The median time spent in the hospital was investigated for all patients in the subgroups. There was a statistically significant difference in the hospitalization duration within the IT/TT group compared with standard chemotherapy (Table 6).
The strengths of our study include the thorough follow-up, the quality of clinical data analyzed by independent clinicians, and the inclusion of patients mostly outside of a clinical trial protocol representing real-life data. To date, this is the largest OS analysis comparing chemotherapy with the new treatment modalities in a real-life setting in metastatic melanoma patients.
The superior outcome of the modern therapies in a real-world setting with a longer follow-up duration in comparison with previous reports could be confirmed. We show that longer survival is possible with MAPK inhibitors, with 1- and 2-year OS rates of 50 and 19.5%. In the TT group, high LDH levels had a significantly negative prognostic impact (P=0.035), suggesting that LDH is an independent parameter associated with clinical outcome in this patient population, which is consistent with prospective published data of the BRAF/MEKi combination treatment 39. Frauchiger et al. 40 also confirmed the predictive value of LDH (mOS for BRAFmut with normal LDH 14.2 vs. 6.95 months for high LDH). Although survival was numerically different in our IT study cohort within LDH low and high patients, the difference did not reach statistical significance, probably due to the low number of IT-treated.
The low PFS of 5.4 months in the IT/TT group compared with chemotherapy (PFS=2.5 months) can be explained by the high number of patients treated with ipilimumab in this group, influencing the PFS rates. Accordingly, we report a low PFS (2.15 months) within the IT group, whereas the PFS of TT patients (n=113) was 7.3 months. This is, however, comparable with the median PFS in the ipilimumab-treated arm in the Keynote 006 trial (mPFS 2.8 months) 31. Only 30% of the patients in the IT group had received pembrolizumab (either first or second line), which, despite having influenced the mOS rates, was not the case for the median PFS. In addition, and as is known, patients in clinical trials are commonly filtered (Eastern Cooperative Oncology Group status 0 or 1), often have normal LDH levels, and have no symptomatic brain metastasis as brain metastases are typically an exclusion criterion from clinical trials. A separate subgroup classification of ipilimumab and pembrolizumab was not performed because of the small number of pembrolizumab-treated patients.
However, the development of new lesions in patients receiving ipilimumab may not always indicate progressive disease or treatment failure, reflecting the concept of pseudoprogression, and may not correspond to the sometimes long-lasting responses in a minority of those patients. To overcome this problem, new immune RECIST criteria immune-related response criteria that provide a better correlation between OS and response were proposed 44.
The study also investigated the survival of patients with the presence of brain metastasis at stage IV disease and found a superior outcome to those without as expected (n=334, mOS 8.1 months, vs. mOS 12.5 months’ P=0.00065). These survival outcomes in brain-metastasis melanoma patients are by far superior to the 4-month survival data reported in the literature 45,46. This difference can be explained by the fact that the majority of patients with brain metastasis in our study received subsequent IT or TT after surgery or irradiation, which clearly confounded the results 47,48. We observed a nonsignificant trend toward an improved survival in patients with brain metastases treated with TT (P=0.06) and a significant survival benefit in those treated with IT+TT. Nevertheless, these results should be interpreted with caution because of the low numbers of patients analyzed by treatment. Combining systemic modern therapies for melanoma with conventional treatment of brain metastasis is a field that requires further investigation and large prospective trials are needed to guide future clinical management of this poor-prognosis group.
Another secondary endpoint of our study was to detect any difference in the hospitalization time between patients treated with checkpoint inhibitors or TT and those with standard chemotherapy (reference group), reflecting differences in treatment-association costs. A statistically significant difference was reported (P=0.01 in TT and P=0.007 in IT), despite the presence of sometimes severe immune-related adverse events (e.g. autoimmune-colitis or hypophysitis) documented with ipilimumab. Consistently, and according to a retrospective-single-center English cohort of patients (n=110) treated with ipilimumab, immune-related adverse events do not represent a significant expense in comparison with the drug cost itself 49.
There are clear limitations in our study, including the retrospective setting, with the potential selection bias or time effects. However, patients from different sites including university and nonuniversity hospitals in Switzerland were included, minimizing the risk that the current results are confounded by patient selection or site-specific influences. At the time of the study design and data collection, only ipilimumab (initially in the second-line setting and as of end of 2014, in the first-line setting) and BRAFi monotherapy was approved in Switzerland for the treatment of metastatic melanoma, which might have biased our results. Pembrolizumab was not approved as first-line treatment until May 2016, followed by the approval of combined nivolumab and ipilimumab in summer 2016.
Furthermore and although we calculated survival outcomes in treatment-naive patients (n=274), we did not differentiate survival data between first-line and second-line or third-line treatments because of the inadequate number of patients.
Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in a real-life setting including those patients with brain metastases. These data confirm that national melanoma registries and cancer statistics are useful for monitoring outcomes of approved therapies or newly established treatment protocols across multiple institutions and patient populations.
The authors are indebted to Mirja Gautschi for her contribution of patients’ data.
This study was partially funded by Roche, Merck Sharp & Dhome (MSD), and Bristol-Myers Squibb (BMS). The funding was provided by an unrestricted educational grant to the University of Zürich.
Professor Dummer receives research funding to the University of Zürich from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, and GlaxoSmithKline (GSK) and has a consultant or advisory board relationship with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Amgen outside the submitted work. Dr Goldinger has temporary consultant or advisory relationships and receives travel support from Roche, Novartis, Bristol-Myers Squibb (BMS), and Merck Sharp & Dhome (MSD); she receives research funding from the University of Zurich and SAKK. PD Dr.med. Roger von Moos plays a consultant role for Novartis, Roche, BMS, and MSD. For the remaining authors there are no conflicts of interest.
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