Advances in Metastatic Melanoma Bring Price Competition, Redefinition of Value, and Likely Increased Payer Utilization Management

Traditionally, payers have been increasingly more proactive in their management of drug expenditures in cancers with the highest prevalence and with the more costly therapeutics—for example, nonsmall cell lung cancer (NSCLC), breast cancer, and colorectal cancer (CRC), according to Kantar Health’s survey of managed care directors. In a follow-up question to these payers, respondents cited the number of available treatment options as the top reason for targeting a specific cancer. This would account for the presence of kidney and prostate cancers on the list of targeted disease states since there has been an increase in the number of available treatments, where previously, few options had been available (Figure 1).

Perhaps adding to this list of increased payer management to a disease state, where up to a few years ago limited treatment options were available, may be the emerging competition to the established standards of care in melanoma. As more treatment opportunities for metastatic melanoma become available, it increases opportunities for payers to manage utilization; it may also provide manufacturers with opportunities to define the value of their respective drugs through clinical and price differentiation.

Melanoma Presentations at ASCO

Melanoma has been a hot topic at the annual American Society of Clinical Oncology (ASCO) meetings since 2010, when the pivotal data for the novel immunotherapy Yervoy (ipilimumab; Bristol-Myers Squibb [BMS]), a CTLA-4 antibody, was presented, and subsequently, led to its FDA approval in 2011. This approval was followed shortly after with another FDA approval for metastatic melanoma in 2011: the BRAF inhibitor, Zelboraf (vemurafenib; Plexxikon/Genentech-Roche/Daiichi-Sankyo).

Remarkably, only three days before this year’s ASCO meeting, GlaxoSmithKline (GSK) made headlines with the tandem FDA approval of its two drugs to treat metastatic melanoma: Tafinlar (dabrafenib), a BRAF inhibitor, and Mekinist (trametinib), a MEK inhibitor.

Figure 1. Cancer Types Specifically Targeted for Utilization Management^a

^aPercentage of managed care organizations (n=16) with oncology as its highest utilization management programs.

Source: Kantar Health; Managed Care Organization Survey, August 2012. “Which of the following cancer types are specifically targeted for utilization management in your organization? Select all that apply.”

Furthermore, this year’s ASCO meeting also presented further progress in the metastatic melanoma immunotherapy space with intriguing phase I data from a series of antibodies targeting PD-1. BMS presented phase I data on its investigational drug nivolumab, and Merck presented phase I data on its PD-1 antibody, lambrolizumab. Not to be left out of the mix, Roche presented phase I data on its PD-L1 antibody, MPDL3208A; and Amgen presented phase III data on its intratumoral immunotherapy, talimogene laherparepvec (T-VEC).

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

With the imminent entrance of Tafinlar and Mekinist, GSK is redefining value. Both drugs were approved with a companion diagnostic called the THxID BRAF test (bioMerieux). The diagnostic will detect V600E and V600K mutations in the BRAF gene. Tafinlar labeling indicates that, like Zelboraf, it is only approved for use in patients with the V600E mutation (approximately 80% of all BRAF mutations). On the other hand, Mekinist is approved for use in patients with both of the BRAF mutations. This difference in labeling between the two drugs represents an opportunity for sophisticated payers to differentially manage utilization.

Price is an obvious difference between Tafinlar and Zelboraf, for which payers could implement step therapy, as both drugs are relatively similar in terms of efficacy. In the United States, the wholesale acquisition cost of Tafinlar will reportedly be $7600 a month, which essentially undercuts Zelboraf’s approximate cost of $10,000 a month. The lower price is likely related to being later to market with no obvious efficacy advantages and having different toxicity profiles.

Arguably, Zelboraf has a lower risk for severe adverse events requiring dose interruption or reduction compared with Tafinlar. This could have contributed to the manufacturer launching at a lower price than Zelboraf. However, GSK has submitted applications to the FDA and the EU for use of Mekinist and Tafinlar in combination with each other, and is awaiting decisions from regulatory authorities. Currently, the use of Mekinist and Tafinlar in combination is not approved.

Currently, Mekinist (priced at $8700/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 despite the combination regimen showing an improvement in progression-free survival (PFS) compared with Tafinlar alone. For the combination or single-use Mekinist to be widely accepted into practice or by payers, the National Comprehensive Cancer Network (NCCN) Guidelines and NCCN Compendium, which guide payer reimbursement, will come into play.

In the meantime, GSK has initiated two phase III trials (NCT01584648/COMBI-AD and NCT01597908/ COMBI-v) 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 it will take an NCCN category 2A (generally reimbursed by payers) or 2B recommendation in the next update of the NCCN Guidelines. It is unclear whether Tafinlar and Mekinist will have an NCCN recommendation for combination use (or even to allow use of Mekinist after progression with a BRAF inhibitor) before launch in early Q3.

Essentially, the combination regimen would bump the cost of therapy to over $16,000 a month, with an average duration of therapy of one year. This would represent a new price point in oncology, likely spurring greater interest in payer utilization management (Figure 2).

Roche has also initiated a phase III trial (NCT01689519) combining Zelboraf with its experimental MEK inhibitor, GDC-0973, in the same manner as GSK’s combination.

Figure 2. Reasons for Management Priority^a

Percentage of MCOs Among Those With Cancer Types That Are Specifically Targeted for UM (n=15)

^aPercentage of managed care organizations with utilization management programs specifically targeting oncology.

Source: Kantar Health; Managed Care Organization Survey, August 2012. “What are the reasons specific cancer(s) are management priority? Select all that apply.”

Reshaping Value Propositions in Melanoma With Immunotherapy

Melanoma tumors use various molecules, such as PD-1, PD-L1, and CTLA-4 to mask itself from the human immune system. The antibody Yervoy binds to CTLA-4 to potentially allow the immune system to attack the tumor cell. Yervoy 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. While the drug increases median survival, the most critical aspects of its activity are not response rate or median overall survival (mOS), but long-term disease stabilizations that lead to unprecedented longterm survival of approximately 30% at 2 years and 20% at 3 and 4 years. However, severe immune-related gastrointestinal (GI) adverse events may lead to costly hospitalizations due to diarrhea or GI perforations.

Yervoy has only a few years to enjoy being the standard immunotherapy. PD-1 and PD-L1 antibodies first made a splash at ASCO 2012, but longer-term follow-up data strongly suggest Yervoy will be replaced or serve as a combination agent. Furthest along in development is BMS’s nivolumab. In a large phase I dose-finding study, nivolumab’s overall response rate (ORR) was 31% across all dosages, but reached 41% with a 2-year survival of 43% in patients who received the planned dosage for the phase III program. A separate phase I study of nivolumab suggested that it is active in both Yervoy-naïve and Yervoy-pretreated patients. BMS has initiated two phase III trials (NCT01721746/Check- Mate-037 and NCT01721772/CheckMate-066 in Yervoy- pretreated and Yervoy-naïve patients, respectively) comparing nivolumab to chemotherapy to confirm the outstanding activity observed for nivolumab in the phase I trial.

In a cross-trial comparison, the phase I results discussed compare very favorably with Yervoy’s activity from its phase III results (11% ORR and 2-year survival of 24%). Additionally, nivolumab appears to have a better safety profile than Yervoy, particularly when comparing immune-related GI events.

However, the greatest excitement for BMS would be the combination of Yervoy and nivolumab. In a clinical trial, the combination yielded a 54% ORR with all responders achieving an 80% reduction in tumor volume. These near-complete responses strongly suggest that inhibiting PD-1 and CTLA-4 could be the next standard of care for metastatic melanoma, though the combination resulted in a high rate of serious adverse events, primarily those associated with Yervoy.

BMS has started a three-arm phase III trial (NCT01844505/Check- Mate-067) comparing each single agent (Yervoy and nivolumab) with the combination. With the superior value proposition of single-agent nivolumab, it would likely have yielded a premium price compared with Yervoy. However, the exciting combination data mean the company will have interesting launch choices, including whether to launch nivolumab with only single-agent data or the combination data from the CheckMate-067 trial.

If the combination data are superior, the company will have to strongly consider the overall cost of therapy and potentially develop a creative patient assistance program. One key issue with the combination is that Yervoy is only dosed with four induction administrations, but nivolumab will be dosed continually until progression, potentially for longer than one year.

In other studies in advanced melanoma presented at ASCO, Merck’s lambrolizumab and Roche’s MPDL3280A, which not have yet reached phase III, showed impressive response rates in phase I trials. At several dosages, lambrolizumab produced a response rate of 38%; however, at the highest dosage (10 mg/kg) the ORR was 52%, including a 10% complete response rate. As with nivolumab, response to lambrolizumab was independent of prior Yervoy treatment. Roche’s MPDL3280A produced a response rate of 29% at several dosages, similar to lambrolizumab and nivolumab.

Lastly, promising data for the intratumoral injection, T-VEC from Amgen, showed an improvement in longterm disease control of advanced melanoma. A trend toward improvement in long-term survival in the pivotal phase III trial (NCT00769704/OPTiM) showed 2-year and 3-year OS had statistical significance at 50% and 41% for T-VEC compared with 41% and 28% for the control arm. Amgen is awaiting mature survival data before filing with the FDA, perhaps by the end of the year.

Implications

The current number of available treatments for BRAFmutated melanoma, the emerging availabilities of immunotherapies, and their likely associated costs, suggest that 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 will give payers impetus to manage drug therapy for advanced melanoma.

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 resistance against the BRAF and MEK inhibitors is inevitable, suggesting that patients with BRAF-mutated melanoma have a definite ceiling in survival without either using an immunotherapy. Unlike the BRAF and MEK inhibitors, Yervoy does not have a biomarker. If a biomarker 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.

Melanoma treatment is likely heading toward combinations, whether it’s a BRAF/MEK combination, a BRAF inhibitor plus an immunotherapy or dual 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 (Figure 3), particularly with the chronic nature of treatment (the emergent immunotherapies and the BRAF and MEK inhibitors).

Figure 3.

Source: Kantar Health; Managed Care Organization Survey, August 2012. “Do/Did you face any financial challenges with paying for your cancer treatment plan? Did anyone at your oncologist’s office suggest applying for financial assistance? Did you discuss the affordability of your treatment with your oncologist or anyone in the practice?”

Gordon Gochenauer is the Director of Commercial Planning at Kantar Health, a global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies.