The real-world impact of cancer immunotherapy on the survival of patients with metastatic melanoma
Authors: M. Donia, E. Ellebaek, T.H. Oellegaard, L. Duval, J.B. Aaby, L. Hoejberg, U.H. Koehler, H. Schmidt, L. Bastholt, I.-M. Svane
Journal: Annals of Oncology (2018)

Background: Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new immunotherapies for metastatic melanoma (MM). We sought to determine the impact of these treatments in the "real-world" of a population-based study. Methods: The Danish MM database contains data on the entire unselected population diagnosed with MM within a nationwide area. To evaluate the impact of novel treatments, all 843 MM cases (excluding ocular) diagnosed in the three non-consecutive years marked by major changes in the availability of 1st line treatments (2012: i.v. IL-2 and BRAFi; 2014: anti-CTLA-4; 2016: anti-PD-1 and MEKi) were retrieved. Patients were grouped into "trial-like" and "trial-excluded" based on seven predefined eligibility criteria used in all MM registration immunotherapy clinical trials, including CNS metastases and PS ≥ 2. Results: The baseline characteristics of patients diagnosed in 2012, 2014 and 2016 were similar. In the "trial-like" population (39% of all MM), the median overall survival (OS) was not yet reached in the 2016 group versus 18.8 months in 2014 (hazard ratio [HR] for death 0.52, 95% CI 0.36-0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27-0.62; p < 0.0001). In the "trial-excluded" population (61% of all MM), 75% of patients had known CNS metastases and/or PS ≥ 2. Here, the median OS was improved to 6.9 months in the 2016 group versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52-0.84; p = 0.0007) and 4.3 months in 2012 (HR 0.65, 95% CI 0.52-0.83; p = 0.0005). To isolate the effects of immunotherapy, the BRAF wild-type population of 2014 and 2016 was analyzed. Here, "trial-like" patients diagnosed in 2016 had an improved overall survival (median OS not reached in 2016 vs 13.3 months in 2014, HR 0.33, 95% CI 0.20-0.55; p < 0.0001), while "trial-excluded" patients had a 1-year improved survival rate in 2016 (35.9% vs 18.8% in 2014, p = 0.0153). Conclusions: The introduction of modern treatments has led to an improved survival of real world patients with MM, regardless of their eligibility to clinical trials and BRAF status. These data support indirectly the application of modern treatments, including anti-PD-1, to patient populations which are not represented in pivotal trials. Legal entity responsible for the study: Herlev and Gentofte Hospital. Funding: Herlev and Gentofte Hospital Research Council. Disclosure: M. Donia: Honoraria for lectures: Bristol-Myers Squibb, MSD, Sanofi Genzyme, AstraZeneca. H. Schmidt: Honoraria for consultancies and lectures: Novartis, Merck, Bristol-Myers Squibb, Incyte; Restricted research grants: MSD. L. Bastholt: Advisory board: Bristol-Myers Squibb, Roche, Novartis, Merck, Eisai, Bayer Healthcare. I-M. Svane: Honoraria for consultancies and lectures: Novartis, Roche, Merck, Bristol-Myers Squibb, Incyte; Restricted research grants: Novartis, BMS. All other authors have declared no conflicts of interest.