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Contains fulltext : 293454.pdf (Publisher’s version ) (Open Access) The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab-nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients' survival based on their baseline and disease characteristics.

Simple Summary BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is known about how these therapies compare to each other in everyday practice. The aim of our study was to describe the toxicity and survival of patients treated with BRAF/MEK therapy and anti-PD-1 therapy in daily practice. We demonstrated that grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early treatment discontinuation (71.1%). We also show that at 12 months, patients treated with BRAF/MEK therapy have less progression than those treated with anti-PD-1 therapy. However, this is no longer the case at 18 months. Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness.

Simple Summary Nodular melanoma is associated with a higher locoregional recurrence rate and worse overall survival outcomes. Whether this histologic subtype affects the efficacy of immunotherapy or targeted therapy is unclear. The aim of our multi-center nationwide study is to identify the efficacy of immunotherapy and BRAF/MEKi therapy in metastatic nodular melanoma compared with the efficacy in metastatic superficial spreading melanoma. Our study results demonstrate no difference between the effectiveness of immunotherapy and BRAF/MEKi in metastatic nodular versus superficial melanoma patients. A shorter distant metastasis-free survival and reduced overall survival (measured as the time between primary melanoma up to death or last follow-up) was observed in the nodular melanoma patient group, suggesting worse overal survival of nodular melanoma is mainly driven by propensity of metastatic outgrowth of nodular melanoma after primary diagnosis. 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.

PURPOSE Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma. MATERIALS AND METHODS 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 BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS 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 BRAF-mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS-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, BRAF-mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF-mutant melanoma compared with NRAS-mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION Ipilimumab-nivolumab–treated patients with BRAF-mutant melanoma display improved PFS and OS compared with patients with NRAS-mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma.

Simple Summary: The survival of advanced melanoma patients has improved significantly over the last decade due to the introduction of new systemic therapies. It is unknown whether survival outcomes of advanced melanoma patients differ between melanoma centers in the Netherlands. This research aimed to assess center variation in treatments and 2-year survival probabilities of advanced melanoma patients diagnosed between 2013 and 2017 in the Netherlands. Significant center variation in 2-year survival probabilities of patients diagnosed in 2014-2015 was observed after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. This study shows the added value of quality monitoring with a national registry that enables the study of variation between centers.Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands. Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers' performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared. Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed.

9577 Background: Few clinical trials address the efficacy of adjuvant systemic treatment in patients with ITM. This study describes the efficacy of adjuvant systemic therapy of ITM patients beyond the clinical trial setting. Methods: All stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between 01-07-2018 and 31-12-2020 were included. Patients were divided into three groups: patients with ITM only, with ITM and nodal disease, and patients with nodal disease only. Differences in recurrence patterns were analysed. An exploratory analysis was performed for stage III patients who underwent surgical resection without adjuvant treatment. Recurrence-free survival (RFS) and overall survival (OS) at 12-months were assessed. Results: A total of 1037 stage III melanoma patients received adjuvant anti-PD-1 therapy, and 260 underwent surgical resection only. Of the adjuvant-treated patients, 16.9% had ITM only, 15.5% had ITM with nodal disease, and 66.8% had nodal disease only. Of the surgical resection only patients 20.4% had ITM only, 12.3% had ITM with nodal disease and 67.3% had nodal disease only. In the adjuvant-treated patients, 12-months RFS was comparable between patients with ITM only and patients with nodal disease only (71.1% vs. 72.2% respectively, p = 0.95), but significantly lower for patients with ITM and nodal disease (57.1%; ITM with nodal disease vs. ITM-only p = 0.01, and ITM with nodal disease vs. nodal disease only p < 0.01). Locoregional metastases occurred as first recurrence site in 72.7% of ITM-only patients, 42.9% of ITM and nodal disease patients and 38.9% of patients with nodal disease only, while distant recurrences occurred in 18.2% of patients with ITM only, in 36.7% of patients with ITM and nodal disease, and in 42.3% of patients with nodal disease only (p = 0.01). OS at 12-months was significantly higher for ITM-only patients compared to patients with ITM and nodal disease (97.7% vs. 90.6%, p < 0.01), and was better compared to patients with nodal disease only (97.7% vs. 94.4%, p = 0.05). OS at 12-months was comparable for patients with ITM and nodal disease and patients with nodal disease only (p = 0.19). In general, surgery-only ITM patients were older and had a worse performance score. 12-months RFS appeared worse compared to adjuvant-treated ITM patients (36.6% vs. 68.3%). In this group of surgery-only ITM patients OS at 12-months also appeared worse compared to adjuvant-treated ITM patients (89.7% vs. 95.5%). Conclusions: RFS rates in ITM-only patients are similar to non-ITM patients, while RFS in patients with ITM and nodal disease is shorter. Adjuvant-treated patients with ITM without nodal disease less often experience distant recurrences and have a superior OS compared to other adjuvant stage III patients. Our results suggest that other treatment strategies for ITM patients with nodal disease should be considered.

9546 Background: Management of checkpoint-inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of immunosuppressive treatment with anti-TNF on checkpoint-inhibitor efficacy. Methods: Advanced melanoma patients experiencing grade ≥3 irAEs after treatment with first-line ipilimumab-nivolumab between 2015 and 2021 were included from the Dutch Melanoma Treatment Registry. Progression-free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS) were analyzed according to toxicity management regimen. A cox proportional hazards model was used to account for the confounders age, sex, performance status, lactate dehydrogenase, site of metastases and type of irAE. Results: Out of 771 ipilimumab-nivolumab treated patients, 350 were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids only and 115 received steroids with second-line immunosuppressants consisting of anti-TNF, mycophenolic acid, tacrolimus and other immunosuppressants. Median PFS was significantly longer for patients treated with steroids (11.3 months) than for patients treated with steroids and second-line immunosuppressants (5.4 months; HR 1.43; 95%CI 1.07-1.90; p = 0.01). Median OS was also significantly longer for the steroids group (46.1 months) than for the steroids and second-line immunosuppressants group (22.5 months; HR 1.64; 95%CI 1.16-2.32; p = 0.005). Results for MSS were similar (not reached versus 28.8 months; HR 1.70; 95%CI 1.16-2.49; p = 0.006). Median PFS, OS and MSS are shown in Table 1. After adjustment for potential confounders, patients treated with steroids + second-line immunosuppressants showed a non-significant trend towards a higher risk of progression (HRadj 1.40; 95%CI 1.00-1.97; p = 0.05), a higher risk of death (HRadj 1.54; 95%CI 1.03-2.30; p = 0.04) and of melanoma-specific death (HRadj 1.62; 95%CI 1.04-2.51; p = 0.032) compared to the steroids group. Conclusions: Second-line immunosuppression for irAEs is associated with impaired PFS, OS, and MSS in advanced melanoma patients treated with first-line ipilimumab-nivolumab, irrespective of being anti-TNF or other second-line immunosuppressants. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in melanoma but also in other tumor types. [Table: see text]

e21502 Background: The COVID-19 pandemic COVID had a severe impact on medical care in The Netherlands. So far, few studies have investigated the influence of COVID-19 on advanced melanoma care nationwide. This study aims to investigate the impact of COVID-19 on the systemic treatment of unresectable stage III and IV advanced melanoma patients in the Netherlands. Methods: Data were obtained from the Dutch Melanoma Treatment Registry (DMTR), a population-based nationwide registry of all stage III and IV melanoma patients amenable for systemic treatment. We compared two patient groups dependent on the date of the first diagnosis of metastasis: during the first COVID-19 wave (March 15th 2020 until May 22nd 2020), and a control group during the same period one year earlier. Furthermore, we divided patients into three geographical regions within the Netherlands (north, middle and south). These regions were based on the maximum number of hospital admissions for COVID-19 patients during the first wave, using data from the National Intensive Care Evaluation (NICE). COVID-19 incidence was highest in the southern part of The Netherlands. We investigated baseline characteristics, type of systemic therapy, time from diagnosis of the irresectable stage III or IV melanoma until the start of systemic therapy, postponement of anti-PD-1 courses in patients actively being treated during the predefined time periods and progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimates. Results: During the first COVID-19 wave, 104 patients were diagnosed with advanced melanoma versus 166 patients during the control period in 2019. No significant differences were found in patient and tumor characteristics, type of systemic therapies or in the time from diagnosis until the start of systemic therapy, between the different periods. However, during the first wave, the time between diagnosis until the start of treatment was significantly longer in the southern regions as compared to the northern and middle regions (33 vs 9 and 15 days, p-value < 0.05). Anti-PD-1 antibody treatment courses were postponed in 79 patients (15.5%) during the first wave versus four patients (1.1%) in the control period. Significantly more patients had a postponed course in the south during the first wave compared to the middle and northern regions (30.2% vs 2.7% vs 16.7%, p-value < 0.001). With limited follow-up, thus far no significant differences in PFS and OS were found. Conclusions: Advanced melanoma care in the Netherlands was severely affected by the COVID-19 pandemic. In the south, where COVID-19 incidence was highest in the first wave, the start of systemic treatment for advanced melanoma was more often delayed, and treatment courses were more frequently postponed. Longer follow-up is needed to establish whether this has had an impact on patient outcome.

e21527 Background: Recent data in Japanese patients suggest poor outcomes for anti-PD1 in acral melanoma (AM), with no data available on combination treatment. The objective of this study was to analyze the efficacy of anti-PD1 monotherapy and anti-PD1 and anti-CTLA4 combination therapy in these patients. Methods: Our study population consisted of patients registered in the nationwide prospective Dutch Melanoma Treatment Registry between 2014 and 2020. We calculated objective response rate (ORR) in all unresectable stage III and IV AM and nonacral cutaneous melanoma (NAM) patients treated with anti-PD1, and combination anti-PD1 and anti-CTLA4. Progression-free survival (PFS), and overall survival (OS) were estimated for first-line treated patients. A Cox proportional hazard analysis was performed to adjust for potential confounders. Results: Nighty-five AM patients received at least one dose of anti-PD1 monotherapy, of whom 58 (61%) as first-line treatment. ORR was 28% (complete response 11%; partial response 18%). Median PFS and OS in patients with first-line treatment were 5.5 months (95% CI 3.5-8.4) and 14 months (95% CI 9.3-25.0). In patients with NAM (n = 1259) ORR was 48% (complete response 18%; partial response 31%). Six-hundred and eighty-eight (55%) patients received anti-PD1 as first-line treatment. Median PFS was 11.7 months (95% CI 9.1-14.9) and median OS was 24 months (95% CI 20.0-29.3) in these patients. Older age, higher ECOG scores, elevated LDH levels, liver metastasis and brain metastasis were significantly associated with lower OS. After adjustment for covariates, acral subtype remained associated with shorter PFS (Hazard Ratio 1.76, 95% CI 1.25-2.48) and OS (Hazard Ratio 1.70, 95% CI 1.17-2.45). Twenty-four AM patients received at least one dose of anti-PD1 plus anti-CTLA4, of which 15 as first-line treatment. ORR was 25% (complete response 4%; partial response 20%). AM patients treated with first-line combination therapy had a median PFS of 3.8 months (95% CI 2.8-NR) and median OS of 7.63 months (95% CI 6.12-NR). ORR in NAM patients treated with combination therapy (n = 599) was 41% (complete response 8%; partial response 33%). Forty-six percent of these patients were treated in the first-line, with a median PFS of 9.7 months (95% CI 6.6-17.1) and median OS of 21.3 months (95% CI 14.6-36.5). Elevated LDH levels and the presence of BRAF mutation were significantly associated with lower OS. No significant association was found between acral subtype and PFS, or OS after adjustment for covariates. Conclusions: This study shows limited efficacy of anti-PD1 for advanced AM, with clinically relevant lower response rates compared to nonacral melanoma types. Although caution is needed because of relatively small numbers and the observational nature of our study, our data confirm limited efficacy of checkpoint inhibition in AM.

9558 Background: The ability to analyze tumor mutation profiles has altered the oncology treatment landscape over the past decades. However, little is known about the effect of specific gene mutations on the response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: All unresectable stage IIIc and IV patients with BRAF V600, NRAS mutations and BRAF and NRAS wild-type patients treated with anti-PD-1 or ipilimumab-nivolumab between 2012 and 2020 were included from the Dutch Melanoma Treatment Registry, a nationwide population-based registry. Outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A Cox model was used to analyze the association of possible prognostic factors with PFS and OS. Results: In total 1358 first-line patients treated with anti-PD-1 and 524 treated with ipilimumab-nivolumab were included. Median follow-up was 25.6 months for anti-PD-1 treated patients and 16.3 months for ipilimumab-nivolumab treated patients. The highest ORR, in first-line, to anti-PD-1 was in patients who were BRAF and NRAS wildtype (50.2%), compared to BRAF V600 (43.8%) and NRAS mutated patients (49.8%). ORR to ipilimumab-nivolumab was highest in NRAS mutated patients (44.9%), while ORR was 39.5% for BRAF mutated patients and 40.3% for wild-type patients. Median PFS in the anti-PD-1 treatment regimen was significantly higher (p = 0.049) for double wild-type patients (16.7 months) patients than for BRAF mutated patients (9.9 months) and NRAS mutated patients (11.3 months). PFS was not significantly different (p = 0.11) in the ipilimumab-nivolumab treatment cohort, with a median PFS of 6.5 months for the wild-type group, 10.8 months for the BRAF group, and 9.1 months for the NRAS group. In the anti-PD-1 treated patients, median OS was significantly higher (p < 0.001) for BRAF mutated patients (32.8 months) compared to NRAS (21.0 months) and wild-type patients (23.0 months). For ipilimumab-nivolumab treated patients, median OS was also significantly higher (p < 0.001) for BRAF mutated patients (36.5 months) than for NRAS mutated patients (11.8 months) and wild-type patients (16.1 months). After adjustment for potential confounders, the presence of a BRAF mutation remained associated with lower PFS in the anti-PD-1 treatment cohort and better OS in both treatment cohorts. Higher age, higher ECOG score, elevated LDH levels, liver metastases and brain metastases were associated with worse survival. Conclusions: PFS in first-line PD-1 was significantly higher for double wild-type patients than for BRAF mutant and NRAS mutant patients. PFS in ipilimumab-nivolumab treated patients did not significantly differ between BRAF mutant, NRAS mutant and double wild-type patients. OS was significantly higher for BRAF mutant patients in both treatment strata, which is probably the result of the subsequent BRAF/MEK-inhibition treatment option in this group.

The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy and time to recurrent disease. Here, we integrated clinical treatment, treatment response and survival data with whole genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability and duplications. The clusters exhibited distinct response rates and survival probabilities which according to our analysis could potentially be improved by genome-informed treatment stratification.