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mML - (neo)adjuvant (NA), nivolumab plus ipilimumab versus anti-PD-(L)1, 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

RFS/DFS 0.40 [0.20, 0.79]< 10%1 study (1/-)99.6 %NAnot evaluable important-

safety endpoints 00

AE leading to death (grade 5) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
AE leading to treatment discontinuation (any grade) 11.33 [4.34, 29.62]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
AE leading to treatment discontinuation (grade 3-4) 11.38 [3.94, 32.84]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
SAE (any grade) 3.69 [1.68, 8.08]< 10%1 study (1/-)0.1 %NAnot evaluable non important-
SAE (grade 3-4) 3.48 [1.58, 7.66]< 10%1 study (1/-)0.1 %NAnot evaluable non important-
STRAE (any grade) 5.69 [2.43, 13.31]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
STRAE (grade 3-4) 4.68 [1.93, 11.38]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
TRAE (any grade) 5.07 [1.04, 24.68]< 10%1 study (1/-)2.2 %NAnot evaluable non important-
TRAE (grade 3-4) 6.66 [2.91, 15.27]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
TRAE leading to death (grade 5) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
TRAE leading to discontinuation (any grade) 11.33 [4.34, 29.62]< 10%1 study (1/-)0.0 %NAnot evaluable non important-
TRAE leading to discontinuation (grade 3-4) 11.38 [3.94, 32.84]< 10%1 study (1/-)0.0 %NAnot evaluable non important-

TRAE (grade 3-4) endpoints 00

Abdominal pain TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Acute kidney injury TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Adrenal insufficiency TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Alopecia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Anaemia TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Arthralgia TRAE (grade 3-4) 0.25 [0.01, 5.62]< 10%1 study (1/-)80.7 %NAnot evaluable non important-
Blood and lymphatic system disorders TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Chills TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Colitis TRAE (grade 3-4) 6.40 [0.31, 130.93]< 10%1 study (1/-)11.7 %NAnot evaluable non important-
Cough TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Decreased appetite TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Diabetes TRAE (grade 3-4) 0.50 [0.02, 15.35]< 10%1 study (1/-)65.1 %NAnot evaluable non important-
Diarrhoea TRAE (grade 3-4) 1.02 [0.06, 16.70]< 10%1 study (1/-)49.5 %NAnot evaluable non important-
Dizziness TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Dry skin TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Dysgeusia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Dyspepsia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Dyspnoea TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Ear and labyrinth disorders TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Endocrine disorders TRAE (grade 3-4) 5.50 [0.62, 48.70]< 10%1 study (1/-)6.4 %NAnot evaluable non important-
Eye disorders TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Fatigue TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Gastritis TRAE (grade 3-4) 4.19 [0.18, 95.03]< 10%1 study (1/-)18.7 %NAnot evaluable non important-
Gastrointestinal disorders TRAE (grade 3-4) 9.36 [1.13, 77.61]< 10%1 study (1/-)2.0 %NAnot evaluable non important-
General disorders and administration site conditions TRAE (grade 3-4) 4.19 [0.18, 95.03]< 10%1 study (1/-)18.7 %NAnot evaluable non important-
Headache TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Hepatitis TRAE (grade 3-4) 3.31 [0.64, 17.15]< 10%1 study (1/-)7.8 %NAnot evaluable non important-
Hepatobiliary disorders TRAE (grade 3-4) 7.53 [1.60, 35.49]< 10%1 study (1/-)0.5 %NAnot evaluable non important-
Hypertension TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Hyperthyroidism TRAE (grade 3-4) 6.40 [0.31, 130.93]< 10%1 study (1/-)11.7 %NAnot evaluable non important-
Hypophysitis TRAE (grade 3-4) 0.50 [0.02, 15.35]< 10%1 study (1/-)65.1 %NAnot evaluable non important-
Hypothyroidism TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Increase AST TRAE (grade 3-4) 3.01 [0.75, 12.00]< 10%1 study (1/-)6.0 %NAnot evaluable non important-
Increased ALT TRAE (grade 3-4) 5.47 [1.46, 20.45]< 10%1 study (1/-)0.6 %NAnot evaluable non important-
Increased lipase level TRAE (grade 3-4) 3.01 [0.75, 12.00]< 10%1 study (1/-)6.0 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Leucopenia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Maculopapular rash TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Metabolism and nutrition disorders TRAE (grade 3-4) 1.02 [0.06, 16.70]< 10%1 study (1/-)49.5 %NAnot evaluable non important-
Musculoskeletal and connective tissue disorders TRAE (grade 3-4) 0.16 [0.01, 3.31]< 10%1 study (1/-)87.9 %NAnot evaluable non important-
Myalgia TRAE (grade 3-4) 0.50 [0.02, 15.35]< 10%1 study (1/-)65.1 %NAnot evaluable non important-
Myositis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Nausea TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Nervous system disorders TRAE (grade 3-4) 0.50 [0.04, 5.68]< 10%1 study (1/-)71.0 %NAnot evaluable non important-
Neutropenia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Palmar-plantar erythrodysaesthesia syndrome TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Pancreatitis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Paraesthesia TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Peripheral neuropathy TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Pneumonitis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Pruritus TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Pyrexia TRAE (grade 3-4) 4.19 [0.18, 95.03]< 10%1 study (1/-)18.7 %NAnot evaluable non important-
Respiratory, thoracic and mediastinal disorders TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Sarcoidosis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Skin and subcutaneous tissue disorders TRAE (grade 3-4) 3.17 [0.32, 31.48]< 10%1 study (1/-)16.4 %NAnot evaluable non important-
Stomatitis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Thrombocytopenia TRAE (grade 3-4) 2.06 [0.07, 62.55]< 10%1 study (1/-)34.2 %NAnot evaluable non important-
Thyroiditis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Uveitis TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Vitiligo TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Vomiting TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non important-
Weight decreased TRAE (grade 3-4) 1.02 [0.02, 52.25]< 10%1 study (1/-)49.6 %NAnot evaluable non 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.