Table 2 Detailed characteristics of the included studies

Aguiar 2017 [19]

To assess cost-effectiveness of immune checkpoint inhibitor with and without the use of PD-L1 testing for patient selection.

PD-L1 expression.

Immunotherapy (Nivolumab, Pembrolizumab,

Atezolizumab)

3 strategies compared:

Treat-all with docetaxel.

Treat-all with immunotherapy.

Test-treat (if PD-L1 expressed with 1% or more, patients were treated with immunotherapy; if not, treated with docetaxel.)

PD-L1 testing cost.

PD-L1 expression cut-off points (PD-L1 > 1% used in base-case analysis, while 5, 10and 50% tested in sensitivity analysis.)

USA

Third-party payer (Medicare) .

Decision- analytic model. (No further details given.)

5-year horizon

QALY

No funding declared.

Bhadhuri 2019 [20]

To evaluate the cost-effectiveness of pembrolizumab monotherapy compared with chemotherapy for metastatic NSCLC with PD-L1 tumour progression score (TPS) > = 50%.

PD-L1 expression.

Pembrolizumab.

2 strategies compared on pre-specified patients expressing high levels of PD-L1:

Treat-all with pembrolizumab.

Treat-all with chemotherapy.

However, a secondary analysis was also performed using a ‘test-treat’ strategy where patients tested for PD-L1 expression and treated with pembrolizumab if the test determined PD-L1 TPS > = 50%.

PD-L1 testing cost.

Switerzland

Third-party payer.

Partitioned survival model.

20-year horizon.

(tested for 5, 10, 30 years).

QALY

Commerical funding.

Chouaid 2017 [21]

To assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs.

EGFR mutation.

Afatinib, Gefitinib.

2 strategies compared on pre-specified patients:

Treated with afatinib.

Treated with gefitinib.

EGFR testing cost.

France

Third-party payer.

Partitioned survival model.

10-year horizon.

QALY

Commercial funding.

Curl 2014 [22]

To compare three strategies (dacarbazine, vemurafenib, vemurafenib plus ipilimumab) for patients with BRAF positive metastatic melanoma.

BRAF mutation.

Dacarbazine, Vemurafenib, Vemurafenib plus Ipilimumab

3 strategies compared on pre-specified patients:

Treated with dacarbazine.

Treated with vemurafenib.

Treated with vemurafenib plus ipilimumab.

BRAF testing cost (Cobas®)

USA

Third-party payer (Medicare).

Decision tree model.

Lifetime

QALY

No funding.

Dottino 2019 [23]

To determine the cost-effectiveness of a poly (ADP-ribose) polymerase (PARP) inhibitor for the maintenance treatment of recurrent ovarian cancer.

BRCA mutation.

Niraparib.

4 maintenance strategies compared:

Observation (no treatment).

Test-treat with gBRAC testing.

Test-treat with BRAC plus HRD (homologuous recombination deficiency) testing.

Treat-all with PARP inhibitor/niraparib.

gBRCA testing cost.

Prevalence of gBRAC mutations.

USA.

Third-party payer (Medicare)

Decision analysis model.

24 months (trial period).

Progression-free QALY

Grant funding.

Ewara 2014 [24]

To assess the cost-effectiveness of three strategies (bevacizumab plus FOLFIRI, cetuximab plus FOLFIRI, panitumumab plus FOLFIRI) for mCRC patients with KRAS WT.

KRAS mutation.

Bevacizumab, Cetuximab, Panitumumab.

3 strategies compared on pre-specified patients:

Treated with bevacizumab plus FOLFIRI.

Treated with cetuximab plus FOLFIRI.

Treated with panitumumab plus FOLFIRI.

KRAS testing cost.

Canada

Third-party payer.

Markov model

100-month horizon.

QALY

No funding.

Genuino 2019 [25]

To assess the cost-effectiveness and budget impact of adjuvant trastuzumab therapy for HER2-positive early-stage breast cancer.

HER2 expression.

Trastuzumab.

2 strategies were compared on pre-specified patients with HER2-positive:

Treat all with trastuzumab and chemotherapy.

Treat all with chemotherapy only.

Percentage of HER2-positivity of breast cancer in the Philippines.

Philippines.

HCS and societal perspective.

Markov model.

Lifetime.

QALY

No funding.

Graham 2014 [26]

To assess the cost-effectiveness of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6.

RAS mutation.

Panitumumab, Bevacizumab.

2 strategies compared on pre-specified patients:

Treated with panitumumab plus mFOLFOX6.

Treated with bevacizumab pus mFOLFOX6.

KRAS and RAS testing cost.

RAS frequency.

USA

Third-party payer.

Semi-Markov model.

Lifetime

QALY

Commercial funding.

Graham 2016 [27]

To assess the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with WT KRAS mCRC.

KRAS mutation.

Cetuximab, Panitumumab.

2 strategies compared on pre-specified patients:

Treated with cetuximab.

Treated with panitumumab.

KRAS testing cost.

USA

Third-party payer.

Semi-Markov model.

Lifetime

QALY

Commercial funding.

Harty 2018 [28]

To investigate the clinical effectiveness and cost-effectiveness of panitumumab plus chemotherapy and cetuximab plus chemotherapy for rat scarcoma (RAS) wild-type (WT) patients for the first-line treatment of mCRC.

KRAS/RAS mutation.

Cetuximab.

2 strategies compared on patients expressing EGFR:

Treated with FOLFIRI alone.

Treated with cetuximab plus FOLFIRI.

EGFR testing cost.

RAS testing cost.

Sensitivity/specificity not considered but all patients were presumed to be correctly stratified because these biomarker testing techniques have high technical accuracy.

UK

Third-party payer.

Markov model.

10-year horizon.

QALY

Commercial funding.

Holleman 2020 [29]

To compare the cost-effectiveness of first line gefitinib, erlotinib, afatinib, and osimertinib in patients with EGFR-mutated NSCLC.

EGFR mutation.

Gefitinib, Erlotinib, Afatinib, Osimertinib.

4 strategies were compared on pre-specified patients with EGFR-positive:

Treat all with gefitinib.

Treat all with erlotinib.

Treat all with afatinib.

Treat all with osimertinib.

EGFR mutation testing cost.

Frequency of EGFR mutations in Dutch patients with NSCLC (11%) was mentioned but unclear if it was incorporated in the model.

Netherlands

Societal perspective.

Markov model.

Lifetime.

QALY.

No funding.

Huxley 2017 [30, 31]

To investigate the clinical effectiveness and cost-effectiveness of panitumumab plus chemotherapy and cetuximab plus chemotherapy for rat scarcoma (RAS) wild-type (WT) patients for the first-line treatment of mCRC.

RAS mutation.

Cetuximab, Panitumumab.

5 strategies compared on pre-specified patients:

Treated with FOLFOX/FOLFIRI.

Treated with cetuximab plus FOLFOX/FOLFIRI.

Treated with panitumumab plus FOLFOX.

RAS testing cost.

RAS prevalence (50% of patients assumed to be RAS wild-type).

UK

Third-party payer.

Markov model.

30-year horizon.

QALY

Governmental funding.

Janmaat 2016 [32]

To determine the ICER of adding cetuximab to first-line chemotherapeutic treatment of patients with advanced esophageal squamous cell carcinoma (ESCC), based on RCT II trial.

EGFR expression.

Cetuximab.

2 strategies compared on pre-specified patients expressing EGFR:

Treated with cetuximab plus cisplatin-5-fluorouracil.

Treated with cisplatin-5-fluorouracil.

EGFR testing cost.

EGFR prevalence (60% patients assumed to be EGFR positive).

Netherlands

Third-party payer.

Monte Carlo simulation using individual patient data.

0.9 years.

QALY

No funding.

Lim 2016 [33]

To evaluate the cost-effectiveness of treating patients guided by EGFR testing compared to no-testing (which is current practice in South Korea).

EGFR expression.

Erlotinib.

2 strategies compared:

Test-treat (if EGFR positive, treated with erlotinib; if EGFR wild-type, treated with conventional chemotherapy; if unknown, re-biopsy required).

No-testing (Treat all with conventional chemotherapy).

EGFR testing cost (Therascreen®, Cobas®).

Testing accuracy (sensitivity/specificity).

South Korea.

Third-party payer.

Markov model.

5-year horizon.

QALY

Governmental funding.

Lu 2016

[8]

To examine the economic outcome of three techniques for testing ALK gene rearrangement combining with crizotinib (first-line), compared with traditional regimen.

ALK gene rearrangement.

Crizotinib.

3 ALK rearrangement testing techniques prior to crizotinib were compared (4 strategies compared):

No gene screening - all treated with standard chemotherapy.

Ventana IHC - if ALK rearrangement positive, treated with crizotinib; if ALK rearrangement negative, treated with standard chemotherapy.

qRT-PCR - if ALK rearrangement positive, treated with crizotinib; if ALK rearrangement negative, treated with standard chemotherapy

Conventional IHC - if IHC ALK rearrangement negative, treated with standard chemotherapy; if IHC ALK rearrangement positive, FISH testing (to confirm) to be performed and then, if FISH ALK rearrangement negative, treated with standard chemotherapy, if FISH ALK rearrangement positive, treated with crizotinib.

Cost of ALK rearrangement testing (Ventana IHC; IHC; qRT-PCR; FISH)

Sensitivity and specificity respectively for Ventana IHC; IHC; qRT-PCR).

ALK prevalence

China

Third-party payer.

Markov model.

10-year horizon.

QALY

Commercial funding.

Lu 2018

[34]

To evaluate the cost-effectiveness of ALK tests (two genes-guided testing) followed by crizotinib for advanced NSCLC compared to standard chemotherapy.

ALK rearrangement.

Crizotinib.

3 strategies compared:

No gene screening - all treated with standard chemotherapy.

NGS panel tests - if ALK rearrangement positive, treated with crizotinib; if ALK rearrangement negative, treated with standard chemotherapy.

Multiplex PCR testing - if ALK positive, treated with crizotinib; if negative, treated with standard chemotherapy.

ALK prevalence.

Cost of ALK rearrangement testing (NGS, Multiplex PCR).

Sensitivity and specificity (NGS panel tests assumed to be 100%; multiplex PCR testing obtained from a published literature).

China

Third- party payer.

Markov model.

10-year horizon.

QALY

Commercial funding.

Morgan 2017

To assess the cost-effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell-lung cancer (NSCLC).

ALK expression.

Crizotinib.

2 strategies compared on pre-specified patients with ALK-positive NSCLC:

Treat all with crizotinib.

Treat all with pemetrexed chemotherapy in combination with cisplatin or carboplatin.

ALK testing cost

ImmunoHistoChemistry (IHC) testing cost

Fluorescence in situ hybridisation (FISH) testing cost

UK

Third-party payer.

‘area-under-the curve’ Markov model.

15-year horizon

QALY

Governmental funding.

Saito 2017

To determine the cost-effectiveness of comprehensive molecular profiling before initiating anti-EGFR therapies in mCRC.

RAS mutation.

Comprehensive profiling that includes PTEN + ERBB2, PTEN + SRC, and BRAF + RNF43 mutations (CancerPlex®).

Bevacizumab, Panitumumab.

3 strategies compared:

No testing

RAS screening

Comprehensive screening

Biomarker testing cost.

Proportion of molecular subgroups (proportion of patients per biomarker status).

Japan

Third-party payer.

Markov model

5-year horizon.

QALY

Unclear (Not reported)

Wen 2015

To explore the costs and effectiveness of RAS screening before monoclonal antibodies in mCRC based on FIRE-3 study.

RAS mutation.

Cetuximab, Bevacizumab.

Four strategies compared on pre-specified patients (FIRE3 trial patients with KRAS wild type status):

KRAS tested - treated with cetuximab and FOLFIRI.

RAS tested - treated with cetuximab and FOLFIRI.

KRAS tested - treated with bevacizumab and FOLFIRI.

RAS tested - treated with bevacizumab and FOLFIRI.

KRAS/RAS testing cost.

China

Third-party payer.

Markov model.

10-year horizon.

QALY

No funding.

Westwood 2014

To compare the performance and cost-effectiveness of KRAS mutation tests in differentiating adults with mCRC who may benefit from first-line treatment of cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone.

KRAS mutation.

Cetuximab.

10 different tests for KRAS mutation status. No comparator approach taken.

Cobas KRAS Mutation Test Kit (Roche Molecular Systems).

Therascreen KRAS RGQ PCR Kit (QIAGEN).

Therascreen KRAS Pyro Kit (QIAGEN).

KRAS LightMix Kit (TIB MOLBIOL).

KRAS StripAssay (ViennaLab).

HRM analysis.

Pyrosequencing.

MALDI-TOF mass spectrometry.

Next-generation sequencing.

Sanger sequencing.

KRAS testing cost.

KRAS testing accuracy (sensitivity/specificity)

KRAS prevalence (KRAS mutant, KRAS wild-type, KRAS unknown test result).

Timing of the test – justifications given.

UK

Third-party payer.

Markov model

Lifetime (23 years)

QALY

Governmental funding.

Wu 2017

To evaluate the economic outcome of adding cetuximab to the standard chemotherapy.

RAS mutation.

Cetuximab.

2 strategies compared:

No testing – treat all with FLOFIRI.

Test-treat (if RAS wild-type, treated with cetuximab plus FOLFIRI, if RAS mutant, treated with FOLFIRI).

RAS testing cost.

RAS prevalence.

China

Third-party payer.

Markov model.

Lifetime

QALY

No funding.

Zhou 2016

To evaluate the cost-effectiveness of predictive testing for extended RAS WT status in the context of targeting the use of cetuximab/bevacizumab.

RAS mutation.

Cetuximab, Bevacizumab.

4 strategies compared on pre-specified patients (CALGB 80405 trial patients with KRAS wild type status):

KRAS WT tested-treated with cetuximab plus chemotherapy.

KRAS WT tested-treated with bevacizumab plus chemotherapy.

RAS WT tested-treated with cetuximab plus chemotherapy.

RAS WT tested-treated with bevacizumab plus chemotherapy.

KRAS/RAS testing cost.

China

Societal perspective.

Markov model.

Lifetime

QALY

No funding.