Abstract 806P
Background
COMBI-APlus (NCT03551626) evaluated an adapted pyrexia management algorithm in patients (pts) with resected stage III BRAF V600E/K-mutant melanoma treated with adjuvant dabrafenib plus trametinib (D + T). The study showed significant improvement in the composite pyrexia events compared to that in COMBI-AD. Here we report the updated long-term toxicity profile and relapse-free survival (RFS) from COMBI-APlus.
Methods
D + T was interrupted at the onset of pyrexia and resumed once pts were symptom-free. The primary end point was the composite rate of grade 3/4 pyrexia, hospitalization or permanent cessation due to pyrexia vs historical control from COMBI-AD (20%; 95% CI; 16.3–24.1).
Results
At a median (min–max) follow-up of 31.6 mo (24.9–38.6), median duration of D + T exposure for all enrolled pts (N=552) was 11.0 mo (0.03–12.42). The composite rate of grade 3/4 pyrexia, hospitalization, and permanent withdrawal due to pyrexia was 7.6% (95% CI; 5.5–10.1). Grade 3/4 pyrexia, hospitalization, and permanent discontinuation due to pyrexia occurred in 20 (3.6%), 24 (4.3%), and 12 (2.2%) pts, respectively. The median (interquartile range [IQR]) time to first onset of pyrexia was 22 days (11–70), and the median duration of first pyrexia event was 2 days (IQR, 2.0–4.0). A total of 542 (98.2%) pts experienced an adverse event (AE). Most AEs appeared in the first quarter of treatment, and >94% of them were fully resolved by end of the study. All pyrexia events were 100% resolved. Exposure-adjusted AEs in the first 3 months were 8.36 occurrences, which reduced to 3.51 in months 9–12; likewise, pyrexia occurrence was reduced from 1.68 to 0.73. Permanent discontinuation due to any AE occurred in 80 (14.5%) pts. At data cut-off (18 Nov 2021), RFS events were reported in 150 (27.2%) pts, whereas relapses occurred in 144 (26.1%) pts. The 12- and 18-mo RFS rates were 91.7 % (95% CI; 89.0–93.8) and 81.5 % (95% CI; 77.8–84.6), respectively.
Conclusions
After >2 years of follow-up, the adapted algorithm reduced the incidence of pyrexia-related toxicities compared to that in COMBI-AD, while D + T maintained RFS benefits.
Clinical trial identification
NCT03551626.
Editorial acknowledgement
Medical writing support/editorial support was provided by Manoj Kumar Goyal (Novartis Healthcare Pvt Ltd) which was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
M. Del Vecchio: Financial Interests, Personal and Institutional, Other: Merck, Novartis, BMS, Sanofi, Pierre Fabre, Merck, Novartis, BMS, Sanofi, Pierre Fabre; Financial Interests, Personal and Institutional, Research Grant: Merck, Novartis, BMS, Sanofi, Pierre Fabre; Financial Interests, Personal and Institutional, Advisory Board: Merck, Novartis, BMS, Sanofi, Pierre Fabre. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Nektar, Novartis, Pierre Fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS. B. Ryll: Financial Interests, Institutional, Other, Support for MPNE yearly activities for 2019 and 2020, projects are always multi-sponsored and support never gives rights to any influence wrt content, program, speakers or other; this reflects MPNE’s total budget: Amgen, Delcath, MSD, Pierre Fabre, Roche; Financial Interests, Institutional, Other, Support for MPNE yearly activities for 2019, 2020 and 2021, projects are always multi-sponsored and support never gives rights to any influence wrt content, program, speakers or other; this reflects MPNE’s total budget: BMS, Novartis; Financial Interests, Personal, Advisory Board, Ethics Board for EAP programs: Clinigen; Financial Interests, Personal, Advisory Board, Access to medicines AD board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Patient Summit: Pfizer; Financial Interests, Personal, Advisory Board, Histology-agnostic ad board: Roche; Financial Interests, Personal, Advisory Board, Patient Expert Ad board: Amgen; Financial Interests, Personal, Invited Speaker, Patient Ad board, internal meeting: Novartis Sweden; Financial Interests, Personal, Invited Speaker, Baltic Oncology Summit, webinars: MSD SE; Financial Interests, Personal, Other, Fee for Service- organisation of a workshop for PA at ESMO 2019: MSD; Financial Interests, Personal, Invited Speaker, WIN symposium: Roche; Financial Interests, Personal, Advisory Board, Melanoma Academy: Novartis; Financial Interests, Personal, Advisory Board, IQVIA Oncology Ad board: IQVIA; Financial Interests, Personal, Advisory Board, Patient AD board: BMS; Financial Interests, Personal, Advisory Board, Advisor for a research project 2021: Pierre Fabre; Financial Interests, Personal, Advisory Board, Member of clinical trial steering committee COMBI-Aplus: Novartis; Financial Interests, Personal, Other, Member of the ASC Oncology Advisory Board: ASC Oncology. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. V. Chiarion Sileni: Financial Interests, Personal, Advisory Board, analysis of treatment modality ( diagnosis, stanging, surgery, radiotherapy, systemic therapy for Merkel cell carcinoma in Italy: Merck-Serono; Financial Interests, Institutional, Invited Speaker, treatment option for BRAF mutated melanoma: Novartis; Financial Interests, Institutional, Invited Speaker, Treatment choices for BRAF mutated melanoma, evidence-based, and biologically supported: Pierre -Fabre; Financial Interests, Institutional, Invited Speaker, Immunotherapy for melanoma treatment present and future: Bristol-Meyers-Squibb; Financial Interests, Personal, Other, Travel, registration, and accommodation to attend ASCO annual meetings: Pierre-Fabre; Financial Interests, Personal, Advisory Board, Travel expenses, registration, and accommodation to attend ASCO annual meeting and ESNO annual meeting: Bristol Meyers-Squibb. V. Ferraresi: Financial Interests, Personal, Invited Speaker: Novartis, BMS, PharmaMar; Financial Interests, Personal, Advisory Board: Novartis, BMS, PharmaMar, GSK. T. Lesimple: Financial Interests, Personal, Advisory Role: Novartis, MSD, Pierre Fabre. P. Saiag: Financial Interests, Personal, Advisory Board: Novartis, Pierre Fabre, BMS, MSD, Roche, Merck Serono; Financial Interests, Institutional, Invited Speaker: Pierre Fabre; Financial Interests, Personal and Institutional, Invited Speaker: Novartis. C. Robert: Financial Interests, Personal, Advisory Board: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, AstraZeneca, Pfizer. H.J. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: MSD, BMS, Novartis, Pierre Fabre, SANOFI; Financial Interests, Invited Speaker: Amgen, Replimune; Financial Interests, Institutional, Invited Speaker: Amgen, MSD, BMS, Replimune, Iovance; Financial Interests, Institutional, Research Grant: BMS, Pfizer. A. Gupta: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal and Institutional, Research Grant: Novartis, BMS; Financial Interests, Personal, Other: Novartis. H. Banerjee: Financial Interests, Institutional, Full or part-time Employment: Novartis. S. Sudhir: Financial Interests, Institutional, Full or part-time Employment: Novartis. F. Miranda: Financial Interests, Institutional, Full or part-time Employment: Novartis. M.R. Lau: Financial Interests, Institutional, Full or part-time Employment: Novartis Pharma AG; Financial Interests, Personal, Stocks/Shares: Novartis. J.J. Grob: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Roche, Pierre Fabre, Novartis, Pfizer, Sanofi, Philogen, Iteos Therapeutics, Sunpharma; Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pierre Fabre, Sanofi, Novartis; Financial Interests, Institutional, Research Grant: Pierre Fabre. All other authors have declared no conflicts of interest.