Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma
Abstract
:1. Introduction
2. Methods
2.1. Statistical Analysis
2.2. Ethics
3. Results
3.1. Patient Demographics
3.2. Efficacy
3.3. Toxicity
3.4. Factors Associated with Outcome
3.4.1. Histology Subtype
3.4.2. Disease Burden
3.4.3. ECOG Performance Status
3.4.4. Line of Treatment
3.4.5. Number of Combinations Administered
3.4.6. BRAF Status
3.4.7. Toxicity and Steroid Treatment
3.4.8. Uni- and Multivariable Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Characteristics | All Patients N = 172 | Non Responders (SD/PD), n = 90 | Responders (CR/PR), n = 79 | p-Value |
---|---|---|---|---|
Age (median, range) | 59 (12–80) | 59 (12–80) | 60 (12–80) | 0.635 |
Male (%) | 99 (58%) | 52 (58%) | 46 (58%) | 0.953 |
Melanoma subtype (%) | ||||
Cutaneous | 116 (67%) | 58 (50%) | 58 (50%) | - |
Mucosal | 8 (5%) | 7 (88%) | 1 (12%) | 0.04 * |
ocular | 13 (8%) | 10 (77%) | 3 (23%) | 0.065 * |
Unknown primary | 35 (20%) | 15 (43%) | 17 (49%) | 0.754 * |
Disease presentation | ||||
Advanced upfront Recurrent disease | 46 (28%) 124 (72%) | 21 (46%) 69 (56%) | 22 (48%) 55 (44%) | 0.235 |
BRAF wild-type | 81 (47%) | 43 (53%) | 38 (47%) | - |
BRAF V600 mutant | 85 (49%) | 44 (52%) | 38 (45%) | 0.984 |
V600E mutation | 50 (30%) | 26 (52%) | 24 (48%) | |
V600K mutation | 3 (2%) | 1 (33%) | 2 (67%) | |
V600 unspecified | 29 (17%) | 17 (59%) | 12 (41%) | |
Unknown status | 6 (3%) | 3 (50%) | 3 (50%) | |
LDH | ||||
Ratio (mean±SD) > ULN (%) | 1.59 ± 2.08 65 (38%) | 2.12 ± 2.71 41 (63%) | 1.0 ± 0.6 23 (35%) | 0.003 |
AJCC 8th edition (%) | ||||
IIIC | 2 (1%) | 0 | 2 (3%) | - |
M1a | 32 (19%) | 16 (50%) | 16 (50%) | |
M1b | 32 (19%) | 16 (50%) | 16 (50%) | 1.000 |
M1c | 68 (39%) | 37 (54%) | 29 (43%) | 0.573 |
M1d | 38 (22%) | 21 (55%) | 16 (42%) | 0.575 |
Number of disease sites (mean ± SD) | 2.5 ± 1.7 | 2.86 ± 1.93 | 2.13 ± 1.33 | 0.005 |
ECOG PS (%) | ||||
0 | 114 (66%) | 46 (40%) | 66 (58%) | - |
1 | 35 (20%) | 23 (66%) | 11 (31%) | 0.008 ** |
≥2 | 13 (8%) | 12 (92%) | 1 (8%) | 0.017 ** |
unknown | 10 (6%) | 9 (90%) | 1 (10%) | |
Treatment naïve | 110 (64%) | 43 (39%) | 64 (58%) | |
Previously treated | 62 (36%) | 47 (76%) | 14 (23%) | <0.001 |
Previous treatments | - | |||
Immunotherapy | 30 (17%) | 23 (77%) | 7 (23%) | |
BRAF inhibitors | 47 (27%) | 36 (77%) | 11 (23%) | |
N° of comb Ipi-Nivo (%) | ||||
All four | 67 (40%) | 27 (40%) | 40 (60%) | |
2–3 | 72 (42%) | 38 (53%) | 34 (47%) | - |
Only one | 33 (19%) | 25 (76%) | 5 (15%) | - |
Weeks on treatment (median, range) | 18 (1–190) | 9 (1–57) | 49 (1–190) | - |
Response | All Patients (n = 159) | Treatment Naïve (n = 99) | Advanced Lines (n = 60) |
---|---|---|---|
CR | 45 (28%) | 36 (36%) | 9 (15%) |
PR | 31 (20%) | 25 (25%) | 6 (10%) |
SD | 11 (7%) | 6 (6%) | 5 (8%) |
PD | 69 (43%) | 29 (29%) | 40 (67%) |
NE | 3 (2%) | 3 (3%) | 0 |
DCR | 55% | 67% | 33% |
ORR | 48% | 61% | 25% |
Characteristics | All Patients, N = 172 | Non Responders (SD/PD), n = 90 | Responders (CR/PR), n = 79 | p-Value |
---|---|---|---|---|
Maximal severity of AE *, (%) | ||||
None | 17 (10%) | 15 (17%) | 1 (1%) | - |
Grade 1–2 | 45 (28%) | 22 (24%) | 23 (29%) | - |
Grade 3–4 | 103 (60%) | 52 (58%) | 50 (66%) | 0.901 ¥ |
Grade 5 | 4 (2%) | 1(1%) | 3 (4%) | - |
Steroid treatment, (%) | 102 (59%) | 51 (57%) | 50 (63%) | 0.381 |
Duration of steroid treatment, weeks—median (range) | 12 (1–153) | 12 (1–106) | 16 (1–153) | 0.039 |
Maximal dose of steroids, mg/kg **—mean ± SD | 1.7 ± 2.3 | 2.1 ± 3.0 | 1.3 ± 1.2 | 0.060 |
Advanced immune suppression † (%) | 11 (6%) | 5 (6%) | 6 (8%) | 0.592 |
Variable | Univariable Analysis | Multivariable Analysis | ||
---|---|---|---|---|
HR for Death (95% CI) | p-Value | HR for Death (95% CI) | p-Value | |
Histology subtype (mucosal vs. cutaneous) | 3.13 (1.41–6.92) | 0.005 | 1.84 (0.69–5.04) | 0.217 |
LDH ratio | 1.20 (1.13–1.28) | 0.003 | 1.07 (0.97–1.18) | 0.176 |
Number of metastatic sites | 1.26 (1.13–1.41) | <0.0001 | 1.14 (0.98–1.34) | 0.092 |
ECOG PS | 3.02 (2.27–4.01) | <0.0001 | 2.00 (1.37–2.90) | <0.0001 |
Line of treatment | 4.06 (2.56–6.46) | <0.0001 | 2.70 (1.41–5.15) | 0.003 |
Number of combinations administered | 0.62 (0.51–7.66) | <0.0001 | 0.68 (0.52–0.89) | 0.005 |
BRAF status (V600 mutant vs. WT) | 0.5 (0.22–1.13) | 0.096 | ||
Best tumor response (NR vs. R) | 12.42 (6.43–24.00) | <0.0001 | 8.67 (3.69–20.39) | <0.0001 |
Grade of AEs (3–4 vs. 1–2) | 1.09 (0.62–1.95) | 0.746 | ||
Exposure to steroids | 0.67 (0.40–1.10) | 0.116 |
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Asher, N.; Ben-Betzalel, G.; Lev-Ari, S.; Shapira-Frommer, R.; Steinberg-Silman, Y.; Gochman, N.; Schachter, J.; Meirson, T.; Markel, G. Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma. Cancers 2020, 12, 2329. https://doi.org/10.3390/cancers12082329
Asher N, Ben-Betzalel G, Lev-Ari S, Shapira-Frommer R, Steinberg-Silman Y, Gochman N, Schachter J, Meirson T, Markel G. Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma. Cancers. 2020; 12(8):2329. https://doi.org/10.3390/cancers12082329
Chicago/Turabian StyleAsher, Nethanel, Guy Ben-Betzalel, Shaked Lev-Ari, Ronnie Shapira-Frommer, Yael Steinberg-Silman, Neta Gochman, Jacob Schachter, Tomer Meirson, and Gal Markel. 2020. "Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma" Cancers 12, no. 8: 2329. https://doi.org/10.3390/cancers12082329