No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Demographics
2.2. Characteristics of Primary Melanoma, Disease-Free Interval and Metastatic Disease
2.3. Treatments Used for Metastatic Disease
2.4. Response to Treatment
2.5. Progression-Free Survival and Overall Survival
3. Discussion
4. Materials and Methods
4.1. Patients and Study Design
4.2. Genetic Analysis
4.3. Treatment and Clinical Outcomes
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Features | NRAS Mutant/BRAF wt n (%) | NRAS wt/BRAF wt n (%) | p Value * |
---|---|---|---|
Total | 162 | 169 | |
Origin of melanoma | |||
Cutaneous Unknown | 137 (85) 25 (15) | 147 (87) 22 (13) | 0.53 |
Gender | |||
Female Male | 58 (36) 104 (64) | 69 (41) 100 (59) | 0.35 |
Adjuvant therapy | |||
Yes No | 22 (14) 140 (86) | 13 (8) 156 (92) | 0.08 |
Therapy (first line) | |||
Anti PD-1 Ipilimumab Anti PD-1 + Ipilimumab | 114 (70) 45 (28) 3 (2) | 132 (78) 35 (21) 2 (1) | 0.27 |
Therapy (second line) | |||
Yes No | 56 (35) 106 (65) | 61 (36) 108 (64) | 0.77 |
Therapy (third line) | |||
Yes No | 17 (10) 145 (90) | 10 (6) 159 (94) | 0.13 |
Disease Features | NRAS Mutant/BRAF wt | NRAS wt/BRAF wt | p Value |
---|---|---|---|
Age at diagnosis, years | 0.86 * | ||
Median (IQR) | 63.4 (53.3–73.8) | 65 (54.0–73.0) | |
Site (%) | < 0.001 ** | ||
Head & neck | 11 (7) | 36 (21) | |
Trunk | 65 (40) | 50 (30) | |
Upper limbs | 20 (12) | 16 (9) | |
Lower limbs | 41 (25) | 37 (22) | |
Other | 0 | 8 (5) | |
Unknown | 25 (15) | 22 (13) | |
Thickness (%) | 0.76 ** | ||
pT1 | 10 (7) | 10 (6) | |
pT2 | 25 (17) | 21 (13) | |
pT3 | 35 (23) | 38 (24) | |
pT4 | 56 (37) | 67 (42) | |
Unknown | 24 (16) | 22 (14) | |
Ulceration (%) | 0.03 ** | ||
yes | 71(44) | 91 (54) | |
No | 51 (31) | 32 (19) | |
Unknown | 40 (25) | 46 (27) | |
Lymph node status 1 (%) | 0.48 ** | ||
Positive | 70 (55) | 68 (51) | |
Negative | 57 (45) | 66 (49) | |
DFI (months) | 0.97 * | ||
Median (IQR) | 15.4 (4–36) | 15 (3–37) |
Clinical Features | NRAS Mutant/BRAF wt | NRAS wt/BRAF wt | p Value |
---|---|---|---|
Age at metastatic disease, years | |||
Median (IQR) | 68 (54–76) | 68.7 (56–76) | 0.94 * |
Serum LDH, n (%) | |||
Normal | 92 (57) | 90 (53) | 0.67 ** |
Elevated | 47 (29) | 51 (30) | |
Unspecified | 22 (14) | 28 (17) | |
Blood cellular count (IQR) | |||
WBC (103/μL) | 6.7 (5.67–8.20) | 6.8 (5.55–7.88) | 0.77 * |
Lymphocytes (103/μL) | 1.66 (1.31–2.06) | 1.65 (1.31–2.1) | 0.99 * |
N/L | 2.51 (1.89–3.60) | 2.51 (1.67–3.6) | 0.89 * |
Platelets (103/μL) | 229 (194.7–297.2) | 236.5 (181–288.2) | 0.82 * |
Site of disease, n (%) ^ | |||
Skin/Soft tissue | 90 (56) | 77 (46) | 0.07 ** |
Lymph node | 112 (69) | 102 (60) | 0.09 ** |
Lung | 75 (46) | 103 (61) | <0.01 ** |
Liver | 34 (21) | 29 (17) | 0.37 ** |
Brain | 12 (7) | 28 (17) | 0.01 ** |
Bone | 20 (12) | 16 (9) | 0.40 ** |
Other | 33 (20) | 16 (9) | <0.01 ** |
N. of metastatic sites, n (%) | |||
<3 | 94 (58) | 108 (64) | 0.27 ** |
≥3 | 68 (42) | 61 (36) | |
Stage at metastatic disease, n (%) | |||
III | 1 (1) | 2 (1) | <0.01 ** |
IVA | 46 (28) | 38 (22) | |
IVB | 41(25) | 56 (33) | |
IVC | 64 (39) | 45 (27) | |
IVD | 10 (6) | 28 (17) | |
Brain progression, n (%) | |||
Yes | 17 (19) | 35 (37) | <0.01 ** |
No | 72 (81) | 59(63) | |
ECOG 1 PS, n (%) | |||
0–1 | 123 (76.4) | 129 (76.3) | 0.91 ** |
2 | 36 (22.4) | 37 (21.9) | |
3 | 2 (1.2) | 3 (1.8) |
Therapy | Response | NRAS Mutant/BRAF wt n (%) | NRAS wt/BRAF wt n (%) | p Value * |
---|---|---|---|---|
All patients | ORR | 68 (42) | 63 (37) | 0.38 |
DCR | 97 (60) | 100 (59) | 0.90 | |
Anti-PD-1 | ORR | 49 (43) | 56 (42) | 0.93 |
DCR | 78 (68) | 88 (67) | 0.77 | |
Ipilimumab | ORR | 16 (36) | 6 (17) | 0.07 |
DCR | 16 (36) | 11 (31) | 0.70 |
NRAS Mutation | Frequency n (%) | ORR n (%) | p Value * | PFS, Median, Months (IQR) | p Value ** | OS, Median, Months (IQR) | p Value ** |
---|---|---|---|---|---|---|---|
Q61K | 60 (37) | 24 (40) | 0.41 | 7.5 (4–20) | 0.35 | 26 (14–48) | 0.39 |
Q61R | 56 (35) | 25 (45) | 12 (5–20) | 28 (18-NA) | |||
Q61L | 17 (10) | 8 (47) | 18 (3-NA) | NA (5-NA) | |||
Q61H | 9 (6) | 4 (44) | 33 (3-NA) | NA (15-NA) | |||
Not Q61 | 8 (5) | 5 (62) | 17 (4-NA) | 22 (8-NA) | |||
Unspecified | 12 (7) | 2(17) | 5 (2–20) | 33 (3-NA) |
Parameter | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
OR | 95% CI | p Value | OR | 95% CI | p Value | |
Sex (M versus F) | 1.09 | (0.69–1.71) | 0.72 | - | - | - |
Age (+1) | 1.00 | (0.99–1.02) | 0.81 | - | - | - |
NRAS status (mut versus wt) | 1.03 | (0.66–1.60) | 0.90 | 1.95 | (1.07–3.54) | 0.03 |
Site of primary melanoma | <0.001 | 0.05 | ||||
Head & neck versus unknown | 1.11 | (0.45–2.71) | 1.43 | (0.42–4.85) | ||
Trunk versus unknown | 0.53 | (0.26–1.10) | 0.50 | (0.20–1.25) | ||
Upper limbs versus unknown | 1.10 | (0.42–2.88) | 0.90 | (0.28–2.92) | ||
Lower limbs versus unknown | 0.31 | (0.14–0.67) | 0.37 | (0.14–0.98) | ||
Other versus unknown | 2.97 | (0.33–26.4) | 3.18 | (0.29–35.2) | ||
AntiPD-1 versus ipilimumab | 4.07 | (2.39–6.95) | <0.001 | 5.81 | (2.78–12.1) | <0.001 |
N. metastatic sites (<3 versus ≥3) | 1.96 | (1.25–3.07) | <0.01 | 2.64 | (1.43–4.88) | <0.01 |
WBC (+1000) | 0.95 | (0.90–1.01) | 0.10 | - | - | - |
Lymphocytes (+1000) | 0.91 | (0.77–1.08) | 0.30 | 0.78 | (0.55–1.11) | 0.16 |
N/L ratio (+1) | 0.88 | (0.77–1.00) | 0.05 | 0.91 | (0.79–1.04) | 0.17 |
Platelet (+100) | 0.66 | (0.50–0.87) | <0.01 | 0.67 | (0.47–0.96) | 0.03 |
LDH (<ULM versus >ULM) | 1.73 | (1.04–2.86) | 0.03 | - | - | - |
ECOG PS (2–3 versus 0–1) | 0.40 | (0.24–0.67) | <0.01 | 0.40 | (0.20–0.82) | 0.01 |
Parameter | Univariate | Multivariable | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p Value | HR | 95% CI | p Value | |
Sex (M versus F) | 0.97 | (0.74–1.27) | 0.81 | 1.39 | (0.99–1.96) | 0.05 |
Age (+1) | 1.01 | (0.99–1.02) | 0.34 | - | - | - |
NRAS status (mut versus wt) | 0.92 | (0.70–1.20) | 0.53 | 0.73 | (0.53–1.00) | 0.05 |
Site of primary melanoma | 0.01 | 0.03 | ||||
Head & neck versus unknown | 0.63 | (0.37–1.06) | 0.53 | (0.27–1.04) | ||
Trunk versus unknown | 1.02 | (0.68–1.54) | 1.12 | (0.70–1.81) | ||
Upper limbs versus unknown | 0.57 | (0.32–1.03) | 0.58 | (0.30–1.14) | ||
Lower limbs versus unknown | 1.30 | (0.84–2.00) | 1.16 | (0.68–1.97) | ||
Other versus unknown | 0.73 | (0.28–1.88) | 0.50 | (0.17–1.51) | ||
AntiPD-1 versus ipilimumab | 0.46 | (0.34–0.61) | <0.0001 | 0.41 | (0.29–0.60) | <0.0001 |
N. metastatic sites (<3 versus ≥3) | 0.63 | (0.49–0.83) | <0.01 | 0.60 | (0.44–0.84) | <0.01 |
WBC (+1000) | 1.01 | (1.00–1.03) | 0.15 | - | - | - |
Lymphocytes (+1000) | 1.03 | (0.92–1.16) | 0.61 | 1.10 | - | - |
N/L ratio (+1) | 1.04 | (1.00–1.09) | 0.06 | 1.05 | - | - |
Platelet (+100) | 1.14 | (0.96–1.35) | 0.14 | 1.21 | (1.01–1.44) | 0.04 |
LDH (<ULM versus >ULM) | 0.65 | (0.48–0.89) | <0.01 | 0.78 | (0.56–1.09) | 0.15 |
ECOG PS (2–3 versus 0–1) | 2.20 | (1.65–2.93) | <0.0001 | 2.02 | (1.42–2.86) | <0.0001 |
Parameter | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
HR | 95% CI | p Value | HR | 95% CI | p Value | |
Sex (M versus F) | 1.01 | (0.75–1.37) | 0.94 | 1.48 | (1.00–2.18) | 0.05 |
Age (+1) | 1.00 | (0.99–1.02) | 0.64 | - | - | - |
NRAS status (mut versus wt) | 0.82 | (0.61–1.11) | 0.20 | 0.72 | (0.51–1.03) | 0.07 |
Site of primary melanoma | 0.03 | 0.01 | ||||
Head & neck versus unknown | 0.77 | (0.43–1.40) | 0.79 | (0.34–1.82) | ||
Trunk versus unknown | 1.11 | (0.69–1.80) | 1.62 | (0.90–2.92) | ||
Upper limbs versus unknown | 0.66 | (0.34–1.28) | 0.79 | (0.34–1.82) | ||
Lower limbs versus unknown | 1.45 | (0.89–2.37) | 2.11 | (1.13–3.93) | ||
Other versus unknown | 0.43 | (0.10–1.82) | 0.67 | (0.15–3.04) | ||
AntiPD-1 versus ipilimumab | 0.82 | (0.59–1.13) | 0.23 | - | - | - |
N. metastatic sites (<3 versus ≥3) | 0.65 | (0.48–0.87) | <.01 | - | - | - |
WBC (+1000) | 1.01 | (1.00–1.04) | 0.03 | 1.02 | (1.00–1.04) | 0.04 |
Lymphocytes (+1000) | 1.00 | (0.89–1.11) | 0.97 | - | - | - |
N/L ratio (+1) | 1.06 | (1.02–1.11) | <0.01 | 1.05 | (0.99–1.11) | 0.09 |
Platelet (+100) | 1.26 | (1.05–1.51) | 0.01 | 1.31 | (1.07–1.59) | <0.01 |
LDH_ (<ULM versus >ULM) | 0.50 | (0.36–0.69) | <0.001 | 0.57 | (0.39–0.82) | <0.01 |
ECOG PS (2–3 versus 0–1) | 1.77 | (1.27–2.45) | <0.001 | 1.52 | (1.02–2.25) | 0.04 |
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Guida, M.; Bartolomeo, N.; Quaglino, P.; Madonna, G.; Pigozzo, J.; Di Giacomo, A.M.; Minisini, A.M.; Tucci, M.; Spagnolo, F.; Occelli, M.; et al. No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study. Cancers 2021, 13, 475. https://doi.org/10.3390/cancers13030475
Guida M, Bartolomeo N, Quaglino P, Madonna G, Pigozzo J, Di Giacomo AM, Minisini AM, Tucci M, Spagnolo F, Occelli M, et al. No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study. Cancers. 2021; 13(3):475. https://doi.org/10.3390/cancers13030475
Chicago/Turabian StyleGuida, Michele, Nicola Bartolomeo, Pietro Quaglino, Gabriele Madonna, Jacopo Pigozzo, Anna M. Di Giacomo, Alessandro M. Minisini, Marco Tucci, Francesco Spagnolo, Marcella Occelli, and et al. 2021. "No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study" Cancers 13, no. 3: 475. https://doi.org/10.3390/cancers13030475