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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

2164 - Adverse events (AEs) over time in patients (pts) treated with adjuvant dabrafenib plus trametinib (D + T) or placebo (Pbo) in the COMBI-AD trial

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Topics

Tumour Site

Melanoma

Presenters

Victoria Atkinson

Citation

Annals of Oncology (2018) 29 (suppl_8): viii442-viii466. 10.1093/annonc/mdy289

Authors

V.G. Atkinson1, A. Hauschild2, M. Santinami3, M. Mandala4, V. Chiarion Sileni5, J. Larkin6, M.S. Nyakas7, C. Dutriaux8, A. Haydon9, L. Mortier10, C. Robert11, J. Schachter12, D. Schadendorf13, X. Feng14, E. de Jong15, B. Mookerjee14, R. Kefford16, R. Dummer17, J.M. Kirkwood18, G.V. Long19

Author affiliations

  • 1 Division Of Cancer Services, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, 4102 - Queensland/AU
  • 2 Department Of Dermatology, University Hospital Schleswig-Holstein, 24105 - Kiel/DE
  • 3 Melanomi E Sarcomi, Fondazione Istituto Nazionale Tumori, Milano/IT
  • 4 Division Of Oncology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo/IT
  • 5 Melanoma Oncology Unit, Veneto Oncology Institute, Padova/IT
  • 6 Department Of Medical Oncology, Royal Marsden NHS Foundation Trust, London/GB
  • 7 Department Of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo/NO
  • 8 Service De Dermatologie Et Dermatologie Pédiatrique, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux/FR
  • 9 Department Of Medical Oncology, The Alfred Hospital, Melbourne/AU
  • 10 Service De Dermatologie, Université de Lille, INSERM U 1189, Lille/FR
  • 11 Department Of Medicine, Institute Gustave Roussy, 94800 - Paris/FR
  • 12 Division Of Oncology, Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer/IL
  • 13 Department Of Dermatology, University Hospital Essen, 45122 - Essen/DE
  • 14 Global Clinical Program, Novartis Pharmaceuticals Corporation, East Hanover/US
  • 15 Global Medical Affairs Oncology, Novartis Pharmaceuticals Corporation, TBD - East Hanover/US
  • 16 Department Of Medical Oncology, Macquarie University, Melanoma Institute Australia, Westmead Hospital, and The University of Sydney, Sydney/AU
  • 17 Department Of Dermatology, University Hospital Zürich Skin Cancer Center, 8091 - Zürich/CH
  • 18 Melanoma Program, Upmc Hillman Cancer Center, & Department Of Medicine, University of Pittsburgh, Pittsburgh/US
  • 19 Department Of Medical Oncology, Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, 2060 - Sydney/AU
More

Resources

Abstract 2164

Background

In COMBI-AD (NCT01682083), adjuvant D + T led to a significant improvement in relapse-free survival vs Pbo in pts with resected BRAF V600–mutant stage III melanoma supporting recent US FDA approval in this indication. There were no new safety signals; however, a higher rate of permanent discontinuation due to AEs was observed compared with metastatic disease (26% [10% due to grade 3/4 AEs]); pyrexia (9%) and chills (4%) were most common. Here we further characterize AEs in COMBI-AD.

Methods

COMBI-AD was a randomized, double-blind, Pbo-controlled phase III trial comparing 12 mo of adjuvant D (150 mg twice daily) + T (2 mg once daily) vs Pbo in pts with resected BRAF V600E/K–mutant stage III melanoma. AEs were graded according to CTCAE v4.0. To assess AEs over time, exposure-adjusted AE rates (no. of occurrences/pt/3-mo exposure) were calculated over 3-mo intervals.

Results

Although most pts in both arms experienced ≥ 1 AE, the majority of AEs reported were low grade (eg, pyrexia [% of pts in D + T arm]: grade 1 [29%], grade 2 [29%], grade 3 [5%], grade 4 [< 1%]). In the first 3 mo of treatment, the exposure-adjusted AE rate of any event in pts treated with D + T was 6.14 occurrences/pt/3-mo exposure. However, the AE rates declined substantially with increased time on treatment (3 to < 6 mo [2.58]; 6 to < 9 mo [1.80]; 9 to < 12 mo [1.65]). Similar results were observed in pts in the Pbo arm, albeit at lower rates. Adjusted AE rates for the 10 most common AEs observed in COMBI-AD in the D + T arm also declined after the initial 3 mo (Table). Results were similar in pts who completed 12 mo of treatment.Table: 1251P

AE occurrences per patient per 3-month exposure

Preferred TermDabrafenib + Trametinib (n = 435)Placebo (n = 432)
0 to3 to6 to9 to0 to3 to6 to9 to
< 3 mo< 6 mo< 9 mo< 12 mo< 3 mo< 6 mo< 9 mo< 12 mo
Pyrexia1.260.650.500.450.080.050.050.02
Fatigue0.530.170.100.130.270.090.050.04
Nausea0.490.140.080.090.200.070.060.05
Headache0.500.170.130.120.270.100.090.07
Chills0.550.290.210.140000
Diarrhea0.320.110.090.100.140.080.060.05
Vomiting0.320.130.090.080000
Arthralgia0.300.120.070.070.090.050.060.05
Rash0.260.070.100.080.080.040.030.02
Cough0.140.040.030.010000

Conclusions

These results show that most AEs with adjuvant D + T occurred during the first 3 mo of treatment and declined thereafter, highlighting the importance of AE management early during treatment to prevent premature discontinuations and allow patients to complete 1 year of adjuvant treatment.

Clinical trial identification

NCT01682083.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Editorial Acknowledgement

Medical writing assistance was provided by Michael Demars, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation.

Disclosure

V.G. Atkinson: Consulting or advisory role: Bristol-Myers Squibb, MSD, Novartis, Merck Serono, Pierre Fabre; Honoraria: Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Merck Serono; Speakers’ bureau: Bristol-Myers Squibb, MSD, Novartis, Roche; Travel, accommodations, expenses: Bristol-Myers Squibb. A. Hauschild: Consultancy: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec; Research funding: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche; Honoraria: Amgen, Bristol-Myers Squibb, Merck Serono, MSD/Merck, Novartis, Philogen, Pierre Fabre, Provectus, Roche. M. Mandala: Research funding, Honoraria, Speakers bureau: Novartis, Roche. V. Chiarion Sileni: Consultancy: Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, Merck Serono. J. Larkin: Consultancy and honoraria: Eisai, Bristol-Myers Squibb, MSD, GlaxoSmithKline, Kymab, Pfizer, Novartis, Roche, Genentech, Secarna, Pierre-Fabre, EUSA Pharma; Research funding: Bristol-Myers Squibb, MSD, Novartis, Pfizer. M.S. Nyakas: Honoraria (institution) for advisory board: Novartis, Incyte. C. Dutriaux: Consultancy: Bristol-Myers Squibb, MSD; Membership on board of directors or advisory committee: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD; Clinical trials investigator: Bristol-Myers Squibb, Roche, Novartis, Merck Serono, MSD, Amgen. A. Haydon: Honoraria: Novartis. L. Mortier: Research funding: Novartis. C. Robert: Advisory board: Merck, MSD, Novartis, Roche. J. Schachter: Honoraria: Bristol-Myers Squibb, MSD; Travel, accommodations, expenses: Bristol-Myers Squibb. D. Schadendorf: Personal fees: Amgen, Boehringer Ingelheim, Leo Pharma, Roche, Novartis, Incyte, Regeneron, 4SC, AstraZeneca, Bristol-Myers Squibb, MS, Pierre Fabre, Merck-EMD, Pfizer, Philiogen, Array; Patients' fees to institution: MSD, Roche, Novartis, Regeneron, Brisol-Myers Squibb, Merck-EMD, Philiogen. X. Feng, E. de Jong: Employee: Novartis. B. Mookerjee: Employment: Novartis; Stock ownership: Novartis, GlaxoSmithKline, AstraZeneca. R. Kefford: Membership on board of directors or advisory committees: Bristol-Myers Squibb, Amgen, Merck, Novartis, Teva; Conference travel: Bristol-Myers Squibb, Amgen. R. Dummer: Intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma outside the submitted work. J.M. Kirkwood: Consultancy: Bristol-Myers Squibb, Novartis, Array Biopharma, Merck, Roche, Amgen, Immunocore, Prometheus; Research funding: Merck. G.V. Long: Consultancy: Amgen, Bristol-Myers Squibb, Merck MSD, Novartis, Roche, Pierre-Fabre, Array; Honoraria: Bristol-Myers Squibb, MSD, Roche, Novartis, Incyte. All other authors have declared no conflicts of interest.

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