Thousands of Melanoma Patients in Europe Not Receiving Novel Agents

Lidija Kandolf-Sekulovic, MD, PhD

Over one-fourth of patients with metastatic melanoma in Europe do not have access to groundbreaking therapies that could extend their lives, according to a survey presented at the 2016 ESMO Congress.¹

Access varied greatly by geographic location. Seventy percent of patients in Western Europe received novel immunotherapy agents; however, in 41% of the centers surveyed in Eastern and Southeastern Europe, only 10% of patients had access to innovative treatments.

Kandolf-Sekulovic et al conducted an online survey in 34 oncology centers across 29 countries in Europe. The survey asked questions about the treatment of metastatic melanoma patients between May 1, 2015, and May 1, 2016. Areas covered on the survey included number of patients treated, percentage of patients receiving novel targeted/immunotherapy agents, registration/reimbursement of novel agents, and the potential for clinical trial participation for patients with stage IV disease.

According to survey estimates, approximately 19,250 patients with metastatic melanoma are treated in Europe each year, including 7450 (38.7%) in Eastern and Southeastern Europe. Of these nearly 20,000 patients, 5228 (27%) were unable to access novel frontline agents recommended by European treatment guidelines. In Eastern and Southeastern Europe, 68.8% (5128/7450) do not have access.

Reimbursement and registration gaps for novel frontline agents contributed greatly to the disparity in access between Western and Eastern/Southeastern Europe. The BRAF/MEK inhibition approach—a standard option for patients with BRAF-mutated melanoma—was registered in 75% of the countries in Western Europe and fully reimbursed in 58%. However, in Eastern and Southeastern countries, these numbers dropped to 42% and 18%, respectively.

The other novel frontline standard, anti—PD-1 immunotherapy, was registered in 100% of the nations of Western Europe; however, the registration rate was only 59% in Eastern and Southeastern countries, with reimbursement provided in 24%.

“Our study raises ethical questions on the inequalities that affect survival based on the country of residence in Europe. It is not new that disparities in healthcare can lead to disparities in overall survival of patients, but these disparities are becoming even sharper for patients with chemotherapy-resistant metastatic melanoma in whom durable responses lasting for years can be seen in up to 20% of patients if treated with innovative medicines. In European healthcare systems that declare universal access to healthcare, these inequalities must be overcome,” said Kandolf-Sekulovic.

Over the past several years, the treatment paradigm in the first-line setting for metastatic melanoma has been revolutionized with the approval of several new immunotherapy agents and targeted therapies. For example, the European Commission has approved the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) for the treatment of BRAF V600—positive unresectable or metastatic melanoma.

Long-term data from the phase III COMBI-d study were presented at the 2016 ASCO Annual Meeting.² The update showed that the 3-year progression-free survival (PFS) rate with the combination of dabrafenib and trametinib was 22% versus 12% with single-agent dabrafenib. The 3-year overall survival (OS) rate was 44% with dabrafenib plus trametinib compared with 32% with dabrafenib alone.

The median OS with dabrafenib and trametinib was 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P = .0107). Median PFS was 11.0 versus 8.8 months (HR, 0.67; 95% CI, 0.53-0.84; P = .0004) and the overall response rate was 69% versus 53% (P = .0014), for the combination and dabrafenib-alone arms, respectively.

The PD-1 inhibitor nivolumab (Opdivo) is approved across Europe as a single-agent and in combination with the CTLA-4 inhibitor ipilimumab (Yervoy) for the frontline treatment of patients with advanced melanoma. Data from the phase III CheckMate-067 trial presented at ASCO 2016 showed that at a minimum follow-up of 18 months, the nivolumab/ipilimumab combination reduced reduced the risk of disease progression by 58% compared with ipilimumab alone, and single-agent nivolumab lowered the risk of progression by 45% versus ipilimumab monotherapy in patients with advanced melanoma.3 The 18-month PFS rates for the combination, single-agent nivolumab, and ipilimumab monotherapy regimens were 46%, 39%, and 14%, respectively.

The European Commission has also approved the anti-PD—1 agent pembrolizumab (Keytruda) in the frontline setting for the treatment of patients with unresectable or metastatic melanoma. Data from the KEYNOTE-001 study presented at ASCO 2016 showed that 40% of patients with newly diagnosed or previously treated advanced melanoma who received frontline pembrolizumab were alive at 3 years.4 Fifteen percent of the patients experienced complete remissions according to immune-related criteria after taking the PD-1 inhibitor and nearly 90% of these responders remain in remission. The median OS was 24.2 months.

In a statement commenting on the disparities detailed in the survey, Alexander Eniu, MD, PhD, chair of the ESMO Global Policy Committee, said, “This study confirms what ESMO has highlighted in the past: access to the best treatment according to evidence-based clinical guidelines such as ESMO’s, is not equal across Europe. ESMO advocates for equal access to treatment and care, which is the fundamental right of any patient. Despite the encouraging rate of new medicine development, there are still unacceptable inequalities in the availability and accessibility of new and effective cancer medications across Europe.”

“The present study focuses on melanoma but the ESMO-led European Consortium Study on the availability and accessibility of antineoplastic medicines across Europe found that the same was true for other types of cancer, especially rare cancers, in countries with lower economic levels. It is important to continue to provide health authorities with data, and to carry on calling attention to the difficulties patients with incurable diseases are facing, in the hope that equal access will soon be a reality, at least in Europe,” added Eniu.

References

1. Kandolf-Sekulovic L, Peris K, Hauschild A, et al. More than 5000 patients with metastatic melanoma in Europe per year do not have access to the new life-saving drugs. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1389O.
2. Flaherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: A Phase III study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J Clin Oncol. 2016;34 (suppl; abstr 9502).
3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol 34, 2016 (suppl; abstr 9505).
4. Robert C, Ribas A, Hamid O, et al. 3-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol. 2016 (suppl; abstr 9503).

“Before 2011 there were no effective treatment options for metastatic melanoma patients, but that has changed tremendously in the last 5 years. We now have medicines which can prolong overall survival of these patients to more than 18 months and, in some patients, durable responses lasting up to 10 years have been reported. However, access to these medicines is limited and patients and physicians are facing increasing difficulties to obtain them. This is especially the case for Eastern and South Eastern European countries, where a majority of patients are still treated with palliative chemotherapy that does not prolong overall survival,” the lead researcher on the survey, Lidija Kandolf-Sekulovic, MD, PhD, associate professor of Dermatology at the Military Medical Academy in Belgrade, Serbia, said in a statement.