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Table 4 ProTarget Drugs and Acceptable Molecular Alterations

From: ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling – a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial

Drug

Acceptable Genomic Alterationsab

Excluded Genomic Alterationsc

Alectinib

EML4-ALK fusions or mutations, ROS1 fusions

None

Atezolizumab

MSI high

None

POLE mutations:

R150X, P286R, P286H, S297F, Y298fs, F367S, V411L, L424V, P436R, V437M, S459F, R573L, E597K, R665W, L698fs, R762W, R793C, K1008N, T1052M, R1111Q, L1235I, V1368M, R1519C, P1547S, R1826W, R1879C, Y1889C, S1892N, A1967V, A2213V, A2243T

POLD1 mutations:

W79L, P112fs, A930fs, N247I, R352C, Q461H, S478N, A864T, E1105D

TMB ≥10 mut/mb

Avelumab

MSI high

None

POLE mutations:

R150X, P286R, P286H, S297F, Y298fs, F367S, V411L, L424V, P436R, V437M, S459F, R573L, E597K, R665W, L698fs, R762W, R793C, K1008N, T1052M, R1111Q, L1235I, V1368M, R1519C, P1547S, R1826W, R1879C, Y1889C, S1892N, A1967V, A2213V, A2243T

POLD1 mutations:

W79L, P112fs, A930fs, N247I, R352C, Q461H, S478N, A864T, E1105D

TMB ≥10 mut/mb

Axitinib

VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT-4) GOF mutations, amplification, or overexpression

None

Erlotinib

EGFR exon 19 deletions in the region E746-E759

EGFR mutations: E709A/G/K, E884K, G719A/C/S, S768I, L858R, L861Q, L833V

Any of the following EGFR mutations: L747S, T790M, or T854A

Exon 20 insertions

Niraparib

Germline or somatic BRCA1/BRCA2 inactivating mutations

ATM/ATR mutations or deletions

HRD positive d

None

Pemigatinib

Mutations in PDGFRA, PDGFRB, or PCM1-JAK2 fusions. FGF/FGFR amplifications, mutation and fusions

None

Trastuzumab plus Pertuzumab

ERBB2 amplification, overexpression, or mutations:

G309A, G309E, S310F, D769H, D769Y, L755S, V777L, V842I, E321G, R896C

ERBB2 P780insertions

ERBB2 deletions in the region L755–T759

None

Trastuzumab emtansine

ERBB2 amplification, or overexpression, or presence of any activating ERBB2 mutations

None

Vemurafenib plus Cobimetinib

BRAF V600E/D/K/R mutations

Any mutations in MAP 2 K1, MAP 2 K2, MEK1, MEK2, NRAS

Vismodegib

PTCH1 deletion or inactivating mutations

SMO mutations: D473G/H/Y, W535L

GLI2 amplification

  1. Patients are eligible to receive one of the listed drugs if they have a non-indicated cancer harbouring a molecular alteration matching the drug
  2. MSI: micro satellite instability; TMB: tumor mutational burden; GOF: gain of function; HRD: homologous recombination deficiency
  3. aSource is FDA approved drug label, manufacturer data, [19,20,21]; Illumina Basespace Knowledge Network, QCI Precision Insight
  4. bFor any of the genes listed, alterations such as point mutations, insertions, deletions, translocations and amplifications or overexpression may be acceptable to match a drug to that gene. If a proposed drug-variant match is not accepted by the automated matching rules process, consider requesting case review by the Molecular Tumor Board
  5. cDetection of any of the alterations in this column will exclude the patient from receiving the matched drug treatment as these alterations are associated with drug resistance
  6. dHRD is evaluated from cytoscan HD (ThermoFisher) SNP array where an HRD score is calculated based on the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale transitions (LST) [22]. When WGS data are available, HRD status can be supported by mutational signatures from Cosmic [23] and CO-Regulation Database (CORD [24])