Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study
Abstract
Simple Summary
Abstract
1. Introduction
2. Patients and Methods
Statistical Analysis
3. Results
3.1. Baseline Patient Characteristics
3.2. Duration of BRAF/MEK Inhibitor Therapy
3.3. Treatment Duration Is Not Correlated with the Risk of TAE, But with a Longer PFS and OS
3.4. Factors Associated with Disease Progression and Survival upon BRAF/MEKi Treatment
3.5. Treatment Outcomes upon BRAF/MEKi Therapy
3.6. Impact of Treatment Discontinuation
3.7. Duration of Response and Second-Line Treatment
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinicopathological Features | N (%) |
---|---|
Median age at initiation of TT (range) | 58 (29–80) |
Female | 15/37 (40.5%) |
Male | 22/37 (59.5%) |
Primary tumor | |
Median Breslow thickness (range) | 3.2 mm (0.5–30.0 mm) 1 |
Ulceration | 11/28 (39.3%) 2 |
Clinical course prior to initiation of targeted therapy | |
Median interval from primary diagnosis to advanced stage melanoma (range) | 15 months (0–285 months) |
Median time from primary diagnosis to initiation of BRAF ± MEKi therapy (range) | 21 months (0–290 months) |
Metastatic lesion | |
Metastatic sites, median (range) | 3 (0–7) |
Lung | 25/37 (67.6%) |
Liver | 6/37 (16.2%) |
Nodal | 18/37 (48.6%) |
Cutaneous | 7/37 (18.9%) |
Bone | 7/37 (18.9%) |
Other | 17/37 (45.9%) |
Cerebral | 16/37 (43.2%) |
ECOG 3-status ≥ 1 at beginning of TT | 4/16 (25%) |
Treatments | |
Treatment with BRAF ± MEKi (first-line)
| 2/37 (5.4%) 1/37 (2.7%) 5/37 (13.5%) 20/37 (54.1%) 9/37 (24.3%) |
Median treatment duration (range)
| 16.0 months (1–60 months) 25 months (16–60 months) 22 months (0–70 months) 3 months (0–49 months) |
Treatment-related adverse events of any grade
| 15/37 (40.5%) 6/37 (18.9%) |
Tumor progression | 22/37 (60%) |
Median progression-free survival (95% CI) in months | 27.0 months (1.5–52.5) |
Second-line treatment
| 21/37 (56.7%) 0 months (0–13 months) 4/15 (27%) 2 months 23 months (0–28 months) 3/5 (60%) 9.5 months |
Follow-up | |
Overall observation period upon TT initation | 100 months |
Median follow-up after TT discontinuation (range) | 19 months (0–70 months) 4 |
Median overall survival (95% CI) in months | 77 months (19–135 months) |
Deceased | 10/37 (27.0%) |
No. | Age | Sex | Initial AJCC Stage | MBM | Mutation | Therapy | TT (mo) | Reason for Cessation | Cessation Time (mo) | Time to Relapse after Cessation (mo) | TP | BOR to 2nd Line Therapy | Status | OS (mo) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 45 | M | IB | no | V600E | Vem | 30 | Physician’s choice | 13 | 56 | yes | PD (IPI) | AWD | 100 |
2 | 48 | M | IIB | no | V600E | Dab + Tram | 30 | Physician’s choice | 9 | - | no | - | AWD | 39 |
3 | 79 | F | IV | yes | V600R | Cob + Vem | 29 | Physician’s choice | 24 | - | no | NA (Cob + Vem) | AWD | 54 |
4 | 75 | M | IIIB | yes | V600E | Dab + Tram | 5 | Physician’s choice | 24 | - | no | - | AWD | 30 |
5 | 55 | M | IIA | no | V600E | Dab + Tram | 12 | Physician’s choice | 28 | 19 | yes | PR (Dab + Tram) | AWD | 59 |
6 | 48 | M | IIIC | yes | V600E | Dab | 11 | Toxicity | 0 | 35 | yes | CR (Tram) | DC | 36 |
7 | 71 | M | IV | no | V600K | Dab + Tram | 11 | Physician’s choice | 0 | 22 | yes | MR (Nivo) | AWD | 34 |
8 | 59 | M | IV | yes | V600E | Cob + Vem | 5 | Toxicity | 0 | 14 | yes | PD (IPI + Nivo) | AWD | 20 |
9 | 45 | M | IV | yes | V600E | Dab + Tram | 3 | Toxicity | 0 | 27 | yes | PD (Nivo) | AWD | 30 |
10 | 33 | F | IIIC | no | V600E | Cob + Vem | 9 | Physician’s choice | 0 | 48 | yes | CR (IPI) | AWD | 59 |
11 | 74 | M | IIIB | no | V600K | Cob + Vem | 6 | Toxicity | 1 | 2 | yes | PD (Atezo) | DC | 10 |
12 | 61 | M | IB | no | V600E | Dab + Tram | 26 | Toxicity | 0 | - | no | - | AWD | 26 |
13 | 55 | F | IIA | yes | V600K | Enco + Bini | 1 | Toxicity | 0 | 19 | yes | CR (Nivo) | AWD | 20 |
Reports Analzying Outcomes after TT Cessation | Number of Patients (CR) | Median Duration of TT Treatment (Months) | Discontinuation due to Toxicity | Median Follow-up after Discontinuation (Months) | Tumor Progression (%) | Median PFS upon TT Cessation | Response to TT Rechallange |
---|---|---|---|---|---|---|---|
Warburton [31] | 13 | 39 | 0% | 19 | 0% | 5 | 100% |
Wyluda [34] | 3 | 12 | 100% | 15 | 0% | NA | NA |
Desvignes [32] | 6 | 6 | 100% | 15 | 100% | 4 | 17% |
Vanhaecke [33] | 16 | 21 | 63% | 12 | 53% | 2.5 | 63% |
Tolk [35] | 12 | 13 | 54% | 17 | 46% | 3 | 50% |
Carlino [22] | 12 | NA | 100% | 16 | 50% | 6.6 | 33% |
Stege | 37 | 16 | 16% | 19 | 69% | 1 | 60% |
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Stege, H.; Haist, M.; Schultheis, M.; Fleischer, M.I.; Mohr, P.; Meier, F.; Schadendorf, D.; Ugurel, S.; Livingstone, E.; Zimmer, L.; et al. Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study. Cancers 2021, 13, 2312. https://doi.org/10.3390/cancers13102312
Stege H, Haist M, Schultheis M, Fleischer MI, Mohr P, Meier F, Schadendorf D, Ugurel S, Livingstone E, Zimmer L, et al. Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study. Cancers. 2021; 13(10):2312. https://doi.org/10.3390/cancers13102312
Chicago/Turabian StyleStege, Henner, Maximilian Haist, Michael Schultheis, Maria Isabel Fleischer, Peter Mohr, Friedegund Meier, Dirk Schadendorf, Selma Ugurel, Elisabeth Livingstone, Lisa Zimmer, and et al. 2021. "Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study" Cancers 13, no. 10: 2312. https://doi.org/10.3390/cancers13102312
APA StyleStege, H., Haist, M., Schultheis, M., Fleischer, M. I., Mohr, P., Meier, F., Schadendorf, D., Ugurel, S., Livingstone, E., Zimmer, L., Herbst, R., Pföhler, C., Kähler, K., Weichenthal, M., Terheyden, P., Nashan, D., Debus, D., Kaatz, M., Ziller, F., ... Loquai, C. (2021). Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study. Cancers, 13(10), 2312. https://doi.org/10.3390/cancers13102312