder.
  • Nivolumab would be listed as a Pharmaceutical Cancer Treatment only (PCT only – Specialist), meaning that only DHB hospitals would be able to claim for its use.
  • Nivolumab would be listed in Section B of the Pharmaceutical Schedule for claiming purposes only, subject to the following special authority criteria:

Initial application – (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 3 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. Nivolumab is to be used as monotherapy at a maximum dose of 3 mg/kg every 2 weeks for a maximum of 12 weeks (6 cycles); and
  4. Baseline measurement of overall tumour burden is documented (see Note); and
  5. 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 if their disease progresses during this time.

Renewal – (unresectable or metastatic melanoma) only from a medical oncologist. Approvals valid for 3 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 12 weeks of treatment; and
  3. No evidence of progressive disease (PD) 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 as monotherapy 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 restrictions would apply in Part II of Section H of the Pharmaceutical Schedule (the Hospital Medicines List; HML).
  • Nivolumab would be administered by DHB hospital infusion services (see background section below for more details regarding dosing and administration).

It is estimated that 350 patients per year with advanced melanoma would be eligible to receive funded treatment with nivolumab under the proposed Special Authority criteria. However PHARMAC’s clinical advice indicates it is reasonable to expect at least 700 patients in year one if a new treatment for advanced melanoma was funded.

As well as the service required to administer nivolumab and monitor disease response, there would be resource implications for DHB hospitals for monitoring adverse events in patients with advanced melanoma receiving nivolumab.

Some patients treated with immune stimulating agents like nivolumab have different patterns of response and may develop progression of disease as measured by conventional RECIST criteria and subsequently demonstrate clinical objective responses and/or stable disease. This is referred to as ‘pseudo-progression’ (where a patient’s disease may initially appear to have progressed but then show a response shortly afterwards). This phenomenon may mean that immunologically driven criteria to assess response to treatment with nivolumab may be appropriate.

PHARMAC is therefore keen to receive feedback from DHB hospitals on the specific resource implications of this proposal and on potential criteria that could be used to account for patients with ‘pseudo-progression’.

Background

Nivolumab as monotherapy is indicated as a treatment for patients with advanced unresectable (stage III) or metastatic (stage IV) melanoma. The recommended dose for nivolumab is 3 mg/kg administered in hospital as intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.

The Medsafe datasheet records that nivolumab monotherapy demonstrated a clinically significant and clinically meaningful improvement in overall survival over dacarbazine in previously untreated patients with BRAF wild-type advanced (unresectable or metastatic) melanoma. It also records there is a potential for an immunogenic response to nivolumab.

Nivolumab is a monoclonal antibody in a class of treatment known as “PD-1 inhibitors” (programmed cell death (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 pembrolizumab (Keytruda), atezolizumab (MPDL3280A) and durvalumab (MEDI4736) – the latter two of which are not yet registered in New Zealand or overseas for advanced melanoma.

Clinical advice

As noted above, PHARMAC has been carefully assessing the funding of PD-1 inhibitors for advanced melanoma. Merck Sharpe & Dohme’s 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 it be funded for the treatment of metastatic or unresectable melanoma stage III or IV with 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 Application tracker - pembrolizumab(external link)).

In February 2016 PHARMAC sought further advice from PTAC about PD1-inhibitors (namely pembrolizumab and nivolumab). In April 2016 the funding application from Bristol-Myers Squibb for nivolumab for the treatment of patients with advanced melanoma was considered by CaTSoP (registration was granted for nivolumab by Medsafe on 28 April).

CaTSoP recommended that nivolumab as monotherapy be funded for patients with unresectable or metastatic (stage IIIc or IV) melanoma, with medium/high priority.

The Subcommittee considered that the evidence for the use of nivolumab as monotherapy was of good strength and quality and provided a strong level of support for a survival benefit with nivolumab monotherapy for advanced melanoma patients over the current standard of care in New Zealand. In contrast, with respect to pembrolizumab, PTAC’s view in November 2015 was that given the short duration and limitations of the reported evidence, whilst the treatment was an advance, there remained uncertainty regarding the optimal dosing regimen and both the long-term benefits and risks of pembrolizumab treatment.

The funding application for nivolumab will be considered by PTAC at its upcoming meeting and PTAC’s advice, along with consultation feedback, will be an important input into any decision made by PHARMAC’s Board on this proposal.

The CaTSoP minute relating to the discussion of nivolumab [PDF, 30 KB] is now available.

The PTAC minute relating to the discussion of nivolumab [PDF, 87 KB] is now also available.

You can track the progress of the application for nivolumab on PHARMAC's application tracker(external link).