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459 Treatment management of BRAF-mutant melanoma patients following tumor recurrence upon adjuvant therapy: A multicenter real-world cohort study from the prospective skin cancer registry ADOREG
  1. Maximilian Haist1,
  2. Henner Stege2,
  3. Friederike Rogall2,
  4. Yuqi Tan1,
  5. Imke von Wasielewski3,
  6. Kai Christian Klespe3,
  7. Friedegund Meier4,
  8. Peter Mohr5,
  9. Katharina Kaehler6,
  10. Michael Weichenthal6,
  11. Dirk Schadendorf7,
  12. Selma Ugurel9,
  13. Elisabeth Livingstone9,
  14. Georg Lodde9,
  15. Lisa Zimmer9,
  16. Ralf Gutzmer10,
  17. Dirk Debus11,
  18. Bastian Schilling12,
  19. Alexander Kreuter13,
  20. Jens Ulrich14,
  21. Frank Meiss15,
  22. Rudolf Herbst16,
  23. Andrea Forschner17,
  24. Ulrike Leiter17,
  25. Claudia Pfoehler18,
  26. Martin Kaatz19,
  27. Fabian Ziller19,
  28. Jessica Hassel20,
  29. Michael Tronnier21,
  30. Michael Sachse22,
  31. Edgar Dippel23,
  32. Patrick Terheyden24,
  33. Carola Berking25,
  34. Markus V Heppt25,
  35. Felix Kieker26,
  36. Sebastian Haferkamp27,
  37. Christopher Gebhardt28,
  38. Jan Simon29,
  39. Stephan Grabbe2 and
  40. Carmen Loquai30
  1. 1Stanford University School of Medicine, Stanford, CA, USA
  2. 2University Medical Center Mainz, Mainz, Rhineland-Palatinate, Germany
  3. 3Hannover Medical School, Hannover, Lower saxony, Germany
  4. 4University Hospital Carl Gustav Carus, Dresden, Saxony, Germany
  5. 5Elbe Kliniken, Buxtehude, Hamburg, Germany
  6. 6University Hospital of Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany
  7. 7West German Cancer Center, University Hospital Essen, Essen, Germany
  8. 9University of Duisburg-Essen, Essen, North-Rhine Westphalia, Germany
  9. 10Medizinische Hochschule Hannover, Bochum, North-Rhine Westphalia, Germany
  10. 11Nuremberg General Hospital, Nuremberg, Bavaria, Germany
  11. 12University Hospital Würzburg, Würzburg, Bavaria, Germany
  12. 13HELIOS St. Elisabeth Klinik Oberhausen, Oberhausen, North-Rhine Westphalia, Germany
  13. 14Harzklinikum Quedlinburg, Quedlinburg, Sachsen-Anhalt, Germany
  14. 15Medical Center, University of Freiburg, Freiburg, Baden-Württemberg, Germany
  15. 16HELIOS Hospital Erfurt, Erfurt, Thüringen, Germany
  16. 17University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany
  17. 18Saarland University Medical Center, Homburg/Saar, Saarland, Germany
  18. 19DRK Hospital Chemnitz-Rabenstein, Chemnitz-Rabenstein, Saxony, Germany
  19. 20Interdisziplinäre Tumorambulanz Nationals Centrium Für Tumorerkrankungen, Heidelberg, Germany
  20. 21HELIOS Hospital Hildesheim, Hildesheim, Lower Saxony, Germany
  21. 22Hospital Bremerhaven Reinkenheide, Bremerhaven, Bremen, Germany
  22. 23Hospital Ludwigshafen, Ludwigshafen, Rhineland-Palatinate, Germany
  23. 24University of Lübeck, Lübeck, Germany
  24. 25Uniklinikum Erlangen, Erlangen, Bavaria, Germany
  25. 26Vivantes Klinikum Neukölln, Berlin, Berlin, Germany
  26. 27University Hospital Regensburg, Regensburg, Bavaria, Germany
  27. 28University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Hamburg, Germany
  28. 29University Hospital Leipzig, Leipzig, Saxony, Germany
  29. 30University Medical Center of the Johanne, Mainz, Germany
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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.

References 1. Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. New England Journal of Medicine. 2018;378(19):1789–801.

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.

3. Weber J, Del Vecchio M, Mandala M, Gogas H, Arance A, Dalle S, et al. Adjuvant nivolumab (NIVO) versus ipilimumab (IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase III CheckMate 238 trial. Annals of Oncology. 2019;30:v533–v4.

4. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.

5. Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. The Lancet Oncology. 2020;21(3):358–72.

6. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. New England Journal of Medicine. 2017;377(19):1813–23.

7. Owen CN, Shoushtari AN, Chauhan D, Palmieri DJ, Lee B, Rohaan MW, et al. Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy. Annals of Oncology. 2020;31(8):1075–82.

8. Bhave P, Pallan L, Long GV, Menzies AM, Atkinson V, Cohen JV, et al. Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis. British Journal of Cancer. 2021;124(3):574–80.

Abstract 459 Table 1

Response to first-line treatments following distant metastasis after adjuvant anti-PD1 therapy

Abstract 459 Table 2

Response to first line treatments following distant metastasis after adjuvant TT

Abstract 459 Figure 1

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

Abstract 459 Figure 2

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.

Abstract 459 Figure 3

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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