PhD, Nurse, Department for Oncology- Pathology, Karolinska Institute, Stockholm
English version of ‘Medicinskt genombrott som inte nådde cancerpatienterna’
Translated by Bettina Ryll and Fredrik Östman, MPNE
The media have paid attention to the fact that survival for patients with malignant Melanoma is improving (1). At the same time, the Swedish Agency for Health and Care Services Analysis has the governmental mandate to oversee the introduction, usage and monitoring of oncology products (2).
Melanoma in the metastatic setting used to have a poor prognosis (median survival 6-9 months) (3). The first immune therapy with T-cell activating antibodies (immune checkpoint inhibitor), Ipilimumab, was approved in 2011. The checkpoint inhibitor leads to tumour response in a minor subgroup of patients but results in a long-term survival of >20% after 5 years, compared to <5% with chemotherapy (4,5). This was a considerable break-through and in 2013, the journal Science declared cancer immune therapy the Scientific Breakthrough of the year (6).
In Sweden’s oncology centres, the usage of Ipilimumab was halted in 2011 despite the fact that municipalities, county councils and regional cancer centres had collaborated on a report that, based on the survival curves of studies, a percentage of long-term survival was to be expected (5,7). The reasons given were cost, uncertainty about the effectiveness, worry about side effects (8) and the need for a controlled introduction. Germany, Belgium and Denmark immediately prescribed Ipilimumab while waiting for recommendations.
We have analysed the sales statistics for Ipilimumab 2011- 2014 in the healthcare regions (Sjukvårdsregionerna) in Sweden. The number of patients in need of treatment is based on the mortality in malignant Melanoma as there is no national registration of the number of cases. About 400- 500 patients require immune therapy per year(9). Patients are scheduled to receive 4 doses of ipilimumab. In clinical studies, patients received 3.4- 3-5 doses on average and we therefore assumed 3,5 doses per patient and a 20% survival for at least 3 years.
Between 2011 and 2015, about 1630 patients required Ipilimumab; out of these, only about 230 (14%) were treated. This corresponds to at least 840 years of lost survival (potentially even cured) for those 280 patients (20%) who would have lived 3 years longer with treatment. We also see in the database of the National Board of Health and Welfare (Socialstyrelsen) that after Ipilimumab was introduced, the mortality in the region Skåne sank from 92 patients in 2013 to 57 patients in 2014.
Clearly, the controlled introduction didn’t work (9). The explanations are unclear but could be differences in physicians’ experiences with the product, differing assessments of risk and processes for the introduction. It effectively seems that no one had confidence in the therapy that revolutionised the treatment of metastatic Melanoma. One can obviously argue that at the time of approval, the evidence for ipilimumab was incomplete but there were clear signs of positive long-term efficacy (10) and similar data has been approved in oncology for a long time.
Obviously, (too) high prices of new cancer drugs impact local budgets considerably. In Europe, Sweden pays some of the highest prices for oncology products (11) but this requires a comprehensive discussion that doesn’t single out specific products.
Despite solid basic research, clinical results and no available treatment alternatives, only very few patients with metastatic melanoma received Ipilimumab (5). We have to learn from this failure for the introduction of therapies in the future.
Potential conflicts of interest: JH has participated in advisory boards for Bristol-Myers Squibb, Merck Sharp& Dome, Novartis and Roche.
JH is co-author of the article »Stora framsteg för systemisk behandling vid malignt melanom« [Läkartidningen. 2017;114:ELM9] that is part of the Melanoma special in LT 19/2017.
Hake CM. Glädjande utveckling vid malignt melanom. Dagens Medicin. 8 mars 2017.
Uppdrag till Myndigheten för vård- och omsorgsanalys att ta fram ett kunskapsunderlag kring införande, användning och uppföljning av cancerläkemedel. Stockholm: Socialdepartementet; 2017. Dnr S2017/00359/FS.
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-206.
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23.
Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889-94.
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432-3.
Davies A, Briggs A, Schneider J, et al. The ends justify the mean: outcome measures for estimating the value of new cancer therapies. Health Outcomes Res Med. 2012;3:e25-36.
Ullenhag G, Enblad G, Hansson J, et al. Nya men dyra cancerläkemedel. Upsala Nya Tidning. 9 aug 2011.
PD1-hämmarna nivolumab (Opdivo) och pembrolizumab (Keytruda) vid avancerat malignt melanom. Införande-/uppföljningsprotokoll för nationellt ordnat införande av läkemedel. 5 feb 2016. Stockholm: Sveriges Kommuner och landsting; 2016.
Eggermont AM, Spatz A, Robert C. Cutaneous melanoma. Lancet. 2014;383(9919):816-27.
Vogler S, Kilpatrick K, Babar ZU. Analysis of medicine prices in New Zealand and 16 European countries. Value Health. 2015;18(4):484-92.
Melanoma Patient Network Europe
Surviving Melanoma in Europe.
Access to prevention, early detection and effective treatment for all.
Professor, Consultant, Department for Oncology- Pathology, Karolinska Institute, Stockholm;
Onkologiska Kliniken, Karolinska University Hospital, Solna