Victoria Atkinson1, Caroline Robert2, Jean J Grob3, Helen Gogas4, Caroline Dutriaux5, Lev Demidov6, Avinash Gupta7, Alexander M Menzies8, Bettina Ryll9, Flora Miranda10, Hiya Banerjee11, Mike Lau12, Michele Del Vecchio13. 1. Division of Cancer Services, Princess Alexandra Hospital, University of Queensland, 199 Ipswich Road, Woolloongabba, Queensland 4102, Australia. Electronic address: victoria.atkinson@health.qld.gov.au. 2. Department of Medicine, Gustave Roussy, Paris-Saclay University, Villejuif, Orsay, France. 3. Dermatology and Skin Cancer Department, Aix-Marseille University, Marseille, France. 4. First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 5. Department of Dermatology, University Hospital of Bordeaux, Bordeaux, France. 6. Tumor Biotherapy, N. N. Blokhin Russian Cancer Research Center, Moscow, Russia. 7. Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. 8. Department of Medical Oncology, Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. 9. Medical Oncology, Melanoma Patient Network Europe, Uppsala, Sweden. 10. Clinical Operations, Global Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. 11. Analytics, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. 12. Global Medical Affairs, Novartis Pharma AG, Basel, Switzerland. 13. Unit of Melanoma Medical Oncology, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Abstract
BACKGROUND: COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K-mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes. METHODS: COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%-24.1%). RESULTS: At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%-10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%-93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events. CONCLUSIONS: The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment. CLINICAL TRIAL REGISTRATION: NCT03551626.
BACKGROUND: COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K-mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes. METHODS: COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%-24.1%). RESULTS: At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%-10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%-93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events. CONCLUSIONS: The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment. CLINICAL TRIAL REGISTRATION: NCT03551626.
Authors: Morgan Homan; Govind Warrier; Christopher D Lao; Sarah Yentz; Shawna Kraft; Leslie A Fecher Journal: Front Oncol Date: 2022-09-23 Impact factor: 5.738