Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry.

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.

Management of heterogeneous tumor response patterns to immunotherapy in patients with metastatic melanoma.

Immunotherapy has revolutionized the treatment of metastatic melanoma. Response to therapy can be complex to evaluate, as Response Evaluation Criteria in Solid Tumor (RECIST) does not capture heterogeneous responses. In this retrospective single-institution analysis, we describe the management, clinicopathological characteristics, RECIST and disease course of metastatic melanoma patients with a heterogeneous response to first-line anti-CLTA-4 and/or anti-PD-1 between September 2011 and September 2020. In 196 patients, 37 had a heterogeneous response to immunotherapy (19%). Distinct identified responses included a mixed response (MR) (15%), pseudoprogressive disease (PP) (3%), and a sarcoid-like reaction (2%). Patients with a MR and possibly no response to therapy (MR-NR) had a higher median lactic acid dehydrogenase (LDH) (P = 0.01), were more often male (P = 0.04), had more involved disease sites (P = 0.01), and had brain metastasis more frequently (P = 0.02). MR patients with later response to therapy (MR-R) and PP patients had a longer overall survival of 1.7 [95% confidence interval (CI), 1.1-2.7] and 1.6 years (95% CI, 1.3-2.0) versus MR-NR 1.2 (0.7-1.7) (P < 0.01). In this cohort study, we identified prognostic clinical characteristics that can contribute to clinical decision-making for patients with a MR. Additionally, patients with pseudoprogression had benefited from therapy continuation, suggesting the importance of not halting therapy early in case of suspected PP. The male sex, more involved disease sites, brain metastasis and had a higher median LDH were associated with a poor survival for patients with a MR, suggesting that these clinical variables could be used to predict whether a mixed responder will possibly respond to therapy.

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.

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.

BACKGROUND: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era. METHODS: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs. RESULTS: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months; p = 0.04] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months; p = 0.01) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%; p = 0.03). CONCLUSIONS: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.

Mixed Response to Immunotherapy in Patients with Metastatic Melanoma.

BACKGROUND: Immunotherapy has improved overall survival in metastatic melanoma. Response to therapy can be difficult to evaluate as the traditionally used RECIST 1.1 criteria do not capture heterogeneous responses. Here we describe the clinical characterization of melanoma patients with a clinically defined mixed response to immunotherapy. METHODS: This was a single institution, retrospective analysis of stage IV melanoma patients who received first-line anti-CTLA-4, anti-PD1, or combination anti-CTLA-4/anti-PD1. Therapy response was assessed via clinical definitions, which consisted of cross-sectional imaging combined with clinical exam. Course of disease, clinicopathological characteristics, and management in patients with a mixed clinical response were analyzed. RESULTS: In 292 patients (anti-CTLA4 = 63; anti-PD1 = 148, anti-CTLA4/anti-PD1 = 81), 103 were responders (35%), 64 mixed responders (22%), and 125 patients had progressive disease (43%). Of patients with a mixed response, 56% eventually had response to therapy (mixed response followed by response, MR-R), while 31% progressed on therapy (MR-NR). MR-NR patients had higher median LDH (p < 0.01), 3 or more organ sites with metastases (p < 0.01), and more frequently had M1d disease (p < 0.01). Mixed responders who underwent surgery (n = 20) had a significantly longer mean OS compared to patients who did not undergo surgery (6.9 years, 95% CI 6.2-7.6 vs. 6.0 years, 95% CI 4.6-7.3, p = 0.02). DISCUSSION: Mixed response to immunotherapy in metastatic melanoma was not uncommon in our cohort (22%). Clinical characteristics associated with progression of disease after initial mixed response included higher LDH, brain metastases, and ≥ 3 organ sites with metastases. Surgical treatment for highly selected patients with a mixed response was associated with improved outcomes.