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mHNSCC - L2 - all population, 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

deaths (OS) 0.81 [0.71, 0.93]< 10%3 studies (3/-)99.9 %some concernnot evaluable moderatecrucial-
deaths (OS) (extension) 0.68 [0.54, 0.86]< 10%1 study (1/-)99.9 %NAnot evaluable important-
PFS (extension) 0.87 [0.68, 1.11]< 10%1 study (1/-)86.7 %NAnot evaluable important-
progression or deaths (PFS) 0.96 [0.85, 1.09]< 10%3 studies (3/-)73.2 %some concernnot evaluable moderateimportant-
DCR 1.00 [0.63, 1.58]> 10%1 study (1/-)50.0 %NAnot evaluable non important-
objective responses (ORR) 1.44 [0.92, 2.23]> 140%3 studies (3/-)94.6 %some concernnot evaluable moderatenon important-
objective responses (ORR) (extension) 2.51 [1.07, 5.86]> 10%1 study (1/-)98.3 %NAnot evaluable non important-

safety endpoints 00

AE (any grade) 0.45 [0.21, 0.94]< 10%1 study (1/-)98.3 %NAnot evaluable non important-
AE (grade 3-4) 0.89 [0.62, 1.28]< 10%1 study (1/-)73.3 %NAnot evaluable non important-
AE leading to death (grade 5) 1.01 [0.52, 1.97]< 10%1 study (1/-)48.4 %NAnot evaluable non important-
AE leading to treatment discontinuation (any grade) 0.97 [0.53, 1.77]< 10%1 study (1/-)54.3 %NAnot evaluable non important-
SAE (any grade) 1.21 [0.80, 1.80]< 10%1 study (1/-)18.2 %NAnot evaluable non important-
STRAE (any grade) 1.16 [0.56, 2.38]< 10%1 study (1/-)34.4 %NAnot evaluable non important-
TRAE (any grade) 0.31 [0.24, 0.40]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
TRAE (grade 3-4) 0.29 [0.20, 0.42]< 110%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
TRAE leading to death (grade 5) 2.06 [0.58, 7.26]< 10%3 studies (3/-)13.1 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (any grade) 0.81 [0.46, 1.45]< 125%3 studies (3/-)76.0 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (grade 3-4) 1.28 [0.53, 3.10]< 10%1 study (1/-)29.1 %NAnot evaluable non important-

TRAE (grade 3-4) endpoints 00

Acute kidney injury TRAE (grade 3-4) 0.67 [0.06, 7.40]< 10%2 studies (2/-)62.8 %some concernnot evaluable moderatenon important-
Adrenal insufficiency TRAE (grade 3-4) 0.95 [0.07, 12.36]< 10%2 studies (2/-)51.7 %some concernnot evaluable moderatenon important-
Alopecia TRAE (grade 3-4) 0.98 [0.06, 15.74]< 10%2 studies (2/-)50.5 %some concernnot evaluable moderatenon important-
Anaemia TRAE (grade 3-4) 0.14 [0.05, 0.42]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
Arthralgia TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Asthenia TRAE (grade 3-4) 0.30 [0.08, 1.14]< 10%3 studies (3/-)96.1 %some concernnot evaluable moderatenon important-
Blood and lymphatic system disorders TRAE (grade 3-4) 0.04 [0.01, 0.31]< 10%1 study (1/-)99.9 %NAnot evaluable non important-
Blood creatinine increased TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Cardiac disorders TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Chills TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Colitis TRAE (grade 3-4) 0.67 [0.04, 10.72]< 10%2 studies (2/-)61.1 %some concernnot evaluable moderatenon important-
Constipation TRAE (grade 3-4) 0.47 [0.02, 14.21]< 10%1 study (1/-)66.4 %NAnot evaluable non important-
Cough TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Decreased appetite TRAE (grade 3-4) 0.49 [0.05, 5.27]< 110%2 studies (2/-)72.0 %some concernnot evaluable moderatenon important-
Dermatitis acneiform TRAE (grade 3-4) 1.01 [0.02, 51.25]< 10%1 study (1/-)49.8 %NAnot evaluable non important-
Diarrhoea TRAE (grade 3-4) 0.52 [0.05, 5.58]< 155%3 studies (3/-)70.4 %some concernnot evaluable moderatenon important-
Dyspepsia TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Dyspnoea TRAE (grade 3-4) 3.83 [0.17, 85.33]< 10%1 study (1/-)20.1 %NAnot evaluable non important-
Eczema TRAE (grade 3-4) 0.47 [0.01, 23.80]< 10%1 study (1/-)64.4 %NAnot evaluable non important-
Endocrine disorders TRAE (grade 3-4) 1.34 [0.12, 14.83]< 10%2 studies (2/-)40.7 %some concernnot evaluable moderatenon important-
Epistaxis TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Erythema TRAE (grade 3-4) 0.23 [0.01, 7.01]< 10%1 study (1/-)79.5 %NAnot evaluable non important-
Eye disorders TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Fatigue TRAE (grade 3-4) 1.11 [0.42, 2.90]< 10%3 studies (3/-)41.9 %some concernnot evaluable moderatenon important-
Febrile neutropenia TRAE (grade 3-4) 0.05 [0.00, 0.79]< 10%1 study (1/-)98.2 %NAnot evaluable non important-
Gastritis TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Gastrointestinal disorders TRAE (grade 3-4) 0.33 [0.14, 0.77]< 10%2 studies (2/-)99.5 %some concernnot evaluable moderatenon important-
General disorders and administration site conditions TRAE (grade 3-4) 0.57 [0.23, 1.40]< 10%1 study (1/-)88.8 %NAnot evaluable non important-
Guillain-Barré syndrome TRAE (grade 3-4) 1.91 [0.06, 57.09]< 10%1 study (1/-)35.7 %NAnot evaluable non important-
Headache TRAE (grade 3-4) 0.47 [0.02, 14.21]< 10%1 study (1/-)66.4 %NAnot evaluable non important-
Hepatitis TRAE (grade 3-4) 2.01 [0.07, 60.26]< 10%1 study (1/-)34.6 %NAnot evaluable non important-
Hepatobiliary disorders TRAE (grade 3-4) 0.94 [0.15, 5.84]< 10%2 studies (2/-)52.4 %some concernnot evaluable moderatenon important-
Hypersensitivity TRAE (grade 3-4) 0.43 [0.03, 5.58]< 10%2 studies (2/-)74.0 %some concernnot evaluable moderatenon important-
Hypertension TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Hyperthyroidism TRAE (grade 3-4) 0.67 [0.04, 10.72]< 10%2 studies (2/-)61.1 %some concernnot evaluable moderatenon important-
Hypophysitis TRAE (grade 3-4) 0.94 [0.03, 28.25]< 10%1 study (1/-)51.4 %NAnot evaluable non important-
Hypothyroidism TRAE (grade 3-4) 1.04 [0.12, 8.89]< 10%3 studies (3/-)48.7 %some concernnot evaluable moderatenon important-
Increase AST TRAE (grade 3-4) 0.35 [0.05, 2.48]< 10%2 studies (2/-)85.3 %some concernnot evaluable moderatenon important-
Increased ALT TRAE (grade 3-4) 0.44 [0.09, 2.29]< 10%3 studies (3/-)83.4 %some concernnot evaluable moderatenon important-
Increased lipase level TRAE (grade 3-4) 3.81 [0.20, 72.71]< 10%1 study (1/-)19.0 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 0.54 [0.06, 4.66]< 10%2 studies (2/-)71.0 %some concernnot evaluable moderatenon important-
Leucopenia TRAE (grade 3-4) 0.09 [0.02, 0.47]< 10%3 studies (3/-)99.8 %some concernnot evaluable moderatenon important-
Maculopapular rash TRAE (grade 3-4) 0.47 [0.04, 6.17]< 10%2 studies (2/-)71.5 %some concernnot evaluable moderatenon important-
Metabolism and nutrition disorders TRAE (grade 3-4) 0.40 [0.10, 1.57]< 10%1 study (1/-)90.5 %NAnot evaluable non important-
Mucosal inflammation TRAE (grade 3-4) 0.25 [0.04, 1.53]< 10%2 studies (2/-)93.2 %some concernnot evaluable moderatenon important-
Musculoskeletal and connective tissue disorders TRAE (grade 3-4) 1.91 [0.06, 57.09]< 10%1 study (1/-)35.7 %NAnot evaluable non important-
Myalgia TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Nausea TRAE (grade 3-4) 0.61 [0.09, 4.33]< 10%3 studies (3/-)68.9 %some concernnot evaluable moderatenon important-
Nervous system disorders TRAE (grade 3-4) 0.47 [0.04, 5.26]< 10%1 study (1/-)72.7 %NAnot evaluable non important-
Neutropenia TRAE (grade 3-4) 0.04 [0.01, 0.22]< 10%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
Palmar-plantar erythrodysaesthesia syndrome TRAE (grade 3-4) 0.43 [0.03, 5.58]< 10%2 studies (2/-)74.0 %some concernnot evaluable moderatenon important-
Pancytopenia TRAE (grade 3-4) 0.16 [0.01, 3.15]< 10%1 study (1/-)88.4 %NAnot evaluable non important-
Paraesthesia TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Peripheral neuropathy TRAE (grade 3-4) 0.50 [0.05, 5.60]< 10%1 study (1/-)71.0 %NAnot evaluable non important-
Peripheral oedema TRAE (grade 3-4) 1.91 [0.06, 57.09]< 10%1 study (1/-)35.7 %NAnot evaluable non important-
Pneumonitis TRAE (grade 3-4) 2.69 [0.30, 24.18]< 10%2 studies (2/-)19.0 %some concernnot evaluable moderatenon important-
Pruritic rash TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Pruritus generalised TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Pruritus TRAE (grade 3-4) 0.43 [0.05, 3.39]< 10%3 studies (3/-)78.8 %some concernnot evaluable moderatenon important-
Pyrexia TRAE (grade 3-4) 0.26 [0.02, 2.98]< 10%2 studies (2/-)85.9 %some concernnot evaluable moderatenon important-
Rash TRAE (grade 3-4) 0.97 [0.10, 9.37]< 10%2 studies (2/-)51.0 %some concernnot evaluable moderatenon important-
Renal and urinary disorders TRAE (grade 3-4) 1.05 [0.08, 13.66]< 10%2 studies (2/-)48.7 %some concernnot evaluable moderatenon important-
Respiratory, thoracic and mediastinal disorders TRAE (grade 3-4) 1.50 [0.46, 4.88]< 10%2 studies (2/-)25.3 %some concernnot evaluable moderatenon important-
Sepsis TRAE (grade 3-4) 0.24 [0.01, 5.27]< 10%1 study (1/-)81.6 %NAnot evaluable non important-
Severe skin reaction TRAE (grade 3-4) 0.54 [0.15, 1.86]< 10%1 study (1/-)83.7 %NAnot evaluable non important-
Skin and subcutaneous tissue disorders TRAE (grade 3-4) 0.27 [0.08, 0.89]< 10%2 studies (2/-)98.4 %some concernnot evaluable moderatenon important-
Skin exfoliation TRAE (grade 3-4) 0.67 [0.04, 10.72]< 10%2 studies (2/-)61.1 %some concernnot evaluable moderatenon important-
Stevens-Johnson syndrome TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Stomatitis TRAE (grade 3-4) 0.30 [0.01, 6.62]< 160%2 studies (2/-)77.3 %some concernnot evaluable moderatenon important-
Thrombocytopenia TRAE (grade 3-4) 0.24 [0.04, 1.30]< 10%3 studies (3/-)95.1 %some concernnot evaluable moderatenon important-
Thyroiditis TRAE (grade 3-4) 0.47 [0.01, 23.80]< 10%1 study (1/-)64.4 %NAnot evaluable non important-
Urticaria TRAE (grade 3-4) 0.47 [0.01, 23.80]< 10%1 study (1/-)64.4 %NAnot evaluable non important-
Vascular disorders TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Weight decreased TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-

AE (grade 3-4) endpoints 00

Back pain AE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Dizziness AE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Rash AE (grade 3-4) 0.23 [0.01, 7.01]< 10%1 study (1/-)79.5 %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.