Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, ...characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan–Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range IQR 5 – 44) and 14 months (IQR 5 – not reached), respectively (
P
= 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58–0.85;
P
< 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies.
Background
Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or ...the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort.
Methods
Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome.
Results
2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%;
p
= 0.58 for PD-1 inhibitors; 42% vs. 29%;
p
= 0.16 for ipilimumab; 38% vs. 43%;
p
= 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival;
p
= 0.61; 17.0 vs. 16.2 months overall survival;
p
= 0.44).
Conclusion
Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.
The aim of this study was to evaluate treatment patterns and overall survival (OS) of patients with BRAFV600 wild-type and BRAFV600-mutant advanced melanoma in the Netherlands.
We selected patients ...of 18 years and over, diagnosed between 2016 and 2017 with unresectable stage IIIC or IV melanoma, registered in the Dutch Melanoma Treatment Registry. To assess the association of BRAFV600-mutation status with OS we used the Cox proportional-hazards model.
A total of 642 BRAFV600 wild-type and 853 mutant patients were included in the analysis. Median OS did not differ significantly between both groups, 15.2 months (95% confidence interval CI: 13.2-19.2) versus 20.6 months (95% CI: 18.3-25.0). Survival rates at 6 and 12 months were significantly lower for BRAFV600 wild-type patients compared with BRAFV600-mutant patients, 72.0% (95% CI: 68.6-75.6) and 56.0% (95% CI: 52.2-60.0) versus 83.4% (95% CI: 80.9-85.9) and 65.7% (95% CI: 62.6-69.0). Two-year survival was not significantly different between both groups, 41.1% (95% CI: 37.2-45.3) versus 47.0% (95% CI: 43.6-60.6). Between 0 and 10 months, BRAFV600 wild-type patients had a decreased survival with a hazard ratio for OS of 2.00 (95% CI: 1.62-2.46) but this effect disappeared after 10 months. At 12 months, BRAFV600-mutant patients had started with second-line systemic treatment more often compared with BRAFV600 wild-type patients (50% vs. 19%).
These results suggest that advanced BRAFV600 wild-type melanoma patients have worse survival than BRAFV600-mutated patients during the first 10 months after diagnosis because of less available treatment options.
Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy ...is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced NM to SSM. Patients with advanced stage IIIc and stage IV NM and SSM treated with anti-CTLA-4 and/or anti-PD-1, or BRAF/MEKi in the first line, were included from the prospective Dutch Melanoma Treatment Registry. The primary objectives were distant metastasis-free survival (DMFS) and overall survival (OS). In total, 1086 NM and 2246 SSM patients were included. DMFS was significantly shorter for advanced NM patients at 1.9 years (CI 95% 0.7−4.2) compared with SSM patients at 3.1 years (CI 95% 1.3−6.2) (p < 0.01). Multivariate survival analysis for immunotherapy and BRAF/MEKi demonstrated a hazard ratio for immunotherapy of 1.0 (CI 95% 0.85−1.17) and BRAF/MEKi of 0.95 (CI 95% 0.81−1.11). A shorter DMFS for NM patients developing advanced disease compared with SSM patients was observed, while no difference was observed in the efficacy of systemic immunotherapy or BRAF/MEKi between NM and SSM patients. Our results suggests that the worse overall survival of NM is mainly driven by propensity of metastatic outgrowth of NM after primary diagnosis.
Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma.
All patients with advanced melanoma treated with first-line ...anti-PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to
and
status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS.
In total, 1764 patients received anti-PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti-PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for
-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with
-mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis,
-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for
-mutant melanoma compared with
-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens.
Ipilimumab-nivolumab-treated patients with
-mutant melanoma display improved PFS and OS compared with patients with
-mutant and double wild-type melanoma.
mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.
The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis.
All systemically treated patients diagnosed with ...advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS.
For this cohort study, we included 6260 systemically treated advanced melanoma patients. At baseline, there was an increase over the years in age, the percentage of patients with an ECOG PS ≥ 2, with brain metastases, and a synchronous diagnosis of primary and unresectable melanoma. Median OS increased from 11.2 months (95% CI 10.0–12.4) for patients diagnosed in 2013 to 32.0 months (95% CI 26.6–36.7) for patients diagnosed in 2019. Median OS was remarkably lower for patients diagnosed in 2020 (26.6 months; 95% CI 23.9–35.1) and 2021 (24.0 months; 95% CI 20.4-NR). Patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019, although this was not significant. The multivariable Cox regression showed a lower hazard of death for the years of diagnosis after 2013. In contrast, patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019.
After a continuous survival improvement for advanced melanoma patients between 2013 and 2019, outcomes of patients diagnosed in 2020 and 2021 seem poorer. This trend of decreased survival remained after correcting for known prognostic factors and previous neoadjuvant or adjuvant treatment, suggesting that it is explained by unmeasured factors, which—considering the timing—could be COVID-19-related.
For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.
The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients ...aged ≥75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment.
We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (≤65 years, 66–74 years and ≥ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS).
Overall, 52.2% of patients were ≤ 65 years and 18.4% of patients ≥75 years. BRAF mutated tumors were found less often in patients ≥75 years: 34.5% versus 65% in patients ≤65 years. Patients ≥75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1–19.3) in patients ≥75 years versus 26.7% (23.1–30.4) in patients ≤65 years, with a Hazard Ratio (HR) of 1.71 (95%CI 1.50–1.95), p < 0.001. Three year Melanoma Specific Survival was 30.4% (22.0–39.2) versus 34.0% (29.7–38.2), HR 1.26 (95% CI 1.07–1.49), p = 0.005 with an adjusted HR of 1.21 (1.00–1.47), p = 0.049.
Patients with metastatic melanoma ≥75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients.
•Patients ≥75 years are underrepresented in clinical trials.•In our real-world cohort 18.4% of patients with metastatic melanoma is aged ≥75 years.•Patients ≥75 year received less frequent treatment independent of BRAF status.•No significant increase in adverse events were reported in patients ≥75 year.•Only borderline statistical significant difference in Melanoma Specific Survival was seen.
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