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metastatic/advanced NSCLC (mNSCLC) - 2nd line (L2), nivolumab 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) 0.68 [0.59, 0.79]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderatecrucial-
deaths (OS) (extension) 0.53 [0.22, 1.23]< 177%2 studies (2/-)93.0 %some concernnot evaluable moderateimportant-
PFS (extension) 0.69 [0.44, 1.07]< 146%2 studies (2/-)95.2 %some concernnot evaluable moderateimportant-
progression or deaths (PFS) 0.77 [0.62, 0.96]< 166%3 studies (3/-)99.0 %some concernnot evaluable moderateimportant-
objective responses (ORR) 2.48 [1.43, 4.31]> 156%3 studies (3/-)99.9 %some concernnot evaluable moderatenon important-
objective responses (ORR) (extension) 1.63 [0.19, 14.17]> 191%2 studies (2/-)67.1 %some concernnot evaluable moderatenon important-

safety endpoints 00

AE (any grade) 0.31 [0.20, 0.48]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
AE (grade 3-4) 0.42 [0.29, 0.59]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
SAE (grade 3-4) 0.10 [0.03, 0.33]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
STRAE (any grade) 0.37 [0.22, 0.62]< 153%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
STRAE (grade 3-4) 0.29 [0.19, 0.45]< 10%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
TRAE (any grade) 0.29 [0.19, 0.46]< 125%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
TRAE (grade 3-4) 0.10 [0.07, 0.17]< 157%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
TRAE leading to death (grade 5) 0.47 [0.12, 1.80]< 10%2 studies (2/-)86.5 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (any grade) 0.48 [0.22, 1.08]< 133%2 studies (2/-)96.2 %some concernnot evaluable moderatenon important-
TRAE leading to discontinuation (grade 3-4) 0.52 [0.16, 1.64]< 144%2 studies (2/-)86.8 %some concernnot evaluable moderatenon important-

TRAE (grade 3-4) endpoints 00

Abdominal pain TRAE (grade 3-4) 0.49 [0.02, 14.75]< 10%1 study (1/-)65.7 %NAnot evaluable non important-
Acute kidney injury TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Alopecia TRAE (grade 3-4) 0.58 [0.07, 5.02]< 10%3 studies (3/-)68.7 %some concernnot evaluable moderatenon important-
Anaemia TRAE (grade 3-4) 0.14 [0.03, 0.53]< 10%3 studies (3/-)99.8 %some concernnot evaluable moderatenon important-
Arthralgia TRAE (grade 3-4) 0.96 [0.06, 15.39]< 10%2 studies (2/-)51.2 %some concernnot evaluable moderatenon important-
Asthenia TRAE (grade 3-4) 0.13 [0.02, 0.72]< 10%2 studies (2/-)99.0 %some concernnot evaluable moderatenon important-
Blood creatinine increased TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Colitis TRAE (grade 3-4) 1.03 [0.08, 13.41]< 10%2 studies (2/-)49.2 %some concernnot evaluable moderatenon important-
Constipation TRAE (grade 3-4) 0.40 [0.04, 4.62]< 10%2 studies (2/-)76.5 %some concernnot evaluable moderatenon important-
Decreased appetite TRAE (grade 3-4) 0.43 [0.07, 2.61]< 10%3 studies (3/-)82.1 %some concernnot evaluable moderatenon important-
Diabetes TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Diarrhoea TRAE (grade 3-4) 0.49 [0.12, 2.01]< 10%3 studies (3/-)83.7 %some concernnot evaluable moderatenon important-
Dizziness TRAE (grade 3-4) 0.98 [0.02, 50.00]< 10%1 study (1/-)50.3 %NAnot evaluable non important-
Dysgeusia TRAE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Eczema TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Endocrine disorders TRAE (grade 3-4) 0.46 [0.01, 23.40]< 10%1 study (1/-)64.7 %NAnot evaluable non important-
Erythema TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Fatigue TRAE (grade 3-4) 0.20 [0.08, 0.47]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
Febrile neutropenia TRAE (grade 3-4) 0.02 [0.00, 0.17]< 10%2 studies (2/-)100.0 %some concernnot evaluable moderatenon important-
Gastrointestinal disorders TRAE (grade 3-4) 0.93 [0.03, 27.74]< 10%1 study (1/-)51.8 %NAnot evaluable non important-
Hepatobiliary disorders TRAE (grade 3-4) 1.39 [0.14, 13.49]< 10%1 study (1/-)38.8 %NAnot evaluable non important-
Hypersensitivity TRAE (grade 3-4) 0.42 [0.03, 5.48]< 10%2 studies (2/-)74.4 %some concernnot evaluable moderatenon important-
Hyperthyroidism TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Hypothyroidism TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Increase AST TRAE (grade 3-4) 0.81 [0.09, 6.95]< 10%2 studies (2/-)57.6 %some concernnot evaluable moderatenon important-
Increased ALT TRAE (grade 3-4) 0.46 [0.05, 3.98]< 10%2 studies (2/-)75.7 %some concernnot evaluable moderatenon important-
Increased lacrimation (TRAE grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 0.46 [0.04, 6.06]< 10%2 studies (2/-)71.9 %some concernnot evaluable moderatenon important-
Leucopenia TRAE (grade 3-4) 0.05 [0.01, 0.21]< 116%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
Maculopapular rash TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Mucosal inflammation TRAE (grade 3-4) 0.21 [0.02, 2.21]< 10%2 studies (2/-)90.1 %some concernnot evaluable moderatenon important-
Myalgia TRAE (grade 3-4) 1.42 [0.11, 18.57]< 10%2 studies (2/-)39.5 %some concernnot evaluable moderatenon important-
Nausea TRAE (grade 3-4) 0.64 [0.12, 3.35]< 10%2 studies (2/-)70.3 %some concernnot evaluable moderatenon important-
Neutropenia TRAE (grade 3-4) 0.02 [0.01, 0.06]< 10%3 studies (3/-)100.0 %some concernnot evaluable moderatenon important-
Palmar-plantar erythrodysaesthesia syndrome TRAE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Paraesthesia TRAE (grade 3-4) 0.96 [0.06, 15.39]< 10%2 studies (2/-)51.2 %some concernnot evaluable moderatenon important-
Peripheral neuropathy TRAE (grade 3-4) 0.16 [0.02, 1.32]< 10%2 studies (2/-)95.5 %some concernnot evaluable moderatenon important-
Peripheral oedema TRAE (grade 3-4) 0.64 [0.05, 8.39]< 10%2 studies (2/-)63.1 %some concernnot evaluable moderatenon important-
Pneumonitis TRAE (grade 3-4) 2.83 [0.58, 13.89]< 10%3 studies (3/-)10.0 %some concernnot evaluable moderatenon important-
Pruritic rash TRAE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Pruritus generalised TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Pruritus TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Pyrexia TRAE (grade 3-4) 0.65 [0.05, 8.46]< 10%2 studies (2/-)62.9 %some concernnot evaluable moderatenon important-
Rash TRAE (grade 3-4) 1.08 [0.17, 6.66]< 10%3 studies (3/-)46.9 %some concernnot evaluable moderatenon important-
Renal and urinary disorders TRAE (grade 3-4) 0.46 [0.01, 23.40]< 10%1 study (1/-)64.7 %NAnot evaluable non important-
Respiratory, thoracic and mediastinal disorders TRAE (grade 3-4) 6.60 [0.37, 116.99]< 10%1 study (1/-)10.2 %NAnot evaluable non important-
Skin and subcutaneous tissue disorders TRAE (grade 3-4) 2.79 [0.14, 56.11]< 10%1 study (1/-)25.4 %NAnot evaluable non important-
Skin exfoliation TRAE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Stomatitis TRAE (grade 3-4) 0.23 [0.01, 5.17]< 10%1 study (1/-)81.9 %NAnot evaluable non important-
Thyroiditis TRAE (grade 3-4) 0.66 [0.04, 10.53]< 10%2 studies (2/-)61.6 %some concernnot evaluable moderatenon important-
Urticaria TRAE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Vitiligo TRAE (grade 3-4) 0.46 [0.01, 23.40]< 10%1 study (1/-)64.7 %NAnot evaluable non important-
Vomiting TRAE (grade 3-4) 0.65 [0.05, 8.46]< 10%2 studies (2/-)62.9 %some concernnot evaluable moderatenon important-

AE (grade 3-4) endpoints 00

Abdominal pain AE (grade 3-4) 0.15 [0.01, 3.09]< 10%1 study (1/-)88.6 %NAnot evaluable non important-
Alopecia AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Anaemia AE (grade 3-4) 0.38 [0.13, 1.09]< 10%1 study (1/-)96.4 %NAnot evaluable non important-
Arthralgia AE (grade 3-4) 0.93 [0.13, 6.67]< 10%1 study (1/-)52.7 %NAnot evaluable non important-
Asthenia AE (grade 3-4) 0.84 [0.35, 2.02]< 10%1 study (1/-)64.9 %NAnot evaluable non important-
Back pain AE (grade 3-4) 2.36 [0.45, 12.26]< 10%1 study (1/-)15.5 %NAnot evaluable non important-
Constipation AE (grade 3-4) 0.93 [0.13, 6.67]< 10%1 study (1/-)52.7 %NAnot evaluable non important-
Cough AE (grade 3-4) 1.87 [0.06, 55.99]< 10%1 study (1/-)36.1 %NAnot evaluable non important-
Decreased appetite AE (grade 3-4) 1.17 [0.31, 4.40]< 10%1 study (1/-)40.8 %NAnot evaluable non important-
Diarrhoea AE (grade 3-4) 0.93 [0.19, 4.66]< 10%1 study (1/-)53.3 %NAnot evaluable non important-
Dizziness AE (grade 3-4) 0.93 [0.06, 15.00]< 10%1 study (1/-)51.9 %NAnot evaluable non important-
Dry skin AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Dysgeusia AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Dyspnoea AE (grade 3-4) 1.32 [0.58, 3.03]< 10%1 study (1/-)25.4 %NAnot evaluable non important-
Erythema AE (grade 3-4) 0.47 [0.02, 13.95]< 10%1 study (1/-)66.8 %NAnot evaluable non important-
Fatigue AE (grade 3-4) 0.45 [0.20, 1.02]< 10%1 study (1/-)97.2 %NAnot evaluable non important-
Febrile neutropenia AE (grade 3-4) 0.01 [0.00, 0.24]< 10%1 study (1/-)99.8 %NAnot evaluable non important-
Headache AE (grade 3-4) 3.75 [0.17, 83.63]< 10%1 study (1/-)20.5 %NAnot evaluable non important-
Hypothyroidism AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Increased ALT AE (grade 3-4) 0.93 [0.06, 15.00]< 10%1 study (1/-)51.9 %NAnot evaluable non important-
Lacrimation increased AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Leucopenia AE (grade 3-4) 0.02 [0.00, 0.31]< 10%1 study (1/-)99.7 %NAnot evaluable non important-
Mucosal inflammation AE (grade 3-4) 0.18 [0.02, 1.58]< 10%1 study (1/-)93.7 %NAnot evaluable non important-
Myalgia AE (grade 3-4) 1.87 [0.06, 55.99]< 10%1 study (1/-)36.1 %NAnot evaluable non important-
Nausea AE (grade 3-4) 2.36 [0.45, 12.26]< 10%1 study (1/-)15.5 %NAnot evaluable non important-
Neutropenia AE (grade 3-4) 0.01 [0.00, 0.07]< 10%1 study (1/-)100.0 %NAnot evaluable non important-
Oropharyngeal pain AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Paraesthesia AE (grade 3-4) 0.93 [0.02, 47.22]< 10%1 study (1/-)51.3 %NAnot evaluable non important-
Peripheral neuropathy AE (grade 3-4) 0.15 [0.01, 3.09]< 10%1 study (1/-)88.6 %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.