Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Patients
2.3. Samples and Mutation Analysis
2.4. Treatments
2.5. Outcomes and Assessments
2.6. Statistical Considerations
3. Results
3.1. Patient Disposition
3.2. Prescreening Phase
3.2.1. Primary Endpoint
3.2.2. Secondary Endpoint
3.2.3. Exploratory Endpoint
3.3. Treatment Phase
3.3.1. Efficacy Outcomes
3.3.2. Correlation of Mutation Testing and Clinical Outcome
3.3.3. Substudy
3.3.4. Exposure and Safety
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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mITT | STITT | |
---|---|---|
n = 172 | n = 40 | |
Age, median years (range) | 62.5 (20–93) | 56.5 (26–82) |
Sex, n (%) | ||
Male | 84 (48.8) | 18 (45.0) |
Female | 88 (51.2) | 22 (55.0) |
ECOG score, n (%) | ||
0 | NE | 21 (52.5) |
1 | NE | 16 (40.0) |
2 | NE | 3 (7.5) |
Time since diagnosis of metastases, median months (range) | 19.3 (0.1–260.7) | 12.4 (0.8–260.7) |
Age at diagnosis of metastases, median years (range) | 59.1 (18–91) | 53.5 (26–83) |
Disease stage at study entry, n (%) | ||
Unresectable stage IIIC | 16 (9.3) | 1 (2.5) |
Stage IV | 156 (90.7) | 29 (97.5) |
Measurable disease at study entry, n (%) | 147 (85.5) | 37 (92.5) |
Number of target lesions, n (%) | ||
0–3 | NE | 22 (55.0) |
>3 | NE | 18 (45.0) |
Type of tissue material, n (%) | ||
Archival | 140 (81.4) | 30 (75.0) |
Recent | 32 (18.6) | 10 (25.0) |
Prior tissue BRAF mutation test result, n (%) | ||
BRAF wild-type | 118 (68.6) | 1 (2.5) |
BRAFV600 mutation | 54 (31.4) | 39 (97.5) |
Prior therapy, n (%) | ||
Immunotherapy | – | 9 (33) |
Targeted therapy | – | 0 |
Other systemic therapy | – | 7 (17.5) |
Investigational treatment | – | 1 (2.5) |
Radiotherapy | – | 8 (20.0) |
A. BRAF | Plasma cfDNA Test Result | |||
---|---|---|---|---|
Wild-Type | Mutant | |||
Tissue test result | Wild-type | 111 | 7 | Patients with wild-type tissue test = 118 |
Mutant | 19 | 35 | Patients with mutant tissue test = 54 | |
Patients with wild-type plasma test = 130 | Patients with mutant plasma test = 42 | |||
B. Plasma | BRAF cfDNA test result | |||
Wild-type | Mutant | |||
NRAS cfDNA test result | Wild-type | 107 | 42 | Patients with wild-type NRAS = 149 |
Mutant | 22 | 0 | Patients with mutant NRAS = 22 | |
Patients with wild-type plasma test = 129 | Patients with mutant plasma test = 42 |
STITT n = 40 | Archival Tissue * n = 29 | Recent Tissue † n = 10 | |
---|---|---|---|
Objective response rate, ‡ n (%) | |||
CR | 3 (8.3) | 3 (11.5) | – |
PR | 26 (72.2) | 20 (76.9) | 6 (60.0) |
SD | 2 (5.6) | – | 2 (20.0) |
PD | 1 (2.8) | – | 1 (10.0) |
Other nonresponders | 4 (11.1) | 3 (11.5) | 1 (10.0) |
Responders (CR + PR), n/n′ (%) | 29/36 (80.6) | 23/26 (88.5) | 6/10 (60.0) |
95% CI | 64.0–91.8 | 69.8–97.6 | 26.2–87.8 |
Duration of Response, n′ ‡ | 29 | 23 | n′ = 6 |
Median, months (95% CI) | 11.0 (9.2–NE) | 11.0 (9.2–NE) | 8.8 (3.6–NE) |
Progression-free survival | |||
Median months (95% CI) | 13.6 (9.5–16.5) | 14.5 (10.8–NE) | 6.2 (3.6–NE) |
System Organ Class/Preferred Term | n = 40 |
---|---|
Any treatment-emergent adverse event, n (%) | 39 (97.5) |
Skin and subcutaneous tissue disorders, n (%) | 33 (82.5) |
Rash | 19 (47.5) |
Photosensitivity reaction | 11 (27.5) |
Maculopapular rash | 9 (22.5) |
Alopecia | 4 (10.0) |
Investigations, n (%) | 22 (55.0) |
Blood creatinine phosphokinase increased | 13 (32.5) |
Gamma-glutamyltransferase increased | 5 (12.5) |
C-reactive protein increased | 4 (10.0) |
General disorders and administration site conditions, n (%) | 21 (52.5) |
Pyrexia | 11 (27.5) |
Fatigue | 8 (20.0) |
Oedema peripheral | 5 (12.5) |
Infections and infestations, n (%) | 21 (52.5) |
Upper respiratory tract infection | 8 (20.0) |
Conjunctivitis | 6 (15.0) |
Urinary tract infection | 4 (10.0) |
Gastrointestinal disorders, n (%) | 20 (50.0) |
Diarrhea | 13 (32.5) |
Vomiting | 6 (15.0) |
Nausea | 5 (12.5) |
Musculoskeletal and connective tissue disorders, n (%) | 14 (35.0) |
Arthralgia | 11 (27.5) |
Musculoskeletal pain | 4 (10.0) |
Myalgia | 4 (10.0) |
Pain in extremity | 4 (10.0) |
Eye disorders, n (%) | 12 (30.0) |
Vision blurred | 6 (15.0) |
Chorioretinopathy | 4 (10.0) |
Nervous system disorders, n (%) | 12 (30.0) |
Headache | 6 (15.0) |
Metabolism and nutrition disorders, n (%) | 7 (17.5) |
Decreased appetite | 4 (10.0) |
Hypokalemia | 4 (10.0) |
Hypertension | 5 (12.5) |
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Rutkowski, P.; Pauwels, P.; Kerger, J.; Jacobs, B.; Maertens, G.; Gadeyne, V.; Thielemans, A.; de Backer, K.; Neyns, B. Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma. Cancers 2021, 13, 3591. https://doi.org/10.3390/cancers13143591
Rutkowski P, Pauwels P, Kerger J, Jacobs B, Maertens G, Gadeyne V, Thielemans A, de Backer K, Neyns B. Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma. Cancers. 2021; 13(14):3591. https://doi.org/10.3390/cancers13143591
Chicago/Turabian StyleRutkowski, Piotr, Patrick Pauwels, Joseph Kerger, Bart Jacobs, Geert Maertens, Valerie Gadeyne, Anne Thielemans, Katrien de Backer, and Bart Neyns. 2021. "Characterization and Clinical Utility of BRAFV600 Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma" Cancers 13, no. 14: 3591. https://doi.org/10.3390/cancers13143591