Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Statistics
2.2.1. Survival Analysis
2.2.2. The Clinical Categorization Algorithm (CLICAL)
2.2.3. Application of the Machine Learning Survival Random Forest Clinical Categorization Algorithm (SRF-CLICAL) and Definition of Prognostic Signatures
2.2.4. Cox Proportional Hazards Analysis
2.2.5. Survival Random Forest Model
2.2.6. Kaplan–Meier Survival Curves
3. Results
3.1. Clinicopathological Features of Melanoma Patients
3.2. The Efficacy of ICI Depending on the Previous Treatment
3.3. The Response to Immunotherapy
3.4. Analysis of the Factors Related to the Efficacy of Immunotherapy (ICI Program)
Role of the Different Treatments Given before Inclusion to the INT-NA
3.5. Treatment of Patients Who Relapsed after the ICI Program at the INT-NA
3.6. Analysis of the Predictive Power of Clinical Variables at Inclusion
3.7. The CLICAL Signature and Prediction of Survival Rates
3.8. The CLICAL Signature and Prediction of Response to ICIs
3.9. The CLICAL Signature Applied to an External Cohort
3.10. The Validation of the CLICAL Algorithm’s Efficiency by Machine Learning Survival Random Forest Analysis (SRF-CLICAL)
3.11. Survival Random Forest Model
3.12. The SRF-CLICAL Signature
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | All | Females | Males | |||
---|---|---|---|---|---|---|
n | % | n | % | n | % | |
Clinical anamnestic variable | ||||||
Sex | 578 | 100 | 258 | 45 | 320 | 55 |
Median age (range) | 61.4 (23–89) | 59.9 (23–89) | 62.5 (22–87) | |||
Age 65–100 | 317 | 55 | 132 | 51 | 185 | 58 |
Age 18–64 | 261 | 45 | 126 | 49 | 135 | 42 |
BRAF mut 600E tested | 548 a | 100 | 241 | 100 | 307 | 100 |
BRAF 600E mutated | 234 | 43 | 108 | 45 | 126 | 41 |
CNS met | 572 | 100 | 257 | 100 | 315 | 100 |
Yes | 162 | 28 | 71 | 28 | 91 | 29 |
No | 410 | 72 | 186 | 72 | 224 | 71 |
LDH | 535 | 100 | 241 | 100 | 294 | 100 |
Very high (>2 × LLR) | 77 | 14 | 39 | 16 | 38 | 13 |
High (≥1 × ≤2 × LLR) | 107 | 20 | 43 | 18 | 64 | 22 |
Normal (<1× LLR) | 351 | 66 | 159 | 66 | 192 | 65 |
Eosinophil counts | 543 | 100 | 242 | 100 | 301 | 100 |
Elevated | 47 | 9 | 18 | 7 | 29 | 10 |
Normal | 496 | 91 | 224 | 93 | 272 | 90 |
NLR | 551 | 100 | 248 | 100 | 303 | 100 |
Abnormal | 247 | 45 | 104 | 42 | 143 | 47 |
Normal | 304 | 55 | 144 | 58 | 160 | 53 |
Treatment groups | ||||||
None (Naïve) | 199 | 34 | 83 | 32 | 116 | 36 |
Immunotherapy | 142 | 25 | 61 | 24 | 81 | 25 |
Target and immunotherapy | 59 | 10 | 29 | 11 | 30 | 9 |
Target | 102 | 18 | 48 | 19 | 54 | 18 |
Cytostatic | 76 | 13 | 37 | 14 | 39 | 12 |
Grouped in Pre-target /No target | ||||||
No target | 417 | 72 | 181 | 70 | 236 | 74 |
Pre-target | 161 | 28 | 77 | 30 | 84 | 26 |
Treatment at inclusion to the INT-NA ICI program | ||||||
Anti-CTLA-4 | 292 | 51 | 129 | 50 | 163 | 51 |
Anti-PD-1 (nivolumab) | 151 | 26 | 68 | 26 | 83 | 26 |
Anti-PD-1 (pembrolizumab) | 135 | 23 | 61 | 24 | 74 | 23 |
RFS | OS | ||||||||
---|---|---|---|---|---|---|---|---|---|
n (%) | Probability of RFS (%) at 24 Months | CI 95% Min–Max | Cumulative Hazard at 24 Months | CI 95% Min–Max | Probability of Survival (%) at 50 Months | CI 95% Min–Max | Cumulative Hazard at 50 Months | CI 95% Min–Max | |
ALL | 578 (100) | 16 | 13–19 | 1.83 | 1.63–2.03 | 8 | 5–11 | 2.46 | 2.12.80 |
CR | 32 (5.5) | 67 | 48–85 | 0.39 | 0.12–0.66 | 81 | 61–100 | 0.19 | 0–0.43 |
PR | 74 (12.8) | 64 | 52–76 | 0.48 | 0.28–0.67 | 58 | 42–75 | 0.52 | 0.24–0.79 |
SD | 103 (17.8) | 24 | 15–33 | 1.48 | 1.09–1.86 | 39 | 25–52 | 0.94 | 0.60–1.28 |
PD | 369 (63.8) | 0 | 0 | 6.42 | 3.91–8.93 | 5 | 2–7 | 2.9 | 2.4–3.4 |
RFS | OS | ||||||||
---|---|---|---|---|---|---|---|---|---|
n (%) | Probability of RFS (%) at 24 Months | CI 95% Min–Max | Cumulative Hazard at 20 Months | CI 95% Min–Max | Probability of Survival (%) at 50 Months | CI 95% Min–Max | Cumulative Hazard at 50 Months | CI 95% Min–Max | |
ALL | 199 (100) | 22 | 16–28 | 1.49 | 1.22–1.76 | 36 | 27–42 | 1.06 | 0.83–1.28 |
CR | 17 (8.5) | 81 | 62–100 | 0.32 | 0–0.66 | 100 | 100 | 0 | 0 |
PR | 29 (14.5) | 73 | 56–90 | 0.31 | 0.08–0.53 | 76 | 52–99 | 0.27 | 0–0.56 |
SD | 36 (17.6) | 31 | 14–43 | 1.13 | 0.61–1.64 | 55 | 34–76 | 0.58 | 0.21–0.96 |
PD | 118 (59.3) | 0 | 0 | 4.28 | 2.73–5.83 | 11 | 6–17 | 2.16 | 1.61–2.71 |
CLICAL SCORE | n | Cumulative Hazard at 32 Months (95% CI) | Still Alive (at Risk) at 32 Months | CLICAL SIGNATURES | n (%) | Cumulative Hazard at 32 Months (95% CI) |
---|---|---|---|---|---|---|
1.143 | 8 | 2.7 (0.29–5.14) # | 0 | Signature I | 46 (9.1) | 3.42 (1.87–4.96) |
1.286 | 38 | 3.23 (1.69–4.77) | 1 | |||
1.429 | 71 | 2.41 (1.59–3.24) | 2 | Signature II | 71 (14.1) | 2.41 (1.59–3.24) |
1.571 | 111 | 1.70 (1.24–2.16) | 10 | Signature III | 111 (22.1) | 1.70 (1.24–2.16) |
1.714 | 127 | 1.14 (0.86–1.43) | 10 | Signature IV | 243 (48.3) | 1.08 (0.89–1.27) |
1.857 | 116 | 1.00 (0.75–1.20) | 30 | |||
2.000 | 31 | 0.50 (0.19–0.81) | 12 | Signature V | 32 (6.4) | 0.48 (0.19–0.77) |
2.143 | 1 | 0.50(0.19–0.81) | 1 |
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Madonna, G.; Masucci, G.V.; Capone, M.; Mallardo, D.; Grimaldi, A.M.; Simeone, E.; Vanella, V.; Festino, L.; Palla, M.; Scarpato, L.; et al. Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy. Cancers 2021, 13, 4164. https://doi.org/10.3390/cancers13164164
Madonna G, Masucci GV, Capone M, Mallardo D, Grimaldi AM, Simeone E, Vanella V, Festino L, Palla M, Scarpato L, et al. Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy. Cancers. 2021; 13(16):4164. https://doi.org/10.3390/cancers13164164
Chicago/Turabian StyleMadonna, Gabriele, Giuseppe V. Masucci, Mariaelena Capone, Domenico Mallardo, Antonio Maria Grimaldi, Ester Simeone, Vito Vanella, Lucia Festino, Marco Palla, Luigi Scarpato, and et al. 2021. "Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy" Cancers 13, no. 16: 4164. https://doi.org/10.3390/cancers13164164