Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2023 Sep;11(9):e007630.
doi: 10.1136/jitc-2023-007630.

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG

Maximilian Haist  1   2 , Henner Stege  3 , Friederike Rogall  3 , Yuqi Tan  2 , Imke von Wasielewski  4 , Kai Christian Klespe  4 , Friedegund Meier  5   6 , Peter Mohr  7 , Katharina C Kähler  8 , Michael Weichenthal  8 , Axel Hauschild  8 , Dirk Schadendorf  9 , Selma Ugurel  9 , Georg Lodde  9 , Lisa Zimmer  9 , Ralf Gutzmer  10 , Dirk Debus  11 , Bastian Schilling  12 , Alexander Kreuter  13 , Jens Ulrich  14 , Frank Meiss  15 , Rudolf Herbst  16 , Andrea Forschner  17 , Ulrike Leiter  17 , Claudia Pfoehler  18 , Martin Kaatz  19 , Fabian Ziller  20 , Jessica C Hassel  21 , Michael Tronnier  22 , Michael Sachse  23 , Edgar Dippel  24 , Patrick Terheyden  25 , Carola Berking  26   27 , Markus V Heppt  26   27 , Felix Kiecker  28 , Sebastian Haferkamp  29 , Christoffer Gebhardt  30 , Jan Christoph Simon  31 , Stephan Grabbe  3 , Carmen Loquai  3   32
Affiliations
Multicenter Study

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG

Maximilian Haist et al. J Immunother Cancer. 2023 Sep.

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. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor 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. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments.

Results: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 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 with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). 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. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004).

Conclusions: BRAFmut melanoma patients who developed DM upon upfront 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 of recurrence followed by a second adjuvant treatment with TT.

Keywords: Adjuvant Drug Therapy; Immune Checkpoint Inhibitors; Melanoma; Molecular Targeted Therapy; Recurrence.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors declare no conflicts of interest affecting this study. Conflicts of interest outside the submitted work are: PM declares research support from Bristol Myers Squibb, Novartis and Merck Sharp & Dome; speakers and advisory board honoraria from Almirall Hermal, Beiersdorf, Bristol Myers Squibb, Merck Sharp & Dome, Immunocore, Merck Serono, Medac, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. KCK declareds speakers and advisory board Honoria from Novartis and BMS, as well as travel support from Novartis, Pierre Fabre, Kyowa Kirin and Sun Pharma. FMeier has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. GL has received travel support for congress participation by Sun Pharma, Pierre-Fabre and research funding from Novartis. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LZ served as consultant and/or has received honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. RG served as consultant or/and has received Honoria from Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Pierre Fabre, Merck-Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, 4SC, Delcath, received travel support from Sun Pharma, Pierre Fabre, and Boehringer-Ingelheim. AH received consultancy and advisory board fees from Agenus Bio, Almirall Hermal, Amgen, Beiersdorf, BMS, Dermagnostix, Eisai, Highlight Therapeutics, Incyte, IO Biotech, Immunocore, MSD/Merck, MerckPfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme, Seagen and Xenthera. UL served as consultant to Roche, Novartis, MSD, Almirall Hermal, Sanofi and Sun Pharma; received travel support from Sun Pharma and Pierre-Fabre, received speaker fees from Roche, Novartis, MSD, Sun Pharma and Sanofi, outside the submitted work. She reports institutional research grants from MSD. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. DD has been on the advisory board or has received honoraria from BMS, MSD, Novartis, Pierre Fabre. IvW declares speakers and advisory board honoraria from Almirall Hermal, Bristol Myers Squibb, Merck Sharp & Dome, Novartis, Pierre Fabre, Sanofi Genzyme, Sun Pharma and Roche. RH reports speakers and advisory board honoraria from Bristol-Myers Squibb (BMS), Immunocore, Novartis, Pierre-Fabre, Roche and SUN pharma outside the submitted work. JCH received research grants from BMS, Sanofi and Sunpharma and served as a consultant and/or received honoria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi and Sunpharma, outside of the submitted work. MVH reports honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Pierre Fabre, Immunocore. BS is on the advisory board or has received honoraria from Immunocore, Almirall, Pfizer, Sanofi, Novartis, Roche, BMS and MSD, research funding from Novartis and Pierre Fabre Pharmaceuticals, and travel support from Novartis, Roche, Bristol-Myers Squibb and Pierre Fabre Pharma, outside the submitted work. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, SUNPHARMA, UCB, Allergy Therapeutics, Pierre Fabre, Kyowa Kirin and LEO. KCK has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre, and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. FZ served as consultant and/or has received honoria from BMS, MSD, Novartis, Pierre-Fabre, Sanofi, Sun Pharma. AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD and CeGaT, outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie. FMeiss served as a consultant and/or has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Roche, Pierre Fabre and MSD. SG declares honoraria for advisory boards, oral presentations, and travel expenses from Roche, Novartis, MSD, and BMS outside the submitted work. CL declares speakers, advisory board honoraria, and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis, Roche, Pierre Fabre, Sun Pharma, Kiowa Kirin, Sanofi, Biontech, and Almirall Hermal outside the submitted work.

Figures

Figure 1
Figure 1
CONSORT diagram of patients investigated in the study. In this ADOREG study, we investigated patients who received adjuvant BRAF/MEKi therapy (n=242) or adjuvant anti-PD1 therapy (n=273). Among patients receiving adjuvant BRAF/MEKi therapy 154 did not show any tumor recurrence in the observation period, while among the 71 patients who progressed to stage IV and received subsequent systemic treatments 28 patients achieved disease control without disease progression at the time of data cut-off. By contrast, among all patients who received adjuvant anti-PD1 treatment, 124 patients did not show a tumor recurrence. Among patients who 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. CONSORT, Consolidated Standards of Reporting Trials; CPI, checkpoint inhibitor; TT, targeted therapy; TVEC, Talimogene laherparepvec.
Figure 2
Figure 2
Survival outcomes for patients with resected stage III melanoma who were treated outside of clinical trials stratified by primary adjuvant therapy. (A) Median recurrence-free survival was significantly longer for patients given adjuvant TT (31.0 months, 95% CI 26.0 to 36.0 vs 17.0 months, 95% CI 11.9 to 22.1, p<0.001) as compared with adjuvant anti-PD1 therapy. (B) Forest plot illustrating results of multivariate Cox regression for recurrence-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 anti-PD1 as compared with upfront adjuvant TT. AJCC, American Joint Committee on Cancer; RFS, recurrence-free survival; TT, targeted therapy. Significance levels: *p<0.05, **p<0.01, ***p<0.001.
Figure 3
Figure 3
Kaplan-Meier survival curves depicting distant metastasis free survival (A), time-to-next treatment (B) and overall survival (C) stratified by adjuvant therapy. Result show that median distant-metastasis-free survival (39.0 months, 95% CI 31.0 to NR vs 41.0 months, 95% CI 29.2 to 52.8, p=0.012) and TTNT (33.0, 95% CI 26.6 to 39.4 vs 20.0 months, 95% CI 14.3 to 25.7, p<0.001) were significantly longer for adjuvant TT. By contrast, median overall survival was not reached in both groups. TTNT, time-to-next treatment; TT, targeted therapy.
Figure 4
Figure 4
Survival outcomes after re-introduction of systemic treatments for locoregional tumor recurrence. Following locoregional tumor recurrence systemic treatment with TT prolonged RFS as compared with CPI therapy (median RFS2: 24.0 months, 95% CI 8.6 to 39.4 vs 6.0 months, 95% CI 3.2 to 8.7, p=0.001) (A). As most patients switched treatment modalities upon locoregional recurrence there was no statistically significant difference in cumulative progression-free survival between patients who received CPI or TT as second treatment (median cPFS: 49.0 vs 28.0 months, p=0.11) (B). Patients with fully resected locoregional recurrence, who received a second adjuvant treatment with TT showed a significantly longer RFS as compared with patients who received a second adjuvant CPI therapy (median RFS2: 41.0 vs 6.0 months, p=0.009) (C). By contrast, patients who received a second adjuvant treatment for resected stage IV disease presented with a shorter RFS compared with patients with adjuvant treatment for resected stage III. Also, for these patients no statistically significant RFS has been observed between either adjuvant anti-PD1, BRAF/MEKi or ipi+nivo (median RFS3: 3 vs 11 months vs NR, p=0.37) (D). cPFS, cumulative progression-free survival; CPI, checkpoint inhibitor; RFS, recurrence-free survival; TT, targeted therapy.
See this image and copyright information in PMC

References

    1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. . Five-year survival with combined Nivolumab and Ipilimumab in advanced Melanoma. N Engl J Med 2019;381:1535–46. 10.1056/NEJMoa1910836 - DOI - PubMed
    1. Long GV, Flaherty KT, Stroyakovskiy D, et al. . Dabrafenib plus Trametinib versus Dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant Melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 2017;28:1631–9. 10.1093/annonc/mdx176 - DOI - PMC - PubMed
    1. Robert C, Grob JJ, Stroyakovskiy D, et al. . Five-year outcomes with Dabrafenib plus Trametinib in metastatic Melanoma. N Engl J Med 2019;381:626–36. 10.1056/NEJMoa1904059 - DOI - PubMed
    1. Lao CD, Khushalani NI, Angeles C, et al. . Current state of adjuvant therapy for Melanoma: less is more, or more is better Am Soc Clin Oncol Educ Book 2022;42:1–7. 10.1200/EDBK_351153 - DOI - PubMed
    1. Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. . Adjuvant Ipilimumab versus placebo after complete resection of high-risk stage III Melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. The Lancet Oncology 2015;16:522–30. 10.1016/S1470-2045(15)70122-1 - DOI - PubMed

Publication types

Substances