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metastatic-recurrent HNSCC (mHNSCC), immune chekpoint inhibitors , 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) 0.84 [0.76, 0.93]< 128%6 studies (6/-)100.0 %some concernnot evaluable moderatecrucial-
deaths (OS) (extension) 0.72 [0.64, 0.81]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderateimportant-
PFS (extension) 0.87 [0.68, 1.11]< 10%1 study (1/-)86.7 %NAnot evaluable important-
progression or deaths (PFS) 1.03 [0.91, 1.17]< 161%6 studies (6/-)30.3 %some concernnot evaluable moderateimportant-
DCR 1.06 [0.77, 1.46]> 10%2 studies (2/-)64.0 %some concernnot evaluable moderatenon important-
objective responses (ORR) 1.01 [0.62, 1.65]> 184%6 studies (6/-)52.2 %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) 0.44 [0.25, 0.75]< 157%3 studies (3/-)99.9 %some concernnot evaluable moderatenon important-
AE (grade 3-4) 1.06 [0.84, 1.34]< 120%3 studies (3/-)31.0 %some concernnot evaluable moderatenon important-
AE leading to death (grade 5) 1.08 [0.80, 1.45]< 10%4 studies (4/-)30.9 %some concernnot evaluable moderatenon important-
AE leading to treatment discontinuation (any grade) 0.90 [0.46, 1.78]< 188%4 studies (4/-)61.6 %some concernnot evaluable moderatenon important-
SAE (any grade) 1.30 [0.98, 1.72]< 10%2 studies (2/-)3.6 %some concernnot evaluable moderatenon important-
STRAE (any grade) 1.16 [0.56, 2.38]< 10%1 study (1/-)34.4 %NAnot evaluable non important-
TRAE (any grade) 0.26 [0.15, 0.45]< 184%6 studies (6/-)100.0 %some concernnot evaluable moderatenon important-
TRAE (grade 3-4) 0.35 [0.14, 0.89]< 196%5 studies (5/-)98.6 %some concernnot evaluable moderatenon important-
TRAE leading to death (grade 5) 1.22 [0.58, 2.57]< 115%6 studies (6/-)30.0 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (any grade) 0.86 [0.55, 1.32]< 10%4 studies (4/-)75.9 %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) 1.18 [0.19, 7.27]< 10%4 studies (4/-)42.9 %some concernnot evaluable moderatenon important-
Alopecia TRAE (grade 3-4) 0.98 [0.10, 9.44]< 10%3 studies (3/-)50.7 %some concernnot evaluable moderatenon important-
Anaemia TRAE (grade 3-4) 0.19 [0.05, 0.78]< 186%6 studies (6/-)99.0 %some concernserious 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) 0.64 [0.26, 1.57]< 128%6 studies (6/-)83.3 %some concernnot evaluable moderatenon important-
Blood and lymphatic system disorders TRAE (grade 3-4) 0.12 [0.01, 2.59]< 197%3 studies (3/-)91.0 %some concernnot evaluable moderatenon important-
Blood creatinine increased TRAE (grade 3-4) 1.30 [0.15, 11.18]< 10%3 studies (3/-)40.5 %some concernnot evaluable moderatenon 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) 0.92 [0.27, 3.19]< 10%4 studies (4/-)55.2 %some concernnot evaluable moderatenon important-
Constipation TRAE (grade 3-4) 0.74 [0.09, 6.36]< 10%3 studies (3/-)60.7 %some concernnot evaluable moderatenon 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) 0.63 [0.20, 1.95]< 140%5 studies (5/-)78.8 %some concernnot evaluable moderatenon important-
Dermatitis acneiform TRAE (grade 3-4) 0.99 [0.06, 15.94]< 10%2 studies (2/-)50.2 %some concernnot evaluable moderatenon important-
Diarrhoea TRAE (grade 3-4) 0.54 [0.22, 1.32]< 111%6 studies (6/-)91.3 %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) 2.30 [0.45, 11.90]< 10%4 studies (4/-)16.1 %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) 1.03 [0.51, 2.06]< 134%6 studies (6/-)46.8 %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) 0.18 [0.06, 0.57]< 156%3 studies (3/-)99.8 %some concernnot evaluable moderatenon important-
General disorders and administration site conditions TRAE (grade 3-4) 0.61 [0.15, 2.52]< 190%3 studies (3/-)75.2 %some concernnot evaluable moderatenon 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) 2.59 [0.39, 17.34]< 10%3 studies (3/-)16.4 %some concernnot evaluable moderatenon 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) 1.02 [0.16, 6.74]< 10%4 studies (4/-)49.0 %some concernnot evaluable moderatenon important-
Hypophysitis TRAE (grade 3-4) 1.55 [0.22, 11.07]< 10%3 studies (3/-)33.0 %some concernnot evaluable moderatenon important-
Hypothyroidism TRAE (grade 3-4) 1.02 [0.19, 5.61]< 10%5 studies (5/-)48.9 %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) 0.45 [0.10, 1.98]< 10%4 studies (4/-)85.4 %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) 0.37 [0.13, 1.00]< 10%4 studies (4/-)97.5 %some concernnot evaluable moderatenon important-
Leucopenia TRAE (grade 3-4) 0.18 [0.06, 0.50]< 125%6 studies (6/-)99.9 %some concernserious 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) 0.47 [0.19, 1.17]< 179%3 studies (3/-)94.8 %some concernnot evaluable moderatenon important-
Mucosal inflammation TRAE (grade 3-4) 0.45 [0.10, 2.11]< 171%5 studies (5/-)84.4 %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-
Myocarditis TRAE (grade 3-4) 1.49 [0.11, 19.48]< 10%2 studies (2/-)38.1 %some concernnot evaluable moderatenon important-
Myositis TRAE (grade 3-4) 0.50 [0.05, 5.51]< 10%2 studies (2/-)71.4 %some concernnot evaluable moderatenon important-
Nausea TRAE (grade 3-4) 0.54 [0.17, 1.67]< 124%6 studies (6/-)85.7 %some concernnot evaluable moderatenon important-
Nephritis TRAE (grade 3-4) 2.32 [0.20, 26.51]< 10%2 studies (2/-)25.0 %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) 0.07 [0.01, 0.57]< 185%5 studies (5/-)99.4 %some concernserious 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-
Pancreatitis TRAE (grade 3-4) 1.49 [0.11, 19.48]< 10%2 studies (2/-)38.1 %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) 0.38 [0.06, 2.57]< 10%2 studies (2/-)83.8 %some concernnot evaluable moderatenon 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) 2.56 [0.91, 7.16]< 10%4 studies (4/-)3.7 %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) 0.51 [0.08, 3.20]< 10%4 studies (4/-)76.2 %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) 0.18 [0.06, 0.55]< 111%5 studies (5/-)99.9 %some concernserious 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) 0.27 [0.12, 0.61]< 130%3 studies (3/-)99.9 %some concernnot evaluable moderatenon important-
Skin and subcutaneous tissue disorders TRAE (grade 3-4) 0.17 [0.07, 0.39]< 10%3 studies (3/-)100.0 %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) 0.46 [0.07, 3.23]< 173%5 studies (5/-)78.1 %some concernnot evaluable moderatenon important-
Thrombocytopenia TRAE (grade 3-4) 0.35 [0.09, 1.42]< 164%6 studies (6/-)92.9 %some concernnot evaluable moderatenon important-
Thyroiditis TRAE (grade 3-4) 0.78 [0.08, 7.48]< 10%3 studies (3/-)58.6 %some concernnot evaluable moderatenon important-
Urticaria TRAE (grade 3-4) 0.47 [0.01, 23.80]< 10%1 study (1/-)64.4 %NAnot evaluable non important-
Uveitis TRAE (grade 3-4) 1.00 [0.06, 15.99]< 10%2 studies (2/-)50.1 %some concernnot evaluable moderatenon important-
Vascular disorders TRAE (grade 3-4) 0.95 [0.02, 48.13]< 10%1 study (1/-)51.0 %NAnot evaluable non important-
Vomiting TRAE (grade 3-4) 0.52 [0.04, 7.08]< 166%2 studies (2/-)68.6 %some concernnot evaluable moderatenon important-
Weight decreased TRAE (grade 3-4) 1.38 [0.26, 7.18]< 10%3 studies (3/-)35.2 %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.