BRAF/MEK inhibitor rechallenge in advanced melanoma patients

Background: Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking. Methods: Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival. Results: The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1–5.2), and median OS was 8.2 months (95% CI, 7.2–9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7–4.0) versus 5.2 months (95% CI, 4.5–5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival. Conclusions: This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge.</p

BRAF/MEK inhibitor rechallenge in advanced melanoma patients

Background: Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking. Methods: Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival. Results: The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1–5.2), and median OS was 8.2 months (95% CI, 7.2–9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7–4.0) versus 5.2 months (95% CI, 4.5–5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival. Conclusions: This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge.</p

Response to immune checkpoint inhibitors in acral melanoma:A nationwide cohort study

Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM). Methods: We included patients with advanced AM and CM treated with first-line anti-programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression-free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS. Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8–5.6) than patients with CM (10.1 months; 95%CI: 8.5–12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26–2.11; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15–2.06; P = 0.004) than CM. Conclusions: This study shows lower effectiveness of anti-PD -1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies

The unfavorable effects of COVID-19 on Dutch advanced melanoma care

The COVID-19 pandemic had a severe impact on medical care. Our study aims to investigate the impact of COVID-19 on advanced melanoma care in the Netherlands. We selected patients diagnosed with irresectable stage IIIc and IV melanoma during the first and second COVID-19 wave and compared them with patients diagnosed within the same time frame in 2018 and 2019. Patients were divided into three geographical regions. We investigated baseline characteristics, time from diagnosis until start of systemic therapy and postponement of anti-PD-1 courses. During both waves, fewer patients were diagnosed compared to the control groups. During the first wave, time between diagnosis and start of treatment was significantly longer in the southern region compared to other regions (33 vs 9 and 15 days, P-value <.05). Anti-PD-1 courses were postponed in 20.0% vs 3.0% of patients in the first wave compared to the control period. Significantly more patients had courses postponed in the south during the first wave compared to other regions (34.8% vs 11.5% vs 22.3%, P-value <.001). Significantly more patients diagnosed during the second wave had brain metastases and worse performance status compared to the control period. In conclusion, advanced melanoma care in the Netherlands was severely affected by the COVID-19 pandemic. In the south, the start of systemic treatment for advanced melanoma was more often delayed, and treatment courses were more frequently postponed. During the second wave, patients were diagnosed with poorer patient and tumor characteristics. Longer follow-up is needed to establish the impact on patient outcomes

Is a History of Optimal Staging by Sentinel Lymph Node Biopsy in the Era Prior to Adjuvant Therapy Associated with Improved Outcome Once Melanoma Patients have Progressed to Advanced Disease?

Introduction: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy?Methods: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS.Results: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19–29) vs. 18 months (95% CI 15–20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma.Conclusion: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB.</p

Adjuvant treatment for melanoma in clinical practice - Trial versus reality

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting. Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method. Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade >= 3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy. Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials. (C) 2021 The Authors. Published by Elsevier Ltd

Response to checkpoint inhibition and targeted therapy in melanoma patients with concurrent haematological malignancies

BACKGROUND: Patients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease- or treatment-related T- or B-cell dysfunction.METHODS: All advanced melanoma patients treated with anti-PD-1-based treatment or targeted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific survival (MSS) were analysed for patients with HM (HM+) and without HM (HM-). A cox model was used to account for confounders associated with PFS and MSS.RESULTS: In total, 4638 advanced melanoma patients received first-line anti-PD-1 monotherapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated patients, the median PFS was 2.8 months for HM+ and 9.9 months for HM- (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM- (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HR adj 1.62; 95% confidence interval [95% CI] 1.15-2.29; p = 0.006) and melanoma-related death (HR adj 1.74; 95% CI 1.09-2.78; p = 0.020). Median PFS and MSS for first-line BRAF(/MEK-) inhibitor-treated HM+ and HM- patients were not significantly different. CONCLUSIONS: Patients with HM and advanced melanoma show significantly worse melanoma-related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM.</p

Adjuvant treatment of in-transit melanoma:Narrowing the knowledge gap left by clinical trials

Few clinical trials address efficacy of adjuvant systemic treatment in patients with in-transit melanoma (ITM). This study describes adjuvant systemic therapy of ITM patients beyond clinical trials. In this study, we included stage III adjuvant-treated melanoma patients registered in the nationwide Dutch Melanoma Treatment Registry between July 2018 and December 2020. Patients were divided into three groups: nodal disease only, ITM only and ITM and nodal disease. Recurrence patterns, recurrence-free survival (RFS) and overall survival (OS) at 12-months were analyzed. In our study population of 1037 patients, 66.8% had nodal disease only, 16.7% had ITM only and 16.2% had ITM with nodal disease. RFS at 12-months was comparable in the nodal only and ITM only group (72.2% vs70.1%, P = .97) but lower in ITM and nodal disease patients (57.8%; P = .01, P &lt; .01). Locoregional metastases occurred as first recurrence in 38.9% nodal disease only, 71.9% of ITM-only and 44.0% of ITM and nodal disease patients. Distant recurrences occurred in 42.3%, 18.8% and 36.0%, respectively (P = .02). 12-months OS was not significantly different for nodal disease only patients compared with ITM-only (94.4% vs 97.6%, P = .06) but was significantly higher for ITM-only compared with ITM and nodal disease patients (97.6% vs 91.0%, P &lt; .01). In conclusion, we showed that in the adjuvant setting, RFS rates in ITM-only patients are similar to non-ITM, though better than in ITM and nodal disease patients. Adjuvant-treated ITM-only patients less often experience distant recurrences and have a superior OS compared with ITM and nodal disease patients.</p

Adjuvant BRAF-MEK Inhibitors versus Anti PD-1 Therapy in Stage III Melanoma:A Propensity-Matched Outcome Analysis

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 &lt; 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.</p