Abstract 1127P
Background
ctDNA testing offers a less invasive alternative to biopsy for identifying BRAF-positive patients (pts) with melanoma who are candidates for targeted therapy, and may have prognostic value. We assessed the concordance between ctDNA and tumour tissue BRAF mutation status, and clinical relevance of ctDNA BRAF mutation status, using data from COLUMBUS.
Methods
In COLUMBUS part 1, 577 pts with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to encorafenib 450 mg QD + binimetinib 45 mg BID, encorafenib 300 mg QD or vemurafenib 960 mg BID. A total of 613 plasma samples were collected during screening. BRAF V600E/K in ctDNA were assessed using BEAMing technology, and concordance of BRAF status between baseline (BL) ctDNA and tissue was assessed. Associations of ctDNA BRAF V600E/K mutation status (yes/no) with BL markers of poor prognosis and centrally confirmed overall response rates (ORRs) were analysed. Data are as-is and the trial is ongoing.
Results
In total, 502 pts had results for both ctDNA and tissue BRAF V600E/K assessments. Of these pts, 317 (63%) had BRAF V600E/K detected by ctDNA, and 420 (84%) had BRAF V600E/K by tissue. Overall agreement (positive agreement; negative agreement) of ctDNA versus tumour tissue was 78% (75%; 96%) for BRAF V600E/K, 81% (75%; 99%) for BRAF V600E and 97% (70%; 99%) for BRAF V600K. BRAF V600E/K detectable by ctDNA were associated with higher lactate dehydrogenase levels, greater number of organs with disease, and greater tumour burden at BL (unadjusted Wilcoxon 2-sample p<0.0001 for each). Within each treatment arm, there were no notable ORR differences between ctDNA BRAF mutation status (95% CIs overlapped; Table).
Conclusions
These findings confirm the reliability of ctDNA for detecting BRAF mutations; ctDNA may serve as an alternative test for BRAF V600E/K mutations. ctDNA BRAF mutations correlated with BL markers of poor prognosis but not with ORR. Table: 1127P
ctDNA BRAF mutation status and ORR by treatment arm
| ctDNA BRAF V600E/K mutation | Centrally confirmed ORR, % (95% CI) | ||
| Encorafenib 450 mg QD + binimetinib 45 mg BID | Encorafenib 300 mg QD | Vemurafenib 960 mg BID | |
| Yes | 69.3 (57.6–79.5) | 57.5 (45.9–68.5) | 42.3 (31.2–54.0) |
| No | 53.3 (34.3–71.7) | 60.0 (38.7–78.9) | 40.7 (22.4–61.2) |
Clinical trial identification
NCT01909453; July 26, 2013.
Editorial acknowledgement
Writing and editorial assistance were provided by Sharon Gladwin, PhD, of Caudex, funded by Pfizer.
Legal entity responsible for the study
Pfizer.
Funding
Pfizer.
Disclosure
C. Robert: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Biothera. K.T. Flaherty: Advisory/Consultancy: Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Bristol-Myers Squibb Company; Advisory/Consultancy: Merck; Advisory/Consultancy: Takeda; Advisory/Consultancy: Verastem; Advisory/Consultancy: Boston Biomedical; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Debiopharm; Officer/Board of Directors: Clovis Oncology; Officer/Board of Directors: Strata Oncology; Officer/Board of Directors: Vivid Biosciences; Officer/Board of Directors: Checkmate Pharmaceuticals; Advisory/Consultancy: X4 Pharmaceuticals; Advisory/Consultancy: PIC Therapeutics; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Amgen; Advisory/Consultancy: Asana; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Fount; Advisory/Consultancy: Aeglea; Advisory/Consultancy: Shattuck Labs; Advisory/Consultancy: Tolero; Advisory/Consultancy: Apricity; Advisory/Consultancy: Oncoceutics; Advisory/Consultancy: Fog Pharma; Advisory/Consultancy: Neon; Advisory/Consultancy: Tvardi; Advisory/Consultancy: xCures, Monopteros, Vibliome; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Sanofi. H.J. Gogas: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self): Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy: Amgen; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche. A.M. Arance Fernandez: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre-Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi. M. Mandala: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Sanofi. G. Liszkay: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Roche. C. Garbe: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: NeraCare; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Philogen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi. D. Schadendorf: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi/Regeneron; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pierre Fabre/Array/Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck EMR; Advisory/Consultancy: Immunocore; Honoraria (institution), Advisory/Consultancy: Nektar; Honoraria (self), Advisory/Consultancy: 4SC. I. Krajsova: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pierre Fabre. R. Gutzmer: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Honoraria (self), Honoraria (institution), Advisory/Consultancy: MSD; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Amgen; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy: Almirall Hermal; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: SUN; Honoraria (self), Honoraria (institution), Advisory/Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Pierre-Fabre; Honoraria (institution): Philogen; Advisory/Consultancy: 4SC; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Johnson & Johnson. J.W.B. de Groot: Advisory/Consultancy: Bristol-Myers Squibb Company; Advisory/Consultancy: Novartis; Advisory/Consultancy: MSD; Advisory/Consultancy: Servier; Advisory/Consultancy: Pierre Fabre. C. Dutriaux: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis Pharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck. C. Loquai: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb Company; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Biontech; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Sun Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Kyowa Kirin; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Sanofi. A. Harney: Shareholder/Stockholder/Stock options: Pfizer. E. Kiprilov: Full/Part-time employment: Pfizer. M.D. Pickard: Full/Part-time employment: Pfizer. J. Cantey-Kiser: Full/Part-time employment, Contractor: Array BioPharma/Pfizer. R. Dummer: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme (MSD); Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb Company; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Sun Pharma; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Catalym; Honoraria (self), Advisory/Consultancy: Second Genome; Honoraria (self), Advisory/Consultancy: Regeneron; Honoraria (self), Advisory/Consultancy: Alligator. P.A. Ascierto: Advisory/Consultancy, Research grant/Funding (institution): Bristol Myers-Squibb Company; Advisory/Consultancy, Research grant/Funding (institution): Roche-Genentech; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Array; Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Medlmmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: Sunpharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco; Advisory/Consultancy: Nektar; Advisory/Consultancy: Boehringer-Ingelheim; Advisory/Consultancy: Primevax; Non-remunerated activity/ies: President of Fondazione Melanoma Onlus, Napoli, Italy; Non-remunerated activity/ies: President of Campania Society of ImmunoTherapy of Cancer (SCITO), Italy; Non-remunerated activity/ies: Member of Steering Committee of Society of Melanoma Research (SMR); Non-remunerated activity/ies: Member of Board of Directors for the Society of Immuno-Therapy of Cancer (SITC).