Adoption of ipilimumab in the United States: a Medicare study

KEYWORDS:

• Immunotherapy
• adoption
• Medicare
• community practice
• diffusion

Over recent decades, the incidence and mortality of malignant melanoma have increased in older adults. Older Americans have much higher incidence rates of advanced melanoma than younger Americans, and the rates increased fast in the last decade. In 2012, almost half of advanced melanoma patients are 65 years or older. We also found that melanoma-related mortality rates increased 4% during 2005–2012 in older patients but decreased in younger patients.

Ipilimumab (Yervoy) is the first immune checkpoint inhibitor approved by the US FDA in 2011 on the basis of its survival improvement in patients with unresectable or metastatic melanoma at any line of therapy [1]. Patients with advanced melanoma historically had a dismal prognosis, with median survival of about 6–9 months [2,3]. Significant improvements in overall survival were demonstrated in advanced melanoma patients treated with ipilimumab in phase III trials [1,4]. Ipilimumab was also well tolerated and associated with a manageable safety profile in trials.

Although enthusiasm in patients and physicians for immunotherapies is high, several factors – such as the unproven concern of more severe adverse events outside clinical trials, the need for toxicity management, and steep costs – could limit their utilization and accessibility in community practices [5]. There have not been research efforts to evaluate the integration of ipilimumab into community practices. We examined the use of ipilimumab therapy in the Medicare Fee-For-Service (FFS) beneficiaries.

Use of ipilimumab in Medicare

Medicare Provider Utilization and Payment Data were used to measure the use of ipilimumab therapy in 2012 and 2013 [6]. The data contain 100% final-action physician/supplier Part B noninstitutional line items. HCPCS code (J9228) was used to identify the ipilimumab therapy provided by physicians. We counted the number of providers who have billed ipilimumab therapy in 2012 and 2013, the quantity of ipilimumab prescribed each year, total Medicare payments to those providers, and the number of unique beneficiary/provider interactions. We compared these measures by year of payment.

We assume that the median number of cycles of ipilimumab administered is usually three, a recommended 3-mg/kg treatment plan, and an average body weight of 65–80 kg in older patients, and that ipilimumab is supplied in 200 and 50 mg vials with little opportunity for vial sharing. We estimated the Medicare payments per patient and the number of patients who received ipilimumab therapy using the quantity prescribed. To make a comparison, we have estimated the number of Medicare FFS beneficiaries that are eligible for ipilimumab therapy, adjusted for the Medicare managed care penetration rates [7]. We obtained the total number of melanoma cases in the most recent 5 years from Surveillance, Epidemiology, and End Results Program and calculated the proportion of unresectable stage III or metastatic melanoma patients who were diagnosed at age 65 years or older [8–10]. Then, we multiply the proportion by the number of new melanoma cases in 2012 and 2013.

In 2012, a total of 803 providers gave Medicare FFS beneficiaries ipilimumab therapy. A total of 682,566 mg of ipilimumab was billed to Medicare for total payments of $67,589,675. There were 1188 unique beneficiary/provider interactions. These numbers had a low single-digit increase in 2013: 854 providers prescribed 699,425 mg of ipilimumab and were paid a total $69,399,522 by Medicare. We estimated that the treatment plan per patient costs Medicare about $59,400–$74,400 and the beneficiary about $11,900–$14,900 if the patient did not have supplemental insurance or co-pay assistance.

We estimated that about 1200 Medicare FFS beneficiaries are eligible for ipilimumab therapy each year during 2012–2013. If we assume a dose of four, an estimated 690–860 of the beneficiaries have received ipilimumab therapy. If we assume the median number of doses is three, around 1000 of them have received ipilimumab therapy. On average, each provider has only treated about one Medicare FFS beneficiary with ipilimumab therapy in any single year, although with some state variations. In fact, there were only four oncologists (mostly from California) who had seen over 10 Medicare FFS beneficiaries for ipilimumab therapy. The top five states that used ipilimumab are California, Indiana, Ohio, Maryland, and Nevada. However, Texas, New York, Florida, and Illinois are more populous than these top five except for California. About 20 states had 10 or fewer Medicare FFS beneficiaries that have received ipilimumab therapy each year during 2012–2013.

Ipilimumab (Yervoy) is rapidly being adopted into the treatment of metastatic or unresectable melanoma. A good majority of eligible Medicare FFS beneficiaries have received ipilimumab in the first 2 years after its FDA approval, although certain variations are seen in some states. Generally speaking, the patterns of cancer care in Medicare beneficiaries and privately insured are highly correlated [11]. We therefore feel confident that most metastatic or unresectable melanoma patients in the United States have received ipilimumab therapy right after its approval. However, we think that most oncologists in the community may have limited experience in treating patients with ipilimumab. Comparative effectiveness research using population-based real-world data is needed to produce actionable evidence regarding the effectiveness and safety of ipilimumab therapy outside of controlled research settings.

Additional comparative effectiveness research is needed

Although newly approved immunotherapy underwent some active comparator analysis in preapproval trials, such information is insufficient to answer all questions regarding optimal prescribing in community practice, especially in older patients [12]. While the incidence rates of advanced melanoma are several times higher in older adults than in younger people, only about 143 melanoma patients aged 65 years or older were treated with ipilimumab in the Phase III trial [13]. Older patients have a poorer outcome, and in particular, the mortality rates are increasing in older men [14]. Elderly patients may also be more vulnerable to side effects from ipilimumab. Actionable evidence regarding the effectiveness and safety of new immunotherapy in older patients is needed outside of controlled research settings.

Medicare FFS programs spent about $140 million on ipilimumab therapy on about 2000 patients in 2 years. In October 2015, the FDA has approved ipilimumab 10 mg/kg every 3 weeks for four doses, then every 12 weeks up to 3 years as adjuvant treatment for patients with resected stage III melanoma – the cost could be as high as $3 million for one patient. With the approval of newer immunotherapy drugs such as pembrolizumab and nivolumab for melanoma and lung cancer, the drug cost will be an enormous issue for American health care. Many think the costs of new immunotherapy drugs are significant and unsustainable [15]. Discussion of value and cost in cancer care should be encouraged.

Ipilimumab is one of the first immunotherapies to become widely available in the setting of solid tumors. In many ways, immunotherapy is a good example of the advances in cancer treatment today – rapid advancement in academic settings alongside lack of actionable evidence and practical experience at community settings. If we can use ipilimumab to successfully address some of these challenges, the same principles will be transferrable to other new cancer treatments.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.