Background Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma.1–6 However, 40% of these patients will develop distant metastasis (DM) within 5 years, which require systemic treatments.2 5 Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM.7 8 This study evaluated the efficacy of subsequent treatments following recurrence upon upfront adjuvant therapy.
Methods For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting (figure 1). Disease characteristics, treatment regimens, details on recurrence, subsequent management and survival outcomes were collected within the prospective, real-world registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to subsequent treatments.
Results Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21.0 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared to anti-PD1 (Hazard ratio adjusted for age, gender and baseline AJCC stage: 0.52; 95% CI: 0.40–0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31.0 vs 17.0 months, p<0.001) (figure 2). Patients who received TT as second adjuvant treatment following resection of locoregional recurrence had a longer RFS2 as compared to adjuvant CPI (median RFS2: 41.0 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to first-line treatment (1L) with Ipilimumab+Nivolumab (IPI+Nivo) (table 1). By contrast, patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L IPI+Nivo (table 2). Overall, median PFS was significantly longer for patients who switched treatments for metastatic disease (median PFS 9 vs 5 months, p=0.004) (figure 3).
Conclusions In this real-world cohort study we demonstrate that BRAFmut melanoma patients who developed DM upon adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection followed by second adjuvant treatment with TT. Upfront adjuvant TT significantly reduced the risk of recurrence compared to adjuvant anti-PD1 therapy.
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2. Eggermont Alexander MM, Kicinski M, Blank Christian U, Mandala M, Long Georgina V, Atkinson V, et al. Five-Year analysis of adjuvant pembrolizumab or placebo in stage III melanoma. NEJM Evidence. 2022;1(11):EVIDoa2200214.
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