Advances in Metastatic Melanoma – Redefining Value Propositions in Market Access

Payers are increasingly more proactive in their management of drug expenditures in cancers, such as breast cancer, non-small cell lung cancer, and colorectal cancer, where there are many therapeutic options.  As more therapeutic alternatives for advanced melanoma become available, it increases opportunities for payers to manage utilization; and it may also provide manufacturers with opportunities to define the value of their respective drugs through clinical and price differentiation.

Near-Term Management of Oral Therapies in BRAF-Mutated Melanoma

With the imminent entrance of Tafinlar (dabrafenib) and Mekinist (trametinib) to the U.S. market in the third quarter of 2013 for BRAF-mutated metastatic melanoma (approximately 40%-50% of market), GlaxoSmithKline is redefining value in this space.  Tafinlar’s labeling indicates that, like Zelboraf [vemurafenib; Plexxikon/Genentech/Roche/Daiichi-Sankyo], it is only approved for use in patients with the V600E mutation (approximately 80% of all BRAF mutations).

Price is an obvious difference between Tafinlar and Zelboraf in which payers could implement step therapy, as both drugs are relatively similar in terms of efficacy. In the U.S., the wholesale acquisition cost of Tafinlar will reportedly be $7,600 a month, which essentially undercuts Zelboraf’s approximate cost of $10,000 a month. The price difference may be partially due to Tafinlar’s later entrance to market, but may also be part of GSK’s long-term strategy for the use of Mekinist and Tafinlar in combination with each other.

Currently, Mekinist (priced at $8,700/month) has a specific limitation in its label to not be used after treatment with a BRAF V600E inhibitor. This may be enforced by payers although Mekinist has the advantage of being the only agent indicated for use in patients with the BRAF V600K mutation.

The combination of Mekinist and Tafinlar showed an improvement in progression-free survival (PFS) compared with Tafinlar alone in a Phase 2 trial.  With this early signal, GSK has initiated two Phase 3 trials (nicknamed COMBI) to confirm the results that the combination therapy is superior to Tafinlar alone or Zelboraf alone. In all likelihood the combination will move forward into clinical practice. The question is whether the combination (or even the use of Mekinist after progression with a BRAF inhibitor) will be reimbursed with an NCCN recommendation before launch in early Q3, at a later point before the COMBI trials report, or after the COMBI results.  The combination regimen would bump cost of therapy for advanced melanoma to $16,000 a month with an average duration of therapy of one year, likely spurring greater interest in payer utilization management.

Reshaping Value Propositions in Melanoma with Immunotherapy

Bristol-Myers Squibb’s immunotherapy, Yervoy (ipilimumab) was a breakthrough drug, and thus was able to be launched at a substantial price with a fixed regimen of four injections costing approximately $120,000. The most critical aspects of its value proposition is its long-term responses that lead to unprecedented long-term survival for advanced melanoma though this is accompanied by immune-related adverse events that often affect the gastrointestinal tract.

Early data suggest that BMS’s follow-up immunotherapy, nivolumab, might be more active than Yervoy and might be active in patients previously treated with Yervoy without the associated immune-related toxicities.  Also, exciting Phase 1 data suggest that the combination of these two drugs will improve long-term survival better than either agent alone.  BMS has initiated three Phase 3 trials to confirm the activity of nivolumab and the combination (nicknamed CheckMate):  nivolumab as a monotherapy in Yervoy-pretreated and Yervoy-naïve patients versus chemotherapy and a third trial comparing nivolumab and Yervoy versus the combination.

BMS will have interesting launch choices including whether to launch nivolumab with only single-agent data or with combination data.  With the superior value proposition suggested in the Phase 1 results, single-agent nivolumab would likely yield a premium price compared with Yervoy.  However, BMS might be faced with a similar issue as GSK and pricing decisions with an assumption that the combination would move forward into the clinic.

Implications

The current number of available treatments for BRAF-mutated melanoma, the emerging availabilities of immunotherapies, and their likely associated costs, suggest strong payer management in advanced melanoma may be utilized in the near future. For a disease that has garnered little attention previously, the emergence of therapies for advanced melanoma will give payers impetus to manage drug therapy.

A key clinical argument remains whether the emergence of the immunotherapies has physicians thinking that they will be used before BRAF inhibitors given the long-term survival these convey in converse to current thinking. Payers and health authorities could mandate a BRAF or MEK inhibitor over Yervoy given the biomarker significance, yet cancer-resistance against the BRAF and MEK inhibitors is inevitable, suggesting that patients with BRAF-mutated melanoma have a definite ceiling in survival without using an immunotherapy.

Unlike the BRAF and MEK inhibitors, Yervoy, a PD-1 inhibitor, does not have a biomarker. If a biomarker such as PD-1 expression can be validated for PD-1 and PD-L1 antibodies, their value proposition would be more substantial, perhaps providing a larger reason to price the drugs highly. The melanoma market has only recently been transformed, and these data and ongoing clinical development with PD-1 and PD-L1 antibodies suggest that it’s set to be transformed even further!

Melanoma treatment is likely heading toward combinations, whether it’s a BRAF/MEK combination, a BRAF inhibitor plus an immunotherapy or duel immunotherapies.  These agents will increasingly affect drug expenditures for patients and payers.  Manufacturers may need to become more creative with patient assistance programs as combination therapies push regimen prices beyond $15,000 a month. The resulting patient out-of-pocket costs for those with a high coinsurance that ranges from 20% to 33%, for example, could be pushed beyond affordability, particularly with the chronic nature of treatment (i.e., the emergent immunotherapies and the BRAF and MEK inhibitors).

By Gordon Gochenauer, Director, Oncology Commercial Strategies, Kantar Health

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