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melanoma (ML), immune chekpoint inhibitors versus chemotherapy, meta-analysis of study results

Outcome Relative effect 95%CI LoD Trt. better when I2 k (RCT/OBS) Bayesian probability Overall ROB Publication bias Degree of certainty Endpoint importance Published MA

efficacy endpoints 00

deaths (OS) 0.71 [0.60, 0.85]< 167%8 studies (8/-)100.0 %lowserious highcrucial-
deaths (OS) (extension) 0.57 [0.38, 0.84]< 184%2 studies (2/-)99.7 %lownot evaluable highimportant-
PFS (extension) 0.42 [0.33, 0.53]< 10%1 study (1/-)100.0 %NAnot evaluable important-
progression or deaths (PFS) 0.57 [0.47, 0.70]< 178%7 studies (7/-)100.0 %lownot evaluable highimportant-
DCR 1.15 [0.79, 1.68]> 10%1 study (1/-)76.8 %NAnot evaluable non important-
DOR 0.41 [0.20, 0.83]< 10%1 study (1/-)99.3 %NAnot evaluable non important-
DOR (extension) 3.45 [1.46, 8.18]> 10%1 study (1/-)99.8 %NAnot evaluable non important-
objective responses (ORR) 2.37 [1.36, 4.13]> 188%8 studies (8/-)99.9 %lownot evaluable highnon important-
objective responses (ORR) (extension) 4.50 [2.79, 7.25]> 10%1 study (1/-)100.0 %NAnot evaluable non important-

safety endpoints 00

AE (any grade) 1.90 [0.83, 4.36]< 158%4 studies (4/-)6.5 %lownot evaluable highnon important-
AE (grade 3-4) 1.87 [1.01, 3.45]< 188%4 studies (4/-)2.3 %lownot evaluable highnon important-
AE leading to death (grade 5) 1.57 [0.89, 2.76]< 10%5 studies (5/-)5.9 %some concernnot evaluable moderatenon important-
AE leading to treatment discontinuation (any grade) 1.63 [0.55, 4.77]< 185%4 studies (4/-)18.9 %lownot evaluable highnon important-
AE leading to treatment discontinuation (grade 3-4) 0.61 [0.29, 1.28]< 10%1 study (1/-)90.5 %NAnot evaluable non important-
SAE (any grade) 1.53 [0.36, 6.48]< 196%2 studies (2/-)28.1 %some concernnot evaluable moderatenon important-
SAE (grade 3-4) 0.74 [0.47, 1.17]< 10%1 study (1/-)90.4 %NAnot evaluable non important-
STRAE (any grade) 1.20 [0.86, 1.66]< 10%2 studies (2/-)14.4 %lownot evaluable highnon important-
STRAE (grade 3-4) 0.99 [0.44, 2.27]< 10%1 study (1/-)50.5 %NAnot evaluable non important-
TRAE (any grade) 1.19 [0.47, 3.03]< 193%6 studies (6/-)35.4 %lownot evaluable highnon important-
TRAE (grade 3-4) 1.41 [0.54, 3.68]< 195%6 studies (6/-)24.3 %lownot evaluable highnon important-
TRAE leading to death (grade 5) 3.31 [0.76, 14.36]< 10%4 studies (4/-)5.6 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (any grade) 1.62 [0.86, 3.05]< 136%3 studies (3/-)6.8 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (grade 3-4) 2.06 [0.87, 4.87]< 10%2 studies (2/-)5.1 %some concernnot evaluable moderatenon important-

TRAE (grade 3-4) endpoints 00

Abdominal pain TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Adrenal insufficiency TRAE (grade 3-4) 5.93 [0.30, 118.96]< 10%1 study (1/-)12.5 %NAnot evaluable non important-
Alopecia TRAE (grade 3-4) 0.97 [0.10, 9.36]< 10%3 studies (3/-)51.0 %some concernnot evaluable moderatenon important-
Anaemia TRAE (grade 3-4) 0.12 [0.03, 0.55]< 10%3 studies (3/-)99.7 %some concernnot evaluable moderatenon important-
Arthralgia TRAE (grade 3-4) 1.28 [0.50, 3.27]< 10%4 studies (4/-)30.0 %lownot evaluable highnon important-
Asthenia TRAE (grade 3-4) 1.41 [0.42, 4.72]< 10%4 studies (4/-)28.7 %lownot evaluable highnon important-
Blood creatinine increased TRAE (grade 3-4) 0.61 [0.02, 18.27]< 10%1 study (1/-)61.1 %NAnot evaluable non important-
Chorioretinopathy TRAE (grade 3-4) 0.61 [0.02, 18.27]< 10%1 study (1/-)61.1 %NAnot evaluable non important-
Colitis TRAE (grade 3-4) 2.86 [0.59, 13.95]< 10%3 studies (3/-)9.8 %some concernnot evaluable moderatenon important-
Constipation TRAE (grade 3-4) 0.97 [0.10, 9.36]< 10%3 studies (3/-)51.0 %some concernnot evaluable moderatenon important-
Cough TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Decreased appetite TRAE (grade 3-4) 0.65 [0.10, 4.04]< 10%4 studies (4/-)67.8 %lownot evaluable highnon important-
Diarrhoea TRAE (grade 3-4) 1.17 [0.35, 3.89]< 146%5 studies (5/-)40.2 %lownot evaluable highnon important-
Dry skin TRAE (grade 3-4) 1.71 [0.27, 10.64]< 10%4 studies (4/-)28.4 %lownot evaluable highnon important-
Erythema TRAE (grade 3-4) 7.41 [0.37, 148.78]< 10%1 study (1/-)9.8 %NAnot evaluable non important-
Eye disorders TRAE (grade 3-4) 0.98 [0.02, 49.62]< 10%1 study (1/-)50.4 %NAnot evaluable non important-
Fatigue TRAE (grade 3-4) 0.42 [0.12, 1.44]< 136%4 studies (4/-)91.6 %some concernnot evaluable moderatenon important-
Headache TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Hepatitis TRAE (grade 3-4) 3.85 [0.77, 19.20]< 10%4 studies (4/-)5.0 %some concernnot evaluable moderatenon important-
Hypersensitivity TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Hyperthyroidism TRAE (grade 3-4) 1.77 [0.35, 8.89]< 10%5 studies (5/-)24.4 %lowserious highnon important-
Hypophysitis TRAE (grade 3-4) 1.43 [0.11, 18.64]< 10%2 studies (2/-)39.4 %some concernnot evaluable moderatenon important-
Hypothyroidism TRAE (grade 3-4) 0.98 [0.14, 6.99]< 10%4 studies (4/-)50.7 %lownot evaluable highnon important-
Increase AST TRAE (grade 3-4) 8.19 [0.17, 397.63]< 181%2 studies (2/-)14.9 %lownot evaluable highnon important-
Increased ALT TRAE (grade 3-4) 9.60 [0.64, 143.88]< 174%2 studies (2/-)5.2 %lownot evaluable highnon important-
Increased lipase level TRAE (grade 3-4) 0.99 [0.64, 1.52]< 10%1 study (1/-)52.3 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Leucopenia TRAE (grade 3-4) 0.08 [0.02, 0.43]< 10%3 studies (3/-)99.8 %some concernnot evaluable moderatenon important-
Maculopapular rash TRAE (grade 3-4) 1.39 [0.82, 2.38]< 10%4 studies (4/-)11.2 %lownot evaluable highnon important-
Myalgia TRAE (grade 3-4) 1.51 [0.36, 6.24]< 10%4 studies (4/-)28.6 %some concernnot evaluable moderatenon important-
Nausea TRAE (grade 3-4) 0.21 [0.06, 0.77]< 10%4 studies (4/-)99.1 %some concernnot evaluable moderatenon important-
Neutropenia TRAE (grade 3-4) 0.07 [0.01, 0.36]< 10%3 studies (3/-)99.9 %some concernnot evaluable moderatenon important-
Pancreatitis TRAE (grade 3-4) 2.61 [0.37, 18.36]< 10%3 studies (3/-)16.9 %some concernnot evaluable moderatenon important-
Pancytopenia TRAE (grade 3-4) 0.16 [0.01, 3.29]< 10%1 study (1/-)87.9 %NAnot evaluable non important-
Paraesthesia TRAE (grade 3-4) 0.97 [0.10, 9.36]< 10%3 studies (3/-)51.0 %some concernnot evaluable moderatenon important-
Peripheral neuropathy TRAE (grade 3-4) 0.24 [0.03, 2.13]< 10%2 studies (2/-)89.9 %some concernnot evaluable moderatenon important-
Peripheral oedema TRAE (grade 3-4) 1.22 [0.02, 61.84]< 10%1 study (1/-)46.1 %NAnot evaluable non important-
Pneumonitis TRAE (grade 3-4) 4.00 [0.65, 24.72]< 10%3 studies (3/-)6.9 %some concernnot evaluable moderatenon important-
Pruritus TRAE (grade 3-4) 2.60 [0.64, 10.60]< 10%5 studies (5/-)9.2 %lownot evaluable highnon important-
Pyrexia TRAE (grade 3-4) 1.04 [0.24, 4.45]< 10%2 studies (2/-)48.0 %lownot evaluable highnon important-
Rash TRAE (grade 3-4) 1.07 [0.60, 1.91]< 10%5 studies (5/-)41.4 %lownot evaluable highnon important-
Thrombocytopenia TRAE (grade 3-4) 0.13 [0.03, 0.56]< 10%3 studies (3/-)99.7 %some concernnot evaluable moderatenon important-
Thyroiditis TRAE (grade 3-4) 1.02 [0.02, 51.42]< 10%1 study (1/-)49.7 %NAnot evaluable non important-
Uveitis TRAE (grade 3-4) 1.42 [0.11, 18.63]< 10%2 studies (2/-)39.4 %some concernnot evaluable moderatenon important-
Vitiligo TRAE (grade 3-4) 0.97 [0.10, 9.36]< 10%3 studies (3/-)51.0 %some concernnot evaluable moderatenon important-
Vomiting TRAE (grade 3-4) 0.39 [0.14, 1.10]< 10%4 studies (4/-)96.2 %lownot evaluable highnon important-

AE (grade 3-4) endpoints 00

Abdominal pain AE (grade 3-4) 1.33 [0.15, 12.01]< 182%2 studies (2/-)39.9 %some concernnot evaluable moderatenon important-
Asthenia AE (grade 3-4) 0.14 [0.02, 0.77]< 10%2 studies (2/-)98.8 %lownot evaluable highnon important-
Chills AE (grade 3-4) 1.02 [0.02, 51.42]< 10%1 study (1/-)49.7 %NAnot evaluable non important-
Constipation AE (grade 3-4) 0.99 [0.17, 5.73]< 10%2 studies (2/-)50.5 %some concernnot evaluable moderatenon important-
Cough AE (grade 3-4) 2.00 [0.18, 22.13]< 10%2 studies (2/-)28.7 %some concernnot evaluable moderatenon important-
Decreased appetite AE (grade 3-4) 3.03 [0.17, 53.71]< 181%2 studies (2/-)22.7 %lownot evaluable highnon important-
Diarrhoea AE (grade 3-4) 21.14 [1.23, 363.94]< 10%1 study (1/-)1.9 %NAnot evaluable non important-
Dyspnoea AE (grade 3-4) 5.55 [1.41, 21.79]< 10%2 studies (2/-)0.7 %some concernnot evaluable moderatenon important-
Fatigue AE (grade 3-4) 2.86 [1.61, 5.08]< 10%2 studies (2/-)0.0 %lownot evaluable highnon important-
Headache AE (grade 3-4) 2.94 [0.58, 14.91]< 10%2 studies (2/-)9.7 %lownot evaluable highnon important-
Hypothyroidism AE (grade 3-4) 1.22 [0.02, 61.84]< 10%1 study (1/-)46.1 %NAnot evaluable non important-
Increase AST AE (grade 3-4) 18.42 [5.64, 60.14]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Increased ALT AE (grade 3-4) 34.83 [8.39, 144.67]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Nausea AE (grade 3-4) 1.38 [0.67, 2.86]< 10%2 studies (2/-)19.0 %some concernnot evaluable moderatenon important-
Neutropenia AE (grade 3-4) 0.03 [0.00, 0.19]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
Peripheral oedema AE (grade 3-4) 4.97 [0.58, 42.77]< 10%1 study (1/-)7.3 %NAnot evaluable non important-
Pruritus AE (grade 3-4) 7.90 [0.98, 63.82]< 10%2 studies (2/-)2.7 %lownot evaluable highnon important-
Pyrexia AE (grade 3-4) 3.79 [0.36, 39.89]< 10%2 studies (2/-)13.6 %some concernnot evaluable moderatenon important-
Rash AE (grade 3-4) 6.71 [1.20, 37.51]< 10%2 studies (2/-)1.5 %some concernnot evaluable moderatenon important-
Thrombocytopenia AE (grade 3-4) 0.03 [0.00, 0.26]< 10%1 study (1/-)99.9 %NAnot evaluable non important-
Vomiting AE (grade 3-4) 1.70 [0.85, 3.42]< 10%2 studies (2/-)6.7 %some concernnot evaluable moderatenon important-
Weight decreased AE (grade 3-4) 1.00 [0.14, 7.12]< 10%2 studies (2/-)50.1 %some concernnot evaluable moderatenon important-

LoD: level of statistical demonstration: Statistically conclusive: statistically significant with a strict control of overall risk of type 1 error (statistically demonstrated), does not take into account the risk of bias; suggested: nominally statistically significant but without a strict control of overall risk of type 1 error; inconclusive: not nominally statistically significant; safety concerns;
Bayesian probability: Bayesian posterior probability of treatment effect (computed with a noninformative prior); ROB: risk of bias; k: number of studies; published MA: number of published meta-analysis on the same topic; degree of certainty adapted from GRADE. Trt. better when: indicates when the relative treatment effect shows that the studied treatment is better than control.