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mML - L1 - BRAF wild, 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) 0.55 [0.27, 1.10]< 186%3 studies (3/-)95.5 %lownot evaluable highcrucial-
deaths (OS) (extension) 0.46 [0.36, 0.59]< 10%1 study (1/-)100.0 %NAnot evaluable important-
PFS (extension) 0.42 [0.33, 0.53]< 10%1 study (1/-)100.0 %NAnot evaluable important-
progression or deaths (PFS) 0.60 [0.32, 1.12]< 195%3 studies (3/-)94.7 %lownot evaluable highimportant-
DCR 0.91 [0.63, 1.32]> 10%1 study (1/-)31.6 %NAnot evaluable non important-
DOR (extension) 3.45 [1.46, 8.18]> 10%1 study (1/-)99.8 %NAnot evaluable non important-
objective responses (ORR) 2.32 [0.75, 7.18]> 195%3 studies (3/-)92.7 %lownot evaluable highnon important-
objective responses (ORR) (extension) 4.50 [2.79, 7.25]> 10%1 study (1/-)100.0 %NAnot evaluable non important-

safety endpoints 00

AE (any grade) 3.12 [0.18, 53.89]< 191%2 studies (2/-)21.9 %lownot evaluable highnon important-
AE (grade 3-4) 1.84 [0.39, 8.56]< 197%2 studies (2/-)22.0 %some concernnot evaluable moderatenon important-
AE leading to death (grade 5) 1.35 [0.44, 4.12]< 10%2 studies (2/-)29.9 %some concernnot evaluable moderatenon important-
AE leading to treatment discontinuation (any grade) 0.55 [0.28, 1.10]< 10%1 study (1/-)95.5 %NAnot evaluable non important-
AE leading to treatment discontinuation (grade 3-4) 0.61 [0.29, 1.28]< 10%1 study (1/-)90.5 %NAnot evaluable non important-
SAE (any grade) 0.73 [0.49, 1.10]< 10%1 study (1/-)93.1 %NAnot evaluable non important-
SAE (grade 3-4) 0.74 [0.47, 1.17]< 10%1 study (1/-)90.4 %NAnot evaluable non important-
STRAE (any grade) 1.06 [0.54, 2.07]< 10%1 study (1/-)43.8 %NAnot evaluable non important-
STRAE (grade 3-4) 0.99 [0.44, 2.27]< 10%1 study (1/-)50.5 %NAnot evaluable non important-
TRAE (any grade) 0.93 [0.60, 1.46]< 10%1 study (1/-)62.3 %NAnot evaluable non important-
TRAE (grade 3-4) 0.62 [0.35, 1.08]< 10%1 study (1/-)95.4 %NAnot evaluable non important-

TRAE (grade 3-4) endpoints 00

Abdominal pain TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Alopecia TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Anaemia TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Arthralgia TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Asthenia TRAE (grade 3-4) 0.50 [0.02, 14.88]< 10%1 study (1/-)65.5 %NAnot evaluable non important-
Constipation TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Cough TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Decreased appetite TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Diarrhoea TRAE (grade 3-4) 2.00 [0.18, 22.23]< 10%1 study (1/-)28.8 %NAnot evaluable non important-
Dry skin TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Fatigue TRAE (grade 3-4) 0.25 [0.01, 5.51]< 10%1 study (1/-)80.8 %NAnot evaluable non important-
Headache TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Hypersensitivity TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Hyperthyroidism TRAE (grade 3-4) 2.00 [0.07, 59.80]< 10%1 study (1/-)34.7 %NAnot evaluable non important-
Hypothyroidism TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Increase AST TRAE (grade 3-4) 1.00 [0.06, 16.02]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Increased ALT TRAE (grade 3-4) 2.00 [0.18, 22.23]< 10%1 study (1/-)28.8 %NAnot evaluable non important-
Infusion-related reactions TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Leucopenia TRAE (grade 3-4) 0.12 [0.01, 2.33]< 10%1 study (1/-)91.7 %NAnot evaluable non important-
Maculopapular rash TRAE (grade 3-4) 2.00 [0.07, 59.80]< 10%1 study (1/-)34.7 %NAnot evaluable non important-
Myalgia TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Nausea TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Neutropenia TRAE (grade 3-4) 0.05 [0.00, 0.92]< 10%1 study (1/-)97.7 %NAnot evaluable non important-
Pancytopenia TRAE (grade 3-4) 0.16 [0.01, 3.29]< 10%1 study (1/-)87.9 %NAnot evaluable non important-
Paraesthesia TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Pruritus TRAE (grade 3-4) 2.00 [0.07, 59.80]< 10%1 study (1/-)34.7 %NAnot evaluable non important-
Pyrexia TRAE (grade 3-4) 0.50 [0.02, 14.88]< 10%1 study (1/-)65.5 %NAnot evaluable non important-
Rash TRAE (grade 3-4) 2.00 [0.07, 59.80]< 10%1 study (1/-)34.7 %NAnot evaluable non important-
Thrombocytopenia TRAE (grade 3-4) 0.05 [0.00, 0.82]< 10%1 study (1/-)98.1 %NAnot evaluable non important-
Vitiligo TRAE (grade 3-4) 1.00 [0.02, 50.40]< 10%1 study (1/-)50.1 %NAnot evaluable non important-
Vomiting TRAE (grade 3-4) 1.00 [0.06, 16.02]< 10%1 study (1/-)50.1 %NAnot evaluable non important-

AE (grade 3-4) endpoints 00

Abdominal pain AE (grade 3-4) 0.98 [0.14, 7.03]< 10%1 study (1/-)50.7 %NAnot evaluable non important-
Anaemia AE (grade 3-4) 1.74 [0.50, 6.04]< 10%1 study (1/-)19.1 %NAnot evaluable non important-
Arthralgia AE (grade 3-4) 0.98 [0.02, 49.71]< 10%1 study (1/-)50.4 %NAnot evaluable non important-
Asthenia AE (grade 3-4) 1.74 [0.50, 6.04]< 10%1 study (1/-)19.1 %NAnot evaluable non important-
Constipation AE (grade 3-4) 0.98 [0.02, 49.71]< 10%1 study (1/-)50.4 %NAnot evaluable non important-
Decreased appetite AE (grade 3-4) 1.97 [0.07, 58.97]< 10%1 study (1/-)35.0 %NAnot evaluable non important-
Dermatitis acneiform AE (grade 3-4) 22.68 [1.32, 388.47]< 10%1 study (1/-)1.7 %NAnot evaluable non important-
Diarrhoea AE (grade 3-4) 4.44 [1.47, 13.42]< 10%1 study (1/-)0.4 %NAnot evaluable non important-
Fatigue AE (grade 3-4) 1.65 [0.39, 7.00]< 10%1 study (1/-)24.9 %NAnot evaluable non important-
Headache AE (grade 3-4) 1.97 [0.07, 58.97]< 10%1 study (1/-)35.0 %NAnot evaluable non important-
Hypertension AE (grade 3-4) 1.77 [0.73, 4.30]< 10%1 study (1/-)10.5 %NAnot evaluable non important-
Increase AST AE (grade 3-4) 3.00 [0.60, 15.03]< 10%1 study (1/-)9.1 %NAnot evaluable non important-
Increased ALT AE (grade 3-4) 1.99 [0.49, 8.06]< 10%1 study (1/-)16.8 %NAnot evaluable non important-
Increased Lipase Level AE (grade 3-4) 2.00 [0.59, 6.74]< 10%1 study (1/-)13.2 %NAnot evaluable non important-
Nausea AE (grade 3-4) 10.02 [0.54, 184.60]< 10%1 study (1/-)6.3 %NAnot evaluable non important-
Peripheral oedema AE (grade 3-4) 0.98 [0.06, 15.80]< 10%1 study (1/-)50.5 %NAnot evaluable non important-
Pruritus AE (grade 3-4) 0.98 [0.02, 49.71]< 10%1 study (1/-)50.4 %NAnot evaluable non important-
Pyrexia AE (grade 3-4) 6.03 [0.72, 50.50]< 10%1 study (1/-)5.0 %NAnot evaluable non important-
Rash AE (grade 3-4) 7.83 [1.77, 34.66]< 10%1 study (1/-)0.3 %NAnot evaluable non important-
Rash maculopapular AE (grade 3-4) 7.98 [0.42, 151.89]< 10%1 study (1/-)8.6 %NAnot evaluable non important-
Sepsis AE (grade 3-4) 12.08 [0.67, 217.70]< 10%1 study (1/-)4.7 %NAnot evaluable non important-
Vomiting AE (grade 3-4) 2.49 [0.48, 12.97]< 10%1 study (1/-)14.0 %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.