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renal cell cancer (RCC), pembrolizumab based treatment , 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) 0.60 [0.48, 0.75]< 10%2 studies (2/-)100.0 %some concernnot evaluable moderatecrucial-
deaths (OS) (extension) 0.68 [0.55, 0.85]< 10%1 study (1/-)100.0 %NAnot evaluable important-
PFS (extension) 0.71 [0.60, 0.84]< 10%1 study (1/-)100.0 %NAnot evaluable important-
progression or deaths (PFS) 0.52 [0.30, 0.91]< 193%2 studies (2/-)98.9 %some concernnot evaluable moderateimportant-
objective responses (ORR) 1.99 [1.75, 2.28]> 10%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
objective responses (ORR) (extension) 2.28 [1.74, 3.00]> 10%1 study (1/-)100.0 %NAnot evaluable non important-

safety endpoints 00

AE (any grade) NaN [NaN, NaN]< 10%1 study (1/-)NaNNAnot evaluable non important-
AE (grade 3-4) 0.11 [0.05, 0.24]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
AE leading to death (grade 5) 0.82 [0.47, 1.43]< 10%2 studies (2/-)76.2 %some concernnot evaluable moderatenon important-
AE leading to treatment discontinuation (any grade) 2.31 [1.58, 3.38]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
TRAE (any grade) 0.62 [0.28, 1.39]< 10%1 study (1/-)87.7 %NAnot evaluable non important-
TRAE (grade 3-4) 1.26 [0.96, 1.65]< 10%1 study (1/-)5.0 %NAnot evaluable non important-
TRAE leading to death (grade 5) 0.56 [0.16, 1.93]< 10%1 study (1/-)81.9 %NAnot evaluable non important-
TRAE leading to discontinuation (any grade) 3.10 [2.12, 4.54]< 10%1 study (1/-)0.0 %NAnot evaluable non important-

TRAE (grade 3-4) endpoints 00

Adrenal insufficiency TRAE (grade 3-4) 5.98 [0.30, 119.72]< 10%1 study (1/-)12.4 %NAnot evaluable non important-
Anaemia TRAE (grade 3-4) 0.07 [0.01, 0.57]< 10%1 study (1/-)99.4 %NAnot evaluable non important-
Arthralgia TRAE (grade 3-4) 1.49 [0.25, 8.96]< 10%1 study (1/-)33.2 %NAnot evaluable non important-
Asthenia TRAE (grade 3-4) 0.49 [0.18, 1.31]< 10%1 study (1/-)92.2 %NAnot evaluable non important-
Colitis TRAE (grade 3-4) 16.13 [0.92, 281.80]< 10%1 study (1/-)3.0 %NAnot evaluable non important-
Decreased appetite TRAE (grade 3-4) 4.53 [0.97, 21.10]< 10%1 study (1/-)2.7 %NAnot evaluable non important-
Diabetes TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Diarrhoea TRAE (grade 3-4) 1.66 [0.92, 3.00]< 10%1 study (1/-)4.5 %NAnot evaluable non important-
Dysgeusia TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Dyspepsia TRAE (grade 3-4) 0.49 [0.02, 14.79]< 10%1 study (1/-)65.5 %NAnot evaluable non important-
Dysphonia TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Fatigue TRAE (grade 3-4) 0.46 [0.21, 0.99]< 10%1 study (1/-)97.7 %NAnot evaluable non important-
Hepatitis TRAE (grade 3-4) 20.26 [1.18, 348.03]< 10%1 study (1/-)2.0 %NAnot evaluable non important-
Hypertension TRAE (grade 3-4) 1.20 [0.85, 1.68]< 10%1 study (1/-)14.7 %NAnot evaluable non important-
Hyperthyroidism TRAE (grade 3-4) 10.01 [0.55, 183.83]< 10%1 study (1/-)6.2 %NAnot evaluable non important-
Hypophysitis TRAE (grade 3-4) 7.99 [0.42, 151.61]< 10%1 study (1/-)8.6 %NAnot evaluable non important-
Hypothyroidism TRAE (grade 3-4) 0.99 [0.06, 15.89]< 10%1 study (1/-)50.3 %NAnot evaluable non important-
Increase AST TRAE (grade 3-4) 4.33 [1.88, 10.00]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Increased ALT TRAE (grade 3-4) 5.19 [2.67, 10.10]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 0.99 [0.06, 15.89]< 10%1 study (1/-)50.3 %NAnot evaluable non important-
Mucosal inflammation TRAE (grade 3-4) 0.56 [0.16, 1.93]< 10%1 study (1/-)81.9 %NAnot evaluable non important-
Myocarditis TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Myositis TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Nausea TRAE (grade 3-4) 0.49 [0.09, 2.71]< 10%1 study (1/-)79.1 %NAnot evaluable non important-
Nephritis TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Neutropenia TRAE (grade 3-4) 0.03 [0.00, 0.24]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
Palmar-plantar erythrodysaesthesia syndrome TRAE (grade 3-4) 1.48 [0.76, 2.89]< 10%1 study (1/-)12.7 %NAnot evaluable non important-
Pancreatitis TRAE (grade 3-4) 0.99 [0.14, 7.07]< 10%1 study (1/-)50.4 %NAnot evaluable non important-
Pneumonitis TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Proteinuria TRAE (grade 3-4) 1.84 [0.67, 5.02]< 10%1 study (1/-)11.8 %NAnot evaluable non important-
Pruritus TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Rash TRAE (grade 3-4) 0.99 [0.06, 15.89]< 10%1 study (1/-)50.3 %NAnot evaluable non important-
Severe skin reaction TRAE (grade 3-4) 1.66 [0.39, 6.99]< 10%1 study (1/-)24.6 %NAnot evaluable non important-
Stomatitis TRAE (grade 3-4) 0.33 [0.09, 1.21]< 10%1 study (1/-)95.3 %NAnot evaluable non important-
Thrombocytopenia TRAE (grade 3-4) 0.02 [0.00, 0.35]< 10%1 study (1/-)99.6 %NAnot evaluable non important-
Thyroiditis TRAE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Uveitis TRAE (grade 3-4) 0.99 [0.02, 50.04]< 10%1 study (1/-)50.2 %NAnot evaluable non important-
Vomiting TRAE (grade 3-4) 0.33 [0.03, 3.17]< 10%1 study (1/-)83.0 %NAnot evaluable non important-

AE (grade 3-4) endpoints 00

Abdominal pain AE (grade 3-4) 5.00 [0.58, 42.98]< 10%1 study (1/-)7.2 %NAnot evaluable non important-
Anaemia AE (grade 3-4) 0.14 [0.04, 0.46]< 10%1 study (1/-)99.9 %NAnot evaluable non important-
Arthralgia AE (grade 3-4) 2.03 [0.59, 6.96]< 10%2 studies (2/-)13.0 %some concernnot evaluable moderatenon important-
Asthenia AE (grade 3-4) 0.83 [0.37, 1.88]< 10%1 study (1/-)66.9 %NAnot evaluable non important-
Back pain AE (grade 3-4) 0.56 [0.16, 1.93]< 10%1 study (1/-)81.9 %NAnot evaluable non important-
Blood creatinine increased AE (grade 3-4) 0.66 [0.11, 3.96]< 10%1 study (1/-)67.5 %NAnot evaluable non important-
Constipation AE (grade 3-4) 1.94 [0.18, 21.52]< 112%2 studies (2/-)29.5 %some concernnot evaluable moderatenon important-
Cough AE (grade 3-4) 0.49 [0.04, 5.47]< 10%1 study (1/-)71.6 %NAnot evaluable non important-
Decreased appetite AE (grade 3-4) 3.22 [1.45, 7.19]< 10%2 studies (2/-)0.2 %some concernnot evaluable moderatenon important-
Diarrhoea AE (grade 3-4) 1.97 [1.31, 2.96]< 10%2 studies (2/-)0.1 %some concernnot evaluable moderatenon important-
Dysgeusia AE (grade 3-4) 1.29 [0.15, 11.06]< 10%2 studies (2/-)40.9 %some concernnot evaluable moderatenon important-
Dyspepsia AE (grade 3-4) 0.49 [0.02, 14.79]< 10%1 study (1/-)65.5 %NAnot evaluable non important-
Dysphonia AE (grade 3-4) 1.46 [0.11, 19.00]< 10%2 studies (2/-)38.8 %some concernnot evaluable moderatenon important-
Dyspnoea AE (grade 3-4) 1.39 [0.44, 4.43]< 10%1 study (1/-)28.7 %NAnot evaluable non important-
Fatigue AE (grade 3-4) 0.62 [0.27, 1.44]< 164%2 studies (2/-)86.5 %some concernnot evaluable moderatenon important-
Headache AE (grade 3-4) 1.99 [0.36, 10.93]< 10%1 study (1/-)21.5 %NAnot evaluable non important-
Hypertension AE (grade 3-4) 1.39 [1.01, 1.90]< 140%2 studies (2/-)2.1 %some concernnot evaluable moderatenon important-
Hyperthyroidism AE (grade 3-4) 10.01 [0.55, 183.83]< 10%1 study (1/-)6.2 %NAnot evaluable non important-
Hypothyroidism AE (grade 3-4) 2.98 [0.32, 28.06]< 120%2 studies (2/-)17.2 %some concernnot evaluable moderatenon important-
Increase AST AE (grade 3-4) 3.12 [1.51, 6.47]< 10%1 study (1/-)0.1 %NAnot evaluable non important-
Increased ALT AE (grade 3-4) 4.86 [2.62, 9.01]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
Mucosal inflammation AE (grade 3-4) 0.49 [0.15, 1.64]< 10%1 study (1/-)87.6 %NAnot evaluable non important-
Nausea AE (grade 3-4) 2.02 [0.47, 8.75]< 150%2 studies (2/-)17.5 %some concernnot evaluable moderatenon important-
Neutropenia AE (grade 3-4) 0.03 [0.00, 0.24]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
Palmar–plantar erythrodysesthesia syndrome AE (grade 3-4) 1.23 [0.74, 2.02]< 10%2 studies (2/-)21.2 %some concernnot evaluable moderatenon important-
Proteinuria AE (grade 3-4) 2.45 [1.35, 4.44]< 10%2 studies (2/-)0.2 %some concernnot evaluable moderatenon important-
Pruritus AE (grade 3-4) 1.98 [0.07, 59.29]< 10%1 study (1/-)34.9 %NAnot evaluable non important-
Pyrexia AE (grade 3-4) 0.99 [0.02, 50.04]< 10%1 study (1/-)50.2 %NAnot evaluable non important-
Rash AE (grade 3-4) 2.14 [0.18, 26.02]< 168%2 studies (2/-)27.7 %some concernnot evaluable moderatenon important-
Stomatitis AE (grade 3-4) 0.56 [0.23, 1.37]< 112%2 studies (2/-)89.9 %some concernnot evaluable moderatenon important-
Thrombocytopenia AE (grade 3-4) 0.02 [0.00, 0.31]< 10%1 study (1/-)99.7 %NAnot evaluable non important-
Vomiting AE (grade 3-4) 0.94 [0.11, 8.34]< 170%2 studies (2/-)52.1 %some concernnot evaluable moderatenon important-
Weight decreased AE (grade 3-4) 19.85 [4.76, 82.76]< 10%2 studies (2/-)0.0 %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.