Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population‐based study

Abstract

Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003–2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre‐ (2003–2010) and post‐ (2011–2016) novel therapy eras. Also, OS in the post‐novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5‐year OS rates were 48.5% and 50.2% in the pre‐ and post‐novel eras, respectively (p = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre‐novel era and post‐novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post‐novel era (p < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients.

The real‐world outcome of metastatic melanoma: Unknown primary vs. known cutaneous

“…In a recent study, Verver et al . reported on the real‐world outcome of patients with metastatic melanoma of unknown primary (MUP) in a population‐based study, showing that treatments introduced in the modern era (2011–2016) appear to have improved the survival of this subgroup of patients.…”

“…Hence, important additional questions still need to be addressed, such as whether some patients with MUP are diagnosed at a very late stage (by definition, the diagnosis of MUP is based on the detection of a disease that is already metastatic); whether inclusion of important prognostic factors in multivariate analyses (such as LDH or PS) will still result in a superior OS for patients with MUP who received first‐line immunotherapy compared to those who received first‐line targeted therapy, as in the study by Verver et al . ; or whether some other cases of MUP have a distinct biology that translates into better outcome compared to MKP even in the modern treatment era.…”

Author's reply to: The real‐world outcome of metastatic melanoma: Unknown primary vs. known cutaneous

“…Since approximately 50% of MUP patients and only~3% of MKP patients present with advanced metastatic disease at initial diagnosis, patients with metachronic metastatic MKP were likely to be underrepresented and were therefore not included in our analyses. 1,6,7 A possible limitation of the current analysis by Ellebaek and colleagues is the difference in at least one of the relevant prognostic factors between the two groups. Although the proportion of "trial-like" patients in both groups was similar (41% MKP vs. 36% MUP, p = 0.46), which was defined as those patients who fulfil eligibility criteria for phase III immunotherapy trials (i.e., WHO performance status of 0 or 1, normal lactate dehydrogenase, no active brain metastasis or leptomeningeal metastases, no serious or uncontrolled medical condition, no autoimmune diseases, no previous malignancies in the last 3 years, no immunosuppressive medications and no unmeasurable disease according to the Response Evaluation Criteria in Solid Tumours, 1.1), there was an imbalance in higher disease stages according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging criteria.…”

“…We thank Dr Ellebaek and colleagues for their interest in our manuscript on real-world outcomes of patients with metastatic melanoma of unknown primary (MUP) in the era of novel therapy. 1 In their response, Ellebaek and colleagues address the important question whether patients with MUP and patients with melanoma of known primary (MKP) have a similar prognosis during novel therapy. To answer this question, they analysed the survival of patients with metastatic MUP and MKP from a nation-wide real-world population in Denmark in the present modern era and demonstrated similar survival between patients with MKP and MUP, with a median survival of 9.7 and 10.0 months, respectively.…”

Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results

“…1,2 Once melanoma has spread into the lymph nodes, or even visceral organs and the brain, it remains a life-threatening disease despite the advent of molecular targeted or immunotherapies. 1,2 Melanoma of unknown primary (MUP) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] represents an unusual subtype of melanoma which was reported to be about 2-9% of melanoma of known primary (MKP) at all stages. 3 Some of the literature in the different geographic regions demonstrated better overall survival of MUP than of MKP.…”