The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Patients and Methods
2.1. Patient Population
2.2. Primary and Secondary Clinical Outcomes
2.3. Statistical Analysis
3. Results
3.1. Patients’ Characteristics
3.2. Factors Associated with Disease Progression and Survival
3.3. Treatment with Immune-Checkpoint Inhibitors Followed by BRAF/MEK-Inhibitors
3.4. Treatment with BRAF/MEK-Inhibitors Prior to Immune-Checkpoint Inhibitor Therapy
3.5. Impact of the Treatment Sequencing with BRAF/MEK Inhibitors and CPI on Survival in BRAF-Mutant Melanoma Patients
3.6. Response to Subsequent Treatments and Re-Induction of CPI Therapy
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AE | adverse events |
BRAF/MEKi | BRAF/MEK inhibitors |
BRAF ± MEKi | BRAF with/or without MEK inhibitors |
BSC | best-supportive care |
CI | confidence interval |
CPI | immune-checkpoint inhibitors |
CR | complete response |
CTLA-4 | cytotoxic-T-lymphocyte antigen 4 |
DCR | disease-control rate |
HR | hazard ratio |
ICB | immune-checkpoint blockade |
LDH | lactate dehydrogenase |
MBM | melanoma brain metastases |
ORR | overall response rate |
OS | overall survival |
PD | progressive disease |
PD-1 | programmed death protein 1 |
PFS | progression-free survival |
PR | partial response |
RCT | randomized controlled trial |
SD | stable disease |
Tx | treatments |
TME | tumor microenvironment |
TT | BRAF/MEK-directed targeted therapy |
TTNT | time to next treatment |
1L | front-line |
2L | second-line |
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Clinical-Pathological Features | BRAF ± MEKi Prior to CPI (Group 1) | BRAF ± MEKi after CPI (Group 2) | p-Value |
---|---|---|---|
Overall number of patients | 98 | 37 | |
Median age at initiation of 1L treatment | 58.5 years (26–86) | 60.0 years (32–81) | 0.184 |
Gender | 0.503 | ||
female | 44 (44.9%) | 19 (51.4%) | |
male | 54 (55.1%) | 18 (48.6%) | |
Primary tumor and metastasis | |||
Median Breslow thickness 1 (range) | 2.3 (0.6–35.0 mm) | 2.15 (0.6–6.0 mm) | 0.171 |
Ulceration 2 | 37/59 (62.7%) | 9/25 (36.0%) | 0.032 |
Elevated serum LDH levels (>245 U/L) 3 | 46/63 (73.0%) | 22/31 (71.0%) | 0.509 |
Melanoma brain metastasis | 52 (53.1%) | 17 (45.9%) | 0.563 |
Liver metastasis | 40 (40.8%) | 9 (24.3%) | 0.056 |
1L Therapy, n (%) cICB (IPI + Nivo) Anti-PD1:
BRAFi or MEKi monotherapy
| 0 (0%) 0 (0%) 0 0 0 (0%) 38 (38.8%) 29 (29.5%) 9 (9.2%) 60 (61.2%) 46 (46.9%) 13 (13.3%) 1 (1.0%) | 17 (45.9%) 14 (37.8%) 7 (18.9%) 7 (18.9%) 6 (16.2%) 0 (0%) 0 (0%) | |
Previous systemic treatments | 42/65 (31.1%) | 13/37 (24.3%) | |
Median duration of 1L therapy (range) | 5.0 months (1–87) | 3.0 months (1–22) | 0.020 |
Overall response to 1L therapy 4 | 35/98 (35.7%) | 7/37 (18.9%) | 0.065 |
Progress during 1L therapy | 98/98 (100%) | 37/37 (100%) | |
Median progression-free survival upon 1L therapy (95% CI) | 6.0 months (4.8–7.2) | 3.0 months (1.3–4.7) | 0.025 |
Time-to-next-treatment in months (range) | 1.0 (0–56) | 3.0 (0–32) | 0.090 |
2L therapy cICB (IPI + Nivo) Anti-PD1:
BRAF or MEKi monotherapy
Median treatment duration 2L therapy Progress during 2L therapy Median progression-free survival upon 2L therapy (95% CI) | 41 (41.8%) 29 (29.6%) 12 (12.2%) 17 (17.3%) 28 (28.6%) 0 0 17/98 (18.4%) 3.0 months (0–41) 87/98 (88.8%) 2.0 months (1.1–2.9) | 0 0 0 8 (21.6%) 2 (5.4%) 3 (8.1%) 3 (8.1%) 29 (78.4%) 22 (59.5%) 7 (18.9%) 14/37 (37.8%) 4.0 months (1–38) 29/37 (78.4%) 5.0 months (1.6–8.4) | 0.024 0.009 0.164 0.019 |
Subsequent treatment lines Patients receiving 3L therapy Overall number of all subsequent (3L+) therapy lines BRAF ± MEKi therapy CPI therapy Other | 41 (41.8%) 70 39 (55.7%) 29 (41.4%) 2 (2.9%) | 21 (56.8%) 30 8 (26.6%) 21 (70.0%) 1 (3.3%) | 0.253 0.373 |
Median follow-up upon initiation of 1L treatment (95% CI) Median overall survival following 1L therapy initiation (95% CI) | 43.0 months (27.4–58.6) 27.0 months (17.9–36.1) | 41.0 months (28.2–53.8) 39.0 months (31.9–46.2) | 0.159 0.269 |
Median overall survival upon cessation of 1L therapy (95% CI) | 18.0 months (9.5–26.4) | 35.0 months (17.9–52.1) | 0.070 |
Deceased | 53 (54.1%) | 15 (40.5%) | 0.181 |
Outcome | Response to Front-Line BRAF ± MEKi Therapy (Group 1) | Response to Front-Line CPI Therapy (Group 2) | p-Value |
---|---|---|---|
Best overall response (%) | 0.120 | ||
Complete response (CR) | 6 (6.1%) | - (0.0%) | |
Partial response (PR) | 29 (29.6%) | 7 (18.9%) | |
Stable disease (SD) | 22 (22.4%) | 14 (37.8%) | |
Progressive disease (PD) | 41 (41.8%) | 16 (43.2%) | |
Objective-response rate (ORR) | 0.065 | ||
Number (%) | 35/98 (35.7%) | 7/37 (18.9%) | |
95% CI 1 | 26.3–46.0% | 8.0–35.2% | |
Disease control rate (DCR) | 0.92 | ||
Number (%) | 57/98 (58.2%) | 21/37 (56.8%) | |
95% CI 1 | 47.8–68.1% | 39.5–72.9% | |
Progress during 1L therapy | 1.0 | ||
Number (%) | 98/98 (100%) | 37/37 (100%) | |
95% CI 1 | 94.4–100% | 90.3–100% |
Outcome | Response to 2L CPI after Initial BRAF ± MEKi Therapy (Group 1) | Response to 2L BRAF ± MEKi Following Initial CPI Therapy (Group 2) | p-Value |
---|---|---|---|
Best overall response (%) | 0.068 | ||
Complete response (CR) | 3 (3.2%) | 2 (5.6%) | |
Partial response (PR) | 15 (15.3%) | 12 (32.4%) | |
Stable disease (SD) | 22 (22.4%) | 9 (23.0%) | |
Progressive disease (PD) | 58 (59.2%) | 14 (37.8%) | |
Could not be assessed | 0 | 0 | |
Objective-response rate (ORR) | 0.024 | ||
Number (%) | 18/98 (18.4%) | 14/37 (37.8%) | |
95% CI 1 | 11.3–27.5% | 22.5–55.2% | |
Disease control rate (DCR) | 0.034 | ||
Number (%) | 40/98 (40.8%) | 23/37 (62.2%) | |
95% CI 1 | 31.0–51.2% | 44.8–77.5% | |
Progress during 1L therapy | 0.164 | ||
Number (%) | 87/98 (88.8%) | 29/37 (78.4%) | |
95% CI 1 | 80.8–94.3% | 61.8–99.1% |
Patient Characteristics, n (%) | Non-Rapid Progressors (n = 102) | Rapid Progressors (n = 33) | p-Value |
---|---|---|---|
Previous treatments | 31 (230.4%) | 11 (33.3%) | 0.454 |
Elevated LDH 1 | 50 (67.6%) | 18 (90.0%) | 0.038 |
MBM | 51 (50.0%) | 18 (54.5%) | 0.104 |
Hepatic metastasis | 35 (34.3%) | 14 (42.4%) | 0.261 |
Gender, male | 50 (49.0%) | 22 (66.6%) | 0.108 |
Age, years | 57.5 (26–81) | 62.0 (28–86) | 0.348 |
BRAF ± MEKi prior to CPI | 71 (72.4%) | 27 (27.6%) | 0.188 |
BRAF/MEKi after CPI | 31 (83.8%) | 6 (16.2%) | - |
Median overall survival following cessation of 1L treatment | |||
All patients (n = 135) | 41.0 months (16.2–65.7) | 4.0 months (1.9–6.1) | <0.001 |
BRAF ± MEKi prior to CPI | 42.0 months (10.6–73.4) | 4.0 months (1.5–6.4) | <0.001 |
BRAF ± MEKi after CPI | 41.0 months (28.9–53.1) | 6.0 months (4.3–7.7) | <0.001 |
Authors | No. of Patients | Elevated LDH at 1L Therapy Initiation | MBM | ORR to 2L CPI (%) | ORR to 2L TT (%) | Median PFS upon 2L TT, Months | Median PFS upon 2L CPI, Months | Median OS (Months) upon Initiation of 1L TT | Median OS (Months) upon Initiation of 1L CPI | Median Follow-Up Time |
---|---|---|---|---|---|---|---|---|---|---|
Ascierto [22] | 93 | nA | nA | 10% | nA | nA | nA | 9.9 months | 14.5 months | 11 months |
Ackerman [28] | 274 | 34% | 20% | 0% | 57% | nA | 2.7 | 13.4 months | 19.6 months | nA |
Johnson [23] | 114 | 40% (TT) vs. 19% (CPI) | 24% (TT) vs. 9% (CPI) | 25% | nA | 2.8 months | 5.0 months | 40.3 months | 27.5 months | nA |
Amini-Adle [34] | 74 | 46.3% | 34.1% | 12.2% | nA | nA | 2.0 months | nA | 7.0 months (from start anti-PD1) | nA |
Czarnecka [9] | 253 | 42.3% | 24.9% | 8% | nA | 12.7 months | 2.4 months | 11.7 months | not reached (14.7—NR) | 23.2 months |
Simeone [29] | 47 | 52.3% | 21.4% | 12.5% | nA | 9 months | 3 months | nA | nA | nA |
Haist et al | 135 | 72.3% | 51.1% | 18.4% | 37.8% | 5.0 months | 2.0 months | 27.0 months | 39.0 months | 41 months |
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Haist, M.; Stege, H.; Ebner, R.; Fleischer, M.I.; Loquai, C.; Grabbe, S. The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study. Cancers 2022, 14, 2082. https://doi.org/10.3390/cancers14092082
Haist M, Stege H, Ebner R, Fleischer MI, Loquai C, Grabbe S. The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study. Cancers. 2022; 14(9):2082. https://doi.org/10.3390/cancers14092082
Chicago/Turabian StyleHaist, Maximilian, Henner Stege, Ronja Ebner, Maria Isabel Fleischer, Carmen Loquai, and Stephan Grabbe. 2022. "The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study" Cancers 14, no. 9: 2082. https://doi.org/10.3390/cancers14092082