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Abstract
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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Response to first-line treatments following distant metastasis after adjuvant anti-PD1 therapy
Response to first line treatments following distant metastasis after adjuvant TT
CONSORT diagram for patients investigated in the study. In this study we investigated treatment outcomes following recurrence following adjuvant melanoma therapy (primary study cohort), as well as efficacy of upfront adjuvant melanoma in general (secondary study cohort). Overall, 242 patients that received adjuvant BRAF/MEKi therapy or adju- vant anti-PD1 therapy (n=273). Among patients receiving BRAF/MEKi therapy 154 did not show any tumor recurrence in the observation period, while among the 71 patients that progressed to stage IV and received subsequent systemic treat- ments 28 patients achieved disease control without disease progression at the time of data cut-off. By contrast, among all patients that received adjuvant anti-PD1 treatment, 124 patients did not show a tumor recurrence. Among patients that progressed to metastatic stage IV upon adjuvant anti-PD1 treatment (n=108) 43 achieved disease control without disease progression at the time of data cut-off. Patients who progressed to metastatic stage IV and who did not receive CPI or TT either received best-supportive care (BSC) including locoregional treatments such as surgery or TVEC or deceased prior to initiation of systemic treatments. Abbreviations: 1L = first-line treatment for metastatic stage IV disease; CPI =check- point inhibitor therapy; BSC = best supportiv care; CTX = chemotherapy; TT = BRAF/MEK-directed targeted therapy
Survival outcomes for patients with resected stage III melanoma that were treated outside of clini- cal trials stratified by upfront adjuvant therapy. (A) Median recurrence-free survival was significantly longer for patients given adjuvant TT as compared to adjuvant anti-PD1 (31.0 months, 95% CI: 26.0–36.0 vs 17.0 months, 95% CI: 11.9–22.1, p<0.001) as assessed by log-rank test. (B) Forest plot illustrating results of multivariable Cox-re- gression for relapse-free survival and corresponding HR. (C) Cox-adjusted Kaplan-Meier curves for recurrence-free survival (bottom, left) and time-point differences in adjusted RFS between patients treated with upfront adjuvant an- ti-PD1 vs upfront adjuvant TT. Abbreviations: TT BRAF/MEK-directed targeted therapy; HR = hazard ratio.
Kaplan Meier survival plots comparing survival outcomes stratified by treatment regimen (A, C) and individual first-line treat- ments (B,C), as well as tumor response rates of first-line treatments following adjuvant treatment failure (E,F). Results show that switching treatment modalities between adjuvant therapy and first metastatic treatment particularly results in longer median PFS (9 months, 95% CI: 5.2–12.8 vs 5 months, 95% CI: 1.3–8.7, p=0.004), although median OS (35.0 months vs NR, p=0.079) was not significantly different between the two treatment re- gimens (C). More specifically we observed that patients with a re-challenge of 1L BRAF/MEKi after failure of adjuvant TT showed the least favorable survival data. These patients presented with a median PFS of 3.0 months (95% CI: 0–6.2) as compared to 8.0 months (95% CI. 1.3–14.7) for patients switching to 1L CPI after previous TT-failure. By conrrast, patients who recurred at distant sites followign adjuvant anti-PD1 and received CPI in the 1L setting achieved a median PFS of 6.0 months (95% CI: 1.5–10.5) and 11.0 months (95% CI: 5.5–16.5) for patients switching from adjuvant anti-PD1 to 1L BRAF/MEKI. Also, median OS was significantly shorter for patients who received BRAF/MEKI both in the adjuvant setting and following distant me- tastasis (median OS: 21.0 months, 95% CI: 14.5–45.5), while median OS was not reached for all other subgroups (p=0.004). In line, tumor responses were strongest for patients that switched treatments following adjuvant treatment failure (E, F). Abbreviations: 1L = first-line treatment for metastastic stage IV disease; BRAF/MEKI = BRAF/MEK-directed targeted therapy; IPI+Nivo = Ipilimumab plus Nivolumab; CPI mono = single-agent checkpoint inhibitor therapy; Tx = treatment; TT = BRAF/MEK-directed targeted therapy. ‘p-value<0.05, ns = not significant.
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