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metastatic/adv melanoma (mML), anti-CTLA-4 , 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) 0.74 [0.67, 0.82]< 152%13 studies (13/-)100.0 %lowlow highcrucial-
deaths (OS) (extension) 0.66 [0.60, 0.73]< 136%6 studies (6/-)100.0 %lownot evaluable highimportant-
MFS 0.75 [0.65, 0.87]< 10%2 studies (2/-)100.0 %lownot evaluable highimportant-
MFS (extension) 0.76 [0.64, 0.90]< 10%1 study (1/-)99.9 %NAnot evaluable important-
progression or deaths (PFS) 0.59 [0.49, 0.72]< 171%7 studies (7/-)100.0 %lownot evaluable highimportant-
RFS (extension) 0.73 [0.65, 0.83]< 10%2 studies (2/-)100.0 %lownot evaluable highimportant-
RFS/DFS 0.72 [0.62, 0.82]< 10%2 studies (2/-)100.0 %lownot evaluable highimportant-
DCR 1.17 [0.92, 1.50]> 10%2 studies (2/-)90.1 %lownot evaluable highnon important-
DOR 0.68 [0.55, 0.85]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
objective responses (ORR) 2.84 [1.66, 4.86]> 190%11 studies (11/-)100.0 %lowlow highnon important-

safety endpoints 00

AE (any grade) 2.10 [1.00, 4.39]< 172%7 studies (7/-)2.5 %lownot evaluable highnon important-
AE (grade 3-4) 0.78 [0.32, 1.88]< 198%7 studies (7/-)71.0 %lownot evaluable highnon important-
AE leading to death (grade 5) 1.68 [0.84, 3.36]< 10%2 studies (2/-)7.1 %some concernnot evaluable moderatenon important-
AE leading to treatment discontinuation (any grade) 3.22 [0.01, 1878.15]< 195%2 studies (2/-)36.6 %lownot evaluable highnon important-
SAE (any grade) 3.19 [2.19, 4.65]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
TRAE (any grade) 1.86 [1.01, 3.42]< 195%12 studies (12/-)2.4 %lowlow highnon important-
TRAE (grade 3-4) 1.92 [0.90, 4.12]< 197%12 studies (12/-)4.7 %lowlow highnon important-
TRAE leading to death (grade 5) 1.94 [0.85, 4.40]< 10%9 studies (9/-)5.7 %lownot evaluable highnon important-
TRAE leading to discontinuation (any grade) 1.64 [0.52, 5.15]< 198%8 studies (8/-)19.9 %lownot evaluable highnon important-
TRAE leading to discontinuation (grade 3-4) 1.00 [0.30, 3.37]< 196%7 studies (7/-)50.1 %lownot evaluable highnon important-

TRAE (grade 3-4) endpoints 00

Adrenal insufficiency TRAE (grade 3-4) 1.30 [0.55, 3.04]< 10%9 studies (9/-)27.4 %lownot evaluable highnon important-
Colitis TRAE (grade 3-4) 1.32 [0.57, 3.09]< 182%11 studies (11/-)26.0 %lowlow highnon important-
Diarrhoea TRAE (grade 3-4) 1.48 [0.69, 3.17]< 182%12 studies (12/-)15.8 %lowlow highnon important-
Endocrine disorders TRAE (grade 3-4) 2.62 [0.67, 10.32]< 174%6 studies (6/-)8.4 %lownot evaluable highnon important-
Eye disorders TRAE (grade 3-4) 0.66 [0.05, 8.68]< 10%2 studies (2/-)62.1 %lownot evaluable highnon important-
Febrile neutropenia TRAE (grade 3-4) 3.99 [0.18, 88.89]< 10%1 study (1/-)19.4 %NAnot evaluable non important-
Gastrointestinal disorders TRAE (grade 3-4) 2.23 [0.58, 8.56]< 194%7 studies (7/-)12.2 %lownot evaluable highnon important-
Guillain-Barré syndrome TRAE (grade 3-4) 3.99 [0.18, 88.89]< 10%1 study (1/-)19.4 %NAnot evaluable non important-
Hepatitis TRAE (grade 3-4) 2.76 [1.23, 6.19]< 10%11 studies (11/-)0.7 %lowlow highnon important-
Hepatobiliary disorders TRAE (grade 3-4) 1.61 [0.20, 13.18]< 187%6 studies (6/-)32.9 %lownot evaluable highnon important-
Hypersensitivity TRAE (grade 3-4) 3.72 [0.39, 35.19]< 10%2 studies (2/-)12.8 %lownot evaluable highnon important-
Hyperthyroidism TRAE (grade 3-4) 1.03 [0.29, 3.72]< 10%7 studies (7/-)48.0 %lownot evaluable highnon important-
Hypophysitis TRAE (grade 3-4) 0.75 [0.34, 1.65]< 144%11 studies (11/-)76.1 %lowlow highnon important-
Hypothyroidism TRAE (grade 3-4) 0.94 [0.33, 2.64]< 10%11 studies (11/-)55.0 %lowlow highnon important-
Increase AST TRAE (grade 3-4) 1.55 [0.40, 6.04]< 176%11 studies (11/-)26.5 %lowlow highnon important-
Increased ALT TRAE (grade 3-4) 1.85 [0.55, 6.29]< 181%11 studies (11/-)16.2 %lowlow highnon important-
Increased lipase level TRAE (grade 3-4) 2.09 [1.14, 3.84]< 119%4 studies (4/-)0.9 %lownot evaluable highnon important-
Infusion-related reactions TRAE (grade 3-4) 3.99 [0.18, 88.89]< 10%1 study (1/-)19.4 %NAnot evaluable non important-
Maculopapular rash TRAE (grade 3-4) 1.25 [0.38, 4.09]< 122%7 studies (7/-)35.6 %lownot evaluable highnon important-
Nervous system disorders TRAE (grade 3-4) 12.34 [1.59, 95.62]< 10%2 studies (2/-)0.8 %lownot evaluable highnon important-
Pancreatitis TRAE (grade 3-4) 3.68 [0.39, 34.85]< 10%2 studies (2/-)13.0 %some concernnot evaluable moderatenon important-
Pancytopenia TRAE (grade 3-4) 1.99 [0.07, 59.56]< 10%1 study (1/-)34.8 %NAnot evaluable non important-
Pericarditis TRAE (grade 3-4) 1.99 [0.07, 59.56]< 10%1 study (1/-)34.8 %NAnot evaluable non important-
Peripheral neuropathy TRAE (grade 3-4) 3.99 [0.18, 88.89]< 10%1 study (1/-)19.4 %NAnot evaluable non important-
Pneumonitis TRAE (grade 3-4) 1.57 [0.52, 4.72]< 10%6 studies (6/-)21.2 %lownot evaluable highnon important-
Polymyalgia Rheumatica TRAE (grade 3-4) 0.50 [0.02, 14.85]< 10%1 study (1/-)65.5 %NAnot evaluable non important-
Pruritic rash TRAE (grade 3-4) 0.75 [0.16, 3.57]< 10%6 studies (6/-)64.1 %lownot evaluable highnon important-
Pruritus TRAE (grade 3-4) 1.28 [0.53, 3.09]< 10%11 studies (11/-)28.9 %lowlow highnon important-
Rash TRAE (grade 3-4) 1.38 [0.68, 2.82]< 126%12 studies (12/-)18.7 %lowlow highnon important-
Respiratory, thoracic and mediastinal disorders TRAE (grade 3-4) 1.17 [0.13, 10.40]< 149%3 studies (3/-)44.6 %lownot evaluable highnon important-
Skin and subcutaneous tissue disorders TRAE (grade 3-4) 2.34 [0.57, 9.58]< 176%7 studies (7/-)11.9 %lowserious highnon important-
Thyroiditis TRAE (grade 3-4) 1.49 [0.24, 9.13]< 10%4 studies (4/-)33.5 %lownot evaluable highnon important-
Uveitis TRAE (grade 3-4) 0.72 [0.08, 6.18]< 10%3 studies (3/-)61.7 %some concernnot evaluable moderatenon important-
Vitiligo TRAE (grade 3-4) 0.74 [0.15, 3.51]< 10%6 studies (6/-)64.8 %lowserious highnon important-

AE (grade 3-4) endpoints 00

Abdominal pain AE (grade 3-4) 0.43 [0.12, 1.47]< 179%6 studies (6/-)91.1 %lownot evaluable highnon important-
Anaemia AE (grade 3-4) 0.44 [0.23, 0.84]< 112%3 studies (3/-)99.3 %lownot evaluable highnon 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-
Colitis AE (grade 3-4) 6.26 [2.61, 15.03]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Constipation AE (grade 3-4) 0.84 [0.32, 2.18]< 10%5 studies (5/-)64.2 %lownot evaluable highnon important-
Cough AE (grade 3-4) 0.43 [0.07, 2.75]< 145%6 studies (6/-)81.1 %lowserious highnon important-
Decreased appetite AE (grade 3-4) 0.73 [0.23, 2.34]< 166%6 studies (6/-)70.0 %lownot evaluable highnon important-
Diarrhoea AE (grade 3-4) 1.99 [0.45, 8.85]< 187%5 studies (5/-)18.5 %lowserious highnon important-
Dyspnoea AE (grade 3-4) 1.34 [0.62, 2.90]< 140%5 studies (5/-)22.6 %lowserious highnon important-
Fatigue AE (grade 3-4) 1.03 [0.23, 4.69]< 195%6 studies (6/-)48.6 %lownot evaluable highnon important-
Headache AE (grade 3-4) 0.54 [0.12, 2.43]< 181%6 studies (6/-)78.6 %lowserious highnon important-
Hypophysitis AE (grade 3-4) 11.01 [2.57, 47.24]< 10%1 study (1/-)0.1 %NAnot evaluable non important-
Hypothyroidism AE (grade 3-4) 0.14 [0.02, 1.16]< 10%1 study (1/-)96.5 %NAnot evaluable non important-
Increase AST AE (grade 3-4) 3.68 [0.17, 79.14]< 195%2 studies (2/-)20.5 %lownot evaluable highnon important-
Increased ALT AE (grade 3-4) 5.45 [0.16, 182.62]< 195%2 studies (2/-)17.6 %lownot evaluable highnon important-
Nausea AE (grade 3-4) 0.53 [0.16, 1.69]< 176%6 studies (6/-)85.8 %lownot evaluable highnon 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) 1.58 [0.06, 40.78]< 185%3 studies (3/-)39.2 %lownot evaluable highnon important-
Pyrexia AE (grade 3-4) 0.46 [0.16, 1.28]< 122%6 studies (6/-)93.1 %lownot evaluable highnon important-
Rash AE (grade 3-4) 1.20 [0.03, 47.44]< 191%3 studies (3/-)46.2 %lownot evaluable highnon 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) 0.76 [0.30, 1.92]< 168%6 studies (6/-)71.7 %lownot evaluable highnon important-
Weight decreased AE (grade 3-4) 0.24 [0.02, 3.70]< 172%3 studies (3/-)84.4 %lownot evaluable highnon 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.