PERTH, Australia – Australia is at risk of falling behind the U.S. and Europe in preventing recurrence of melanoma, the Melanoma Institute Australia warns. It is urging the Australian government to undertake a timely review of immunotherapy treatments effective in preventing the spread of melanoma and to fast track listings on the government-subsidized Pharmaceutical Benefits Scheme (PBS).

During its recent quarterly meeting, the Pharmaceutical Benefits Advisory Committee (PBAC) considered three melanoma treatments for listing: Bristol-Myers Squibb Co.'s Opdivo (nivolumab), Merck Sharp & Dohme's (MSD) Keytruda (pembrolizumab) and Novartis AG's targeted dabrafenib/trametinib combination therapy in BRAF-positive patients.

The PBAC rejected Keytruda and deferred the listing for Opdivo, although it did approve the dabrafenib/trametinib combination therapy, which is effective for less than half those patients, according to the Melanoma Institute.

"It is a sad irony that Australia has the highest melanoma rates in the world, yet we risk falling behind the USA and many European countries where this immunotherapy preventing melanoma recurrence in the majority of these high-risk patients is already available and subsidized," said Georgina Long, co-medical director of Melanoma Institute Australia.

"Australian patients would like certainty that they will be able to access affordable immunotherapy treatment which has proven successful in clinical trials and which many hundreds of patients have been forced to access on compassionate grounds or face costs of tens of thousands of dollars," she said.

MSD, a subsidiary of Merck & Co. Inc., resubmitted a request to include Keytruda as adjuvant therapy for patients who have had completely surgically resected stage III malignant melanoma.

"The PBAC acknowledged that there was a high clinical need for effective therapies to reduce the risk of recurrence of resected stage III melanoma and considered that in some circumstances recurrence was less likely for those treated with pembrolizumab compared with placebo (standard of care)," the PBAC outcome statement said.

Even so, the committee concluded that the magnitude of the clinical benefit was uncertain due to limited follow-up in the key trial, Keynote 054. It said that the modeled incremental survival benefit was "substantially overestimated and, as a result, the economic model did not provide a reliable basis for assessing the cost-effectiveness of pembrolizumab."

"The PBAC also remained concerned about the high overall financial opportunity cost," it said.

In its application for reconsideration, MSD made the clinical claim that for patients with resected stage III melanoma, pembrolizumab is superior to placebo in terms of efficacy. In terms of safety, it said pembrolizumab has inferior but manageable safety.

The PBAC considered that the claim that pembrolizumab was superior compared to placebo in terms of recurrence-free survival was reasonable but, due to the immaturity of the data, considered that the magnitude of the treatment effect was highly uncertain. In terms of overall survival, the PBAC considered that further evidence was required to quantify the relationship between recurrence-free and overall survival with PD-1 inhibitor therapy.

Keytruda is currently listed for unresectable stage III or stage IV malignant melanoma. It is also listed for relapsed or refractory Hodgkin lymphoma and previously untreated stage IV metastatic non-small-cell lung cancer.

Luke Cornish, head of public affairs for MSD Australia, told BioWorld that the patient population in Australia for completely surgically resected stage III malignant melanoma is roughly 2,000 patients per year.

Although overall survival data are not yet available in that patient population, for the primary endpoint of relapse-free survival in Keynote 054, at six months, the trial demonstrated a statistically significant improvement in recurrence-free survival for Keytruda-treated patients vs. placebo-treated patients, with a "p" value of less than 0.0001, he said.

"Since the approach of using immuno-oncology treatments in the adjuvant setting is relatively new, the PBAC wants to be assured of the outcomes for patients. However, we are continuing to work with them to give them the appropriate information. The PBAC continues to make decisions based on the established framework but advances in treatment approaches will require the Australian health system to adapt to keep pace and be fit for purpose," Cornish added.

Arduous process

The process to get innovative new drugs listed on Australia's PBS can be a long and arduous one, and pharma companies waiting to get innovative drugs listed will continue to face mounting pressure and lengthy price negotiations.

A focus on value-based pricing and health technology assessments for every drug listed on the PBS often results in Australia listing new molecular entities much later than its OECD peers. And yet, Australian patients pay less for the drugs that do make it on the government-subsidized list than many of those same peers.

For all of the drugs listed on the PBS, Australian patients only pay a maximum of AU$38.80 (US$31.14) per prescription, and patients with concessions pay as little as AU$6.30 per prescription. National Health Service England has a similar reimbursement scheme, whereby patients pay roughly $11.30 per prescription for reimbursed drugs. Compare that to cancer patients in the U.S., who pay about $750 per prescription, according to IMS Health.

To get on the PBS list, pharma companies must prepare a submission proposal about 17 weeks before the Pharmaceutical Benefits Advisory Committee (PBAC) is scheduled to meet. The submission includes essential details about the drug such as clinical evaluations, as well as an economic evaluation, cost-effectiveness analysis and a cost minimization plan. The PBAC also requests financial estimates given the proposed patient population.

The sponsor can request a hearing at the PBAC meeting for major submissions. The PBAC then considers the comparative effectiveness and cost of each drug and then issues a PBAC Outcomes document, which includes information from a drug utilization subcommittee and an economic subcommittee. The PBAC then recommends drugs for listing to the health minister.

Following a positive PBAC recommendation, the sponsor is required to submit pricing information, and then price negotiations begin. If a drug is projected to cost more than AU$20 million in any year, the health minister refers the listing to the Cabinet for consideration before the drug can be formally listed. If the PBAC renders a negative decision for a drug, the sponsor can prepare a resubmission, and it can request a presubmission meeting to better understand the issues raised in the PBAC meeting. (See BioWorld, Sept. 12, 2017.)

BMS' Opdivo was the first immunotherapy to be reimbursed on the PBS. Without the subsidy, patients would have paid more than AU$130,000 per year.

BMS had sought yet again to list Opdivo for adjuvant treatment of patients who have had completely surgically resected stage III or stage IV malignant melanoma. The committee said that it deferred the recommendation for nivolumab "to allow for further discussions regarding an acceptable price and risk sharing arrangement."

BMS has submitted another request to extend the current listings for nivolumab and ipilimumab for the treatment of unresectable stage III or IV malignant melanoma to allow use as first-line therapies in patients who are BRAF V600 mutation-positive. That request is slated for the upcoming November PBAC meeting.

"It is frustrating, disheartening and disappointing for Australia to be leading the international melanoma research effort, yet our own government is lagging behind the rest of the world in ensuring high-risk patients have subsidized access to this proven immunotherapy treatment," said Richard Scolyer, co-medical director of Melanoma Institute Australia.

"We urge the federal government to fast track further consideration of this immunotherapy and remain hopeful it will eventually be listed on the PBS," he said.

The PBAC did recommend Novartis' dabrafenib/trametinib combination therapy for patients who have had completely resected BRAF V600 mutation-positive stage IIIB, IIIC or IIID malignant melanoma.

The PBAC said it was satisfied that dabrafenib plus trametinib provides, for some patients, a significant improvement in efficacy over routine follow-up, in terms of recurrence-free survival, and a likely benefit in terms of overall survival, although there are currently limited data. The PBAC considered that dabrafenib plus trametinib was inferior compared with placebo in terms of comparative safety. The PBAC noted changes that were made to the economic model and considered that the resulting incremental cost-effectiveness ratio was acceptable at the proposed price.

The PBAC considered that, in the context of the uncertain use across the adjuvant and unresectable or metastatic settings, a risk-sharing arrangement consisting of combined subsidization caps across both adjuvant and unresectable or metastatic settings would be appropriate.

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