Sophia Kreft1, Anja Gesierich1, Thomas Eigentler2, Cindy Franklin3, Sara Valpione4, Selma Ugurel5, Jochen Utikal6, Sebastian Haferkamp7, Christian Blank8, James Larkin9, Claus Garbe2, Dirk Schadendorf5, Paul Lorigan4, Bastian Schilling10. 1. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany. 2. Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany. 3. Department of Dermatology, University Hospital Cologne, Cologne, Germany. 4. University of Manchester and Christie NHS Foundation Trust, Manchester, UK. 5. Department of Dermatology, University Hospital, Essen, Germany; German Cancer Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. 7. Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. 8. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 9. The Royal Marsden NHS Foundation Trust, London, UK. 10. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany. Electronic address: schilling_b@ukw.de.
Abstract
OBJECTIVES: Targeted therapy (TT) is an effective treatment for advanced BRAFV600-mutated melanoma, but most patients eventually acquire resistance and progress. Here, we evaluated the outcome of second-line immune checkpoint blockade (ICB) after progression on dual BRAF and MEK inhibition. METHODS: Patients with metastatic melanoma progressing on combined BRAF + MEK inhibition and receiving second-line ICB between 2015 and 2019 in 9 tertiary referral centres were enrolled. Demographic and clinical data and blood counts of all patients were collected retrospectively. RESULTS: We identified 99 patients with stage IV melanoma receiving ICB (nivolumab, pembrolizumab [n = 39] or ipilimumab plus nivolumab [n = 60]) after progression on combined TT. The median progression-free survival was similar in the PD-1 and ipilimumab plus nivolumab group (2.6 months [95% confidence interval {CI}, 2.0-3.1] vs. 2.0 [95% CI, 1.4-2.6], p = 0.15). The objective response rate was 18.0% in the PD-1 and 15.0% in the ipilimumab plus nivolumab group (p = 0.70). The disease control rate was 25.7% for monotherapy and 18.3% for combined ICB (p = 0.39). The median overall survival was 8.4 months (95% CI, 5.1-11.7) for patients receiving PD-1 monotherapy and 7.2 months (95% CI, 5.2-9.1) for patients receiving ipilimumab plus nivolumab (p = 0.86). The latter was associated with a higher rate of treatment-related adverse events (AEs). No significant association of laboratory values or clinicopathological characteristics with response to second-line ICB was observed. CONCLUSIONS: PD-1 monotherapy and combined ipilimumab plus nivolumab show similar activity and outcome in patients with melanoma resistant to BRAF + MEK inhibition. However, combined ipilimumab plus nivolumab was associated with a higher rate of treatment-related AEs compared with monotherapy.
OBJECTIVES: Targeted therapy (TT) is an effective treatment for advanced BRAFV600-mutated melanoma, but most patients eventually acquire resistance and progress. Here, we evaluated the outcome of second-line immune checkpoint blockade (ICB) after progression on dual BRAF and MEK inhibition. METHODS:Patients with metastatic melanoma progressing on combined BRAF + MEK inhibition and receiving second-line ICB between 2015 and 2019 in 9 tertiary referral centres were enrolled. Demographic and clinical data and blood counts of all patients were collected retrospectively. RESULTS: We identified 99 patients with stage IV melanoma receiving ICB (nivolumab, pembrolizumab [n = 39] or ipilimumab plus nivolumab [n = 60]) after progression on combined TT. The median progression-free survival was similar in the PD-1 and ipilimumab plus nivolumab group (2.6 months [95% confidence interval {CI}, 2.0-3.1] vs. 2.0 [95% CI, 1.4-2.6], p = 0.15). The objective response rate was 18.0% in the PD-1 and 15.0% in the ipilimumab plus nivolumab group (p = 0.70). The disease control rate was 25.7% for monotherapy and 18.3% for combined ICB (p = 0.39). The median overall survival was 8.4 months (95% CI, 5.1-11.7) for patients receiving PD-1 monotherapy and 7.2 months (95% CI, 5.2-9.1) for patients receiving ipilimumab plus nivolumab (p = 0.86). The latter was associated with a higher rate of treatment-related adverse events (AEs). No significant association of laboratory values or clinicopathological characteristics with response to second-line ICB was observed. CONCLUSIONS: PD-1 monotherapy and combined ipilimumab plus nivolumab show similar activity and outcome in patients with melanoma resistant to BRAF + MEK inhibition. However, combined ipilimumab plus nivolumab was associated with a higher rate of treatment-related AEs compared with monotherapy.
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