Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

IGF-2

Overexpression

60-90

Cixutumumab (IGF-1R inhibitor):

• Phase 1, with temsirolimus: Durable SD 40% (1)

Linsitinib (IGF-1R inhibitor):

• Phase 1: 1 PR and 4 SD out of 12 ACC pts (2,3)

Figitumumab (IGF-1R inhibitor):

• Phase 1: Short-term SD in 57% (4)

EGFR

Mutation/overexpression

4

Gefitinib (EGFR inhibitor):

• Phase 2: RR 0% (5)

Erlotinib (EGFR inhibitor):

• Phase 2, with gemcitabine: RR 10% (6)

BRAF

Mutation

3

Sorafenib (VEGFR/RAF inhibitor):

• Phase 2, with paclitaxel: RR 0% (7)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

IDH1

R132 mutation

20% of IHCCA

AG-120 (IDH1 inhibitor):

• Phase I trial, for IDH1R132 mutant pts: 1/20 pt had PR, 11/20 pts had SD, with the 1 PR and 5 SDs >6 mo (1)

FGFR2 fusions

FGFR2-BICC1 and several other fusions

10%-15% of IHCCA

BGJ398 (FGFR inhibitor):

• Phase 2: RR 15%, disease control rate (ORR + SD) 75%, PFS 25 wk. Among 61 pts, most had FGFR2 alterations, including translocation (n = 48), mutation (n = 8), and amplification (n = 3) (2)

BRAF

Mutation

5%

Selumetinib (MEK 1/2 inhibitor):

• Phase 2: RR 12% (3 pts had confirmed PRs, including 1 pt with unconfirmed CR) (3)

HER2/neu

Amplification

4%

Trastuzumab (anti-HER2 antibody):

• Phase 2, with pertuzumab (anti-HER2 dimerization inhibitor): 4 PRs, 3 SD >4 mo, out of 11 pts with HER2+ biliary cancer (HER2-amplified/overexpressed, n = 8; HER2-mutated, n = 3 [D277Y, S310F, and A775-G776insYVMA]) (4)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

PD-1/PD-L1

Expression not needed for activity

Variable

For second line, platinum failures:

Pembrolizumab (PD-1 inhibitor) (FDA approved):

• Phase 3: RR 21.1%, mOS 10.3 mo (1)

Nivolumab (PD-1 inhibitor) (FDA approved):

• Phase 2: RR 19.6%, mOS 8.7 mo (2)

Atezolizumab (PD-L1 inhibitor) (FDA approved):

• Phase 2: RR 15%, mOS 7.9 mo (3)

FGFR3

Mutation

20

BGJ398 (FGFR3 inhibitor):

• Phase 2: RR 36% (9/25 with FGFR3 mutation/translocation) (4)

Erdafitinib (FGFR3 inhibitor):

• Phase 1/2: RR 43.5% (10/23 with FGFR3 mutation/translocation, continuous dose), 36% (4/11 with FGFR3 mutation/translocation, intermittent dose) (5)

HRAS

Mutation

7

Lonafarnib (farnesyltransferase inhibitor):

• Phase 2: No activity in 19 pts (no selection for mutations) (6)

Tipifarnib (R115777) (farnesyltransferase inhibitor):

• Phase 2: RR 2/34 (6%) (no selection for mutations) (7)

PIK3CA

Mutation

20

GSK2126458 (GSK358) (PI3K/MTOR inhibitor):

• Phase 1: RR 1/3 with mutant PIK3CA, 2/15 with WT (8)

Everolimus (mTOR inhibitor):

• Phase 2: RR 2/45 pts. One CR had a TSC1 mutation (9,10)

MK-2206 (AKT inhibitor):

• Phase 1: No response in 1 pt (no selection for mutations) (11)

TSC1

Mutation

9

AKT1

Mutation

3

PTEN

Mutation

3

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

VEGFR

Expression

100

Bevacizumab (VEGF inhibitor):

• Phase 2 (single agent) (recurrent disease): RR 28%, PFS at 6 mo 43% (1)

• Phase 2, with irinotecan, RT: RR 38%, PFS at 6 mo 50% (1)

• Phase 2: RR 35%, PFS at 6 mo 29% (single agent and RT) (FDA approved) (2)

Sorafenib (VEGFR/PDGFR/RAS/RET inhibitor):

• Phase 1, with RT: OS 18 mo (ND), 24 mo (recurrent disease)

EGFR

Amplification/overexpression

40

Erlotinib (EGFR inhibitor):

• Phase 2, with temozolamide and RT (ND): PFS 8 mo, OS 19.3 mo (3)

Gefitinib (EGFR inhibitor):

• Phase 2, combination with RT (ND pediatric): PFS at 1 yr 21%, OS at 1 yr 57% (4)

Vandetanib (VEGFR/EGFR/RET inhibitor):

• Phase 1, with RT (ND): SD 90%, PFS 8 mo, OS 11 mo (5)

• Phase 1/2, with RT (recurrent disease): PFS 3 mo, OS 6 mo (6)

Mutation

6

PDGFR

Overexpression

Unknown

Imatinib (BCR-Abl/cKIT/PDGFR inhibitor):

• Phase 2 (advanced disease): RR 3.4%, SD 19%, OS 26 wk (with hydroxyurea) (7)

Sunitinib (VEGFR/PDGFR/RET/KIT/FLT3 inhibitor):

• Phase 2 (recurrent disease): No objective responses (8)

PTEN

Mutation/deletions

17

Temsirolimus (mTOR inhibitor):

• Phase 1, with temozolomide and RT (ND): ORR 4%, SD 96% (median follow-up of 10 mo) (9)

Everolimus (mTOR inhibitor):

• Phase 1, with temozolomide and RT (ND): ORR 6%, SD 83% (after 6 mo) (10)

PIK3CA

Mutation

5

PIK3R1

Mutation

4

MGMT

Methylation

45

• Methylation of promoter region of gene in tumors associated with superior responses to temozolomide, OS 21.7 vs. 15.3 mo (11)

TGF-β

Overexpression

Unknown

LY2157299 (TGF-β inhibitor):

• Phase 1: ORR 18% (12)

Trabedersen (AP12009, TGF-β inhibitor):

• Phase 1/2: RR 38% (13)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

Cytosine deaminase

N/A

N/A

Vocimagene amiretrorepvec (Toca511) (retroviral replicating vector):

• Phase 1, with 5-fluorocytosine: OS 13.6 mo, statistically improved relative to external control (HR 0.45, p = 0.003) (14)

POLE

Mutation

Unknown

Pembrolizumab (PD-1 inhibitor):

• Case report: Germline DNA mismatch-repair deficiency and tested positive for a POLE mutation encoding L424V substitution. Patient had evidence of a clinical and immunologic response (15)

Biallelic mismatch repair deficiency (bMMRD)

Mutation

Unknown

Nivolumab (PD-1 inhibitor):

• bMMRD is caused by homozygous germline mutations in 1 of the 4 MMR genes (PMS2, MLH1, MSH2, and MSH6) and is arguably the most penetrant cancer predisposition syndrome, with 100% of biallelic mutation carriers developing cancers in the first 2 decades of life (16)

• Durable responses of recurrent GBM to immune checkpoint inhibition (16)

IL13Rα2

Expression

Unknown

Chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2):

• Case report: After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 mo after the initiation of CAR T-cell therapy (17)

IDH1

Mutation

Unknown

AG-120 (IDH1 inhibitor):

• Phase 1: 10 out of 20 pts with IDH1 mutant-positive glioma had SD, with 4 maintained beyond 5 mo (18)

EGFR

Amplification and/or mutation

57.4%

ABT-414 (EGFR antibody drug conjugate with anti-microtubule agent monomethyl auristatin F):

• Phase I: PFS 6.1 mo (19)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

NF1/NF2

Loss

100

Everolimus (mTOR inhibitor):

• Phase 2: RR 0% (20)

EGFR

Overexpression

40

Lapatinib (EGFR/HER2 inhibitor):

• Phase 2, NF2: ORR 24% (time to response: 4.5 mo), PFS at 12 mo 64% (21)

Erlotinib (EGFR inhibitor):

• Phase 2, NF1: SD 5% (22)

VEGFR

Expression

100

Bevacizumab (VEGF inhibitor):

• Retrospective review, NF2: ORR 55% (23)

• Case study: 2 pts treated with single-agent SD of 9+ and 10+ mo, 2 pts treated with combination with temsirolimus (mTOR inhibitor) SD 4+ and 9+ mo (with 33% volumetric reduction) (24)

PDGFR

Overexpression

Unknown

Imatinib (BCR-Abl/cKIT/PDGFR):

• Phase 2, NF1: ORR 17% (26% in those treated for >6 mo) (25)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

PTCH1

Mutation (hedgehog pathway activation)

7

Vismodegib (SMO/hedgehog inhibitor):

• Phase 1, pediatric pts: ORR 33% (activated hedgehog pathway), 0% (without activation) (26)

• Phase 1, advanced disease: 1/1 PR

Erismodegib (SMO/hedgehog inhibitor):

• Phase 1, advanced disease: ORR 8% (CR) (27)

• Phase 1: 1 PR and 1 metabolic PR (activated hedgehog pathway) (28)

VEGFR

Expression

100

Bevacizumab (VEGF inhibitor):

• Phase 1, with irinotecan and temozolomide, pediatric pts: ORR 67% at 3 mo and 55% at 6 mo, PFS 11 mo, OS 13 mo (29)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

PDGFR

Overexpression

Unknown

Imatinib (BCR-Abl/cKIT/PDGFR inhibitor):

• Phase 2, with hydroxyurea: SD at 6 mo 67% (30)

EGFR

Overexpression

40

Erlotinib or gefitinib (EGFR inhibitors):

• Phase 2: PFS at 6 mo 29% (irrespective of drug) (31)

VEGFR

Expression

100

Bevacizumab (VEGF inhibitor):

• Retrospective analysis: RR 29% of tumors (duration 3.7 mo), PFS at 6 mo 93%, PFS at 12 mo 62% (32)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

ESR1

Mutation

20-30^*

• Predicts resistance to aromatase inhibitors and associated with shorter survival (1)

• Specific variants predict for lack of response to fulvestrant or everolimus (e.g., Y537S) (2,3)

Fulvestrant (estrogen receptor downregulator):

• In ESR1 mutants, PFS 5.7 vs. 2.6 mo for exemestane (4)

ERBB2 (HER2)

Mutation

2^†

• Typically exclusive with ERBB2 amplifications (5)

• Kinase domain mutations predict response to TKIs (e.g., neratinib) (6)

• Extracellular domain mutations predict for response/resistance to trastuzumab/pertuzumab (7)

Neratinib (dual HER2/EGFR inhibitor):

• Phase 2: CBR (CR/PR/SD ≥ 6 mo) 31% (8). Combination with fulvestrant in progress (9)

FGFR1

Amplification

10-15

• Associated with endocrine resistance and poor prognosis (10)

• Predicts for response to FGFR inhibitors (11,12)

PIK3CA

Mutation

30-35

• Predicts response to PI3K/Akt/mTOR inhibitors

Everolimus (mTOR inhibitor) (FDA approved):

• Phase 3: PFS 10.6 vs. 4.1 mo for placebo (13). Pts with no or one genetic alteration in CCND1, PI3K, or FGFR pathways had greater treatment effect (14)

• Phase 2, with tamoxifen: CBR 61% vs. 42% for placebo (15)

• Phase 1b, with anastrozole: CBR 27% with PI3K pathway alterations vs. 8% without alterations (16)

Buparlisib (alpha-selective PI3K inhibitor):

• Phase 3, with fulvestrant: In pts with PIK3CA mutations, PFS 4.7 vs. 1.6 mo for placebo (17)

Alpelisib (alpha-selective PI3K inhibitor):

• Phase 1b, with letrozole: CBR 44% in PIK3CA mutants vs. 20% in WT (18)

AZD5363 (AKT inhibitor):

• Phase 1b: ORR 28% in pts with AKT1 mutations (19)

PTEN

Mutation/loss

3/29

AKT1

Mutation

3-8

PIK3R1

Mutation

2

^* Variable, based on prior AI exposure. Uncommon in primary breast cancer.^† Higher prevalence in invasive lobular carcinoma (10%).

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

ERBB2 (HER2)

Amplification

20

Trastuzumab (HER2 inhibitor) (FDA approved):

• Phase 3: Single agent, first line, RR 26% (20)

• Phase 3, with chemotherapy: RR 50% vs. 32% for chemo alone, PFS 7.4 vs. 4.6 mo (21)

• Phase 3, with lapatinib, neoadjuvant: RR 51% vs. 30% with trastuzumab alone vs. 24% with lapatinib alone (22)

Lapatinib (dual HER2/EGFR inhibitor) (FDA approved):

• Phase 2: Single agent, after trastuzumab, RR 12.6% (23)

• Phase 3, with trastuzumab: PFS 11.1 vs. 8.1 mo for lapatinib (24)

• Phase 3, with capecitabine: PFS 8.4 vs. 4.1 mo for capecitabine (25)

Pertuzumab (HER2 dimerization inhibitor) (FDA approved):

• Phase 3, with trastuzumab and docetaxel: PFS 18.5 vs. 12.4 mo with trastuzumab and docetaxel, RR 80% vs. 69% (26)

• Single agent, RR 3.4% (27). With trastuzumab, RR 17.6% (27)

• Phase 3, with adjuvant trastuzumab: IDFS 7.1% vs. 8.7% for trastuzumab alone (28)

Neratinib (dual HER2/EGFR inhibitor) (FDA approved):

• Phase 3, after adjuvant trastuzumab: IDFS 94.2% vs. 91.9% with placebo (29)

T-DM1 (ado-trastuzumab emtansine) (antibody drug conjugate to HER2; trastuzumab linked with emtansine) (FDA approved):

• Phase 3: PFS 9.6 vs. 6.4 mo for lapatinib and capecitabine, RR 44% vs. 31% (30)

• Phase 3: PFS 6.2 vs. 3.3 mo for treatment of physician’s choice, third line or greater (31)

PIK3CA

Mutation

25-30

• PIK3CA mutations or PTEN loss associated with decreased response with trastuzumab (32,33)

• Decreased PFS with pertuzumab, 12.5 vs. 21.8 mo for WT (34). No difference in outcomes with T-DM1 based on PIK3CA mutations (35)

• Decreased pCR with trastuzumab and lapatinib, 28.6% vs. 53.1% for WT (36)

Everolimus (mTOR inhibitor):

• Phase 3, with trastuzumab and paclitaxel, in pts with hyperactive PI3K pathway^*, PFS 13.9 vs. 10.9 mo for placebo (37,38)

• Phase 3, with trastuzumab and vinorelbine, in pts with hyperactive PI3K pathway^*, PFS 8.1 vs. 5.6 mo for placebo (38,39)

^* PIK3CA mutations and/or PTEN loss and/or AKT1 mutation.

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

PIK3CA

Mutation

8

• Higher prevalence in metaplastic cancers ˜40% (40,41)

Temsirolimus (mTOR inhibitor):

• Phase 1, with bevacizumab and liposomal doxorubicin: RR 32% in metaplastic (40)

PTEN

Mutation/loss

35

BRCA1/2

Mutation (germ line)

5

Olaparib (PARP inhibitor) (FDA approved):

• Phase 3: PFS 7.0 vs. 4.2 mo for standard therapy in germline BRCA1/2. RR 59.9% vs. 28.8% (42)

• Phase 2: RR 20% vs. 9.5% with prior platinum (43)

Carboplatin:

• Phase 3: RR 68% vs. 28% in non-BRCA carriers (44)

• Phase 2 (carboplatin/cisplatin): RR 54.5% vs. 25.6% in non-BRCA carriers (45)

AR

Expression

12

Bicalutamide (androgen receptor inhibitor):

• Phase 2: CBR 19%, PFS 12 wk (46)

Enzalutamide (androgen receptor inhibitor):

• CBR 29% (36% in androgen signature positive vs. 7%), PFS 14 wk (47)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

PD-1/PD-L1

Overexpression

Variable

Pembrolizumab (PD-1 inhibitor):

• Phase 1: RR 18.5%, median duration of response not reached (15 to ≥ 47.3 wk), CBR (CR/PR/SD ≥ 6 mo) 25.9%. PD-L1 positivity (expression in stroma or >1% of tumor cells by IHC) (48)

• FDA approved for MSI-H or dMMR cancers (1%-2% of breast cancers) (49)

Avelumab (PD-L1 inhibitor):

• Phase 1: PR 8.8% in TNBC (44% PR in PD-L1 positive, 4/9) (50)

Atezolizumab (PD-L1 inhibitor):

• Phase 1: ORR 24% in PD-L1 positive (2+ or 3+ IHC), CR 10%, PR 14% (51)

Actionable Target

Abnormality

Prevalence (1,2)

Clinical Experience with Targeted Agent

PIK3CA

Mutation

37.5% (squamous cell)

14%-25% (adenocarcinoma)

Temsirolimus (mTOR inhibitor):

• Phase 2: RR 3%, SD 58% (3)

PTEN

Protein loss

13% (squamous cell)

3.6% (adenocarcinoma)

VEGF-A

Expression

Associated with poorer prognosis (4)

Bevacizumab (VEGF inhibitor):

• Phase 2: RR 11%, SD 24% (5)

• Retrospective analysis, with 5FU or capecitabine: RR 34%, SD 33% (6)

• Phase 3, with cisplatin/paclitaxel or topotecan/paclitaxel: RR 48% (7)

Sunitinib (VEGFR/PDGFR/RET/KIT/FLT3 inhibitor):

• Phase 2: RR 0%, SD 84% (8)

Pazopanib (VEGFR inhibitor):

• Phase 2: RR 9%, SD 24% (9)

EGFR

Overexpression

54%-71% (all histologies)

Cetuximab (EGFR inhibitor):

• Phase 2: RR 0%, SD 14% (10)

• Phase 2, with topotecan and cisplatin: Trial terminated due to toxicity (11)

• Phase 2 frontline with chemoradiation vs. chemoradiation alone: 2-yr OS 83% vs. 87% favoring chemoradiation alone (12)

• Phase 2, with carboplatin and paclitaxel vs. carboplatin/paclitaxel alone: RR 43% chemo alone vs. 38% for cetuximab arm (13)

Erlotinib (EGFR inhibitor):

• Phase 2: RR 0%, SD 16% (14)

• Phase 2 (frontline with chemoradiation): CR 94.4%, 3-yr OS 80% (15)

Gefitinib (EGFR inhibitor):

• Phase 2: RR 0%, SD 20% (16)

Matuzumab (EGFR inhibitor):

• Phase 2: RR 5%, SD 24% (17)

Lapatinib (HER2 inhibitor):

• Phase 2: RR 5%, SD 44% (9)

• Phase 1 (with cisplatin and hyperthermia): Deemed not feasible due to toxicity (18)

EGFR

Mutation

7.5% (squamous cell) 0% (adenocarcinoma)

Actionable Target

Abnormality

Prevalence (%) (1,2,20,21,22)

Clinical Experience with Targeted Agent

PDGFR

Expression

Not determined

Imatinib (PDGFR/BCR-Abl/KIT inhibitor):

• Phase 1: RR 0%, SD 8% (19)

PD-1/PD-L1

Expression

80 PD-1 (squamous cell)

17 PD-L1 (squamous cell)

38 PD-1 (adenocarcinoma)

0 PD-L1 (adenocarcinoma)

Pembrolizumab (PD-1 inhibitor):

• Phase 1b: ORR 12.5%, 6-mo OS 66.7% (23)

Microsatellite instability

6

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

BRAF

Mutation

5-8

Vemurafenib (BRAF inhibitor):

• Phase 2, with cetuximab (EGFR inhibitor) and irinotecan: PFS 4.3 vs. 2.0 mo (HR 0.48), PR 16% vs. 4%, DCR (PR + SD) 67% vs. 22% favoring the arm with vemurafenib (1)

Dabrafenib (BRAF inhibitor):

• Phase 2, with trametinib and panitumumab: RR and SD of 10% and 80% for dabrafenib + panitumumab, 0% and 53% for trametinib + panitumumab, and 18% and 67% for dabrafenib + trametinib + panitumumab (2)

Encorafenib (BRAF inhibition):

• Phase 2, with cetuximab (EGFR inhibitor) ± alpelisib (PI3Kα inhibitor): RR 27% and DCR 79% with the triplet and 22% and 78% with the doublet (3)

HER2 (ERBB2)

Amplification

2-11

Trastuzumab (HER2 inhibitor) + lapatinib (HER2 inhibitor/EGFR inhibitor):

• Phase 2: RR 30%, PR 26%, including 1 CR, SD 44%, in pts with refractory KRAS WT and HER2-amplified/overexpressed (4)

Pertuzumab (HER2 inhibitor) + Trastuzumab (HER2 inhibitor):

• Phase 2a: RR 28%, SD 39% (5)

PD-1, PD-L1

MSI-H pts

Pembrolizumab (PD-1 inhibitor) (FDA approved for pts with MSI-H or dMMR):

• Phase 2: PR 40% (4/10) vs. 0%, PFS and OS not reached vs. 2.2 and 5.0 mo, in prior treated pts with mismatch repair deficiency (6)

Nivolumab (PD-1 inhibitor) (FDA approved for pts with MSI-H or dMMR):

• Phase 2, monotherapy: RR 31%, DCR 69% in MSI-H tumors (7)

• Phase 2, + ipilimumab (CTLA4 inhibitor): PR and SD of 52.4% and 31% with combination with ipilimumab in MSI-H tumors (8)

Atezolizumab (PD-L1 inhibitor):

• Phase 1b, with bevacizumab: RR 30% and SD 60% in MSI-H pts (9)

MSS pts

Atezolizumab (PD-L1 inhibitor):

• Phase 1, with cobimetinib (MEK inhibitor): RR 17%, SD 22% in all CRC pts. RR 20%, SD 20% in mutant KRAS pts (10)

CTLA-4

Tremelimumab (CTLA-4 inhibitor):

• Phase 2, monotherapy in treatment-refractory mCRC pts: RR 2% (11)

RAS (KRAS/NRAS)

Mutation (resistance)

30-50

Cetuximab (EGFR inhibitor) (FDA approved):

• Phase 3, monotherapy: RR 13% in WT KRAS vs. 1% in mutant KRAS (codons 12/13). PFS (3.7 vs. 1.9 mo) and OS (9.5 vs. 4.8 mo) favored cetuximab compared with BSC in WT KRAS. No difference in mutant KRAS pts (12)

• Phase 3: RR 72%, PFS 10.3 mo, OS 33.1 mo in first-line setting associated with chemotherapy in WT KRAS and NRAS (13)

Panitumumab (EGFR inhibitor) (FDA approved):

• Phase 3, monotherapy: RR 16% in WT KRAS vs. 1% in mutant KRAS. In pts with WT KRS, NRAS, and BRAF, RR 18%. In pts with WT KRAS and mutations in NRAS or BRAF, RR 0% (14)

• Phase 3: PFS 10.0 vs. 8.6 mo, OS 23.9 vs. 19.7 mo with chemotherapy in KRAS WT pts on first-line setting (15)

VEGF/VEGFR

Regorafenib (VEGFR inhibitor) (FDA approved):

• Phase 3, monotherapy: OS 6.4 vs. 5.0 mo, PFS 1.9 vs. 1.7 mo. RR 1% vs. 0.4% compared with placebo (16)

Ramucirumab (VEGFR2 inhibitor) (FDA approved):

• Phase 3: OS 13.3 vs. 11.7 mo, PFS 5.7 vs. 4.5 mo, RR 13.4% vs. 12.5% in association with chemotherapy compared with placebo + chemotherapy (17)

Bevacizumab (VEGF inhibitor) (FDA approved):

• Phase 3: RR 45% vs. 35%, OS 20 vs. 16 mo; TTP 11 vs. 6.0 mo with chemotherapy in first line (18)

Aflibercept (VEGF inhibitor) (FDA approved):

• Phase 3: RR 19.8% vs. 11.1% placebo, OS 13.5 vs. 12.1 mo placebo; PFS 6.9 vs. 4.7 mo placebo with chemo in second line (19)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

EGFR

Mutation

19%

Gefitinib (EGFR TKI):

• Phase 2: OS 3.7 vs. 3.6 mo with placebo (1)

Afatinib (EGFR TKI):

• Phase 2: ORR 14.3%, DCR 73.3%, OS 6.6 mo (2)

EGFR

Overexpression

30%-90%

Panitumumab (EGFR inhibitor):

• Phase 3: Trial was stopped at interim futility analysis (3)

PI3K

Mutation

PI3KCA 13%

BKM120 (PI3K inhibitor)

• Phase 2: DCR 51.2%, mOS 9.0 mo (4)

PD-1

Overexpression

PD-L1/PD-L2

43.9% (5)

Nivolumab (PD-1 inhibitor)^*:

• Phase 2: ORR 17%, DCR 42%, mOS 10.8 mo (6)

Pembrolizumab (PD-1 inhibitor):

• Phase 1b: ORR 30% (7)

MSI-H, dMMR

Mutation

N/A

Pembrolizumab (PD-1 inhibitor) (FDA approved for pts with MSI-H or dMMR):

• PR in 1 pt, DOR range 18.2+ mo (8)

^* Asian pts.

Actionable Target

bnormality

Prevalence

Clinical Experience with Targeted Agent

EGFR

Overexpression

30%-90%

Cetuximab (EGFR inhibitor):

• Phase 3, with cisplatin/capecitabine: RR with cetuximab 51% (HER2+), 27% (HER2-), OS 10.7 vs. 9.4 mo (without cetuximab) (1)

Panitumumab (EGFR inhibitor):

• Phase 3, with epirubicin/oxaliplatin/capecitabine: OS 8.8 vs. 11.3 mo (without panitumumab) (2)

HER2

Overexpression/amplification

20%-30%

Trastuzumab (HER2 inhibitor) (FDA approved):

• Phase 3, with cisplatin/5FU/capecitabine: RR 47% (with trastuzumab), OS 13.8 vs. 11.1 mo (without trastuzumab) (3)

Lapatinib (HER2/EGFR inhibitor):

• Phase 3, with capecitabine/oxaliplatin: RR 53% (with lapatinib), OS 12.2 vs. 10.5 mo (without lapatinib) (4)

VEGFR

Overexpression

30%-60%

Bevacizumab (VEGF inhibitor):

• Phase 3, with cisplatin/capecitabine: RR 38% (with bevacizumab), OS 12.1 vs. 10.1 mo (without bevacizumab) (5)

Ramucirumab (VEGFR2 inhibitor):

• Phase 3: OS 5.2 vs. 3.8 mo (supportive care) (6)

HGF/c-MET

Overexpression

21%

Tivantinib (MET inhibitor)^*:

• Phase 2: RR 0% (unselected pts), SD 37%, PFS 43 d (7)

Foretinib (MET inhibitor):

• Phase 2: RR 0% (unselected pts), SD 23% (8)

mTOR

Overexpression

20%

Everolimus (mTOR inhibitor):

• Phase 3, with best supportive care: 5.4 vs. 4.3 mo (best supportive care only) (9)

PIK3CA

Mutation

24% (10)

PD-1/PD-L1

Overexpression

PD-L1 40% (11)

Nivolumab (PD-1 inhibitor):

• Phase 3: OS 5.3 vs. 4.1 mo with placebo^* (12)

Pembrolizumab (PD-1 inhibitor) (FDA approved after 2 lines of therapy in PD-L1 positive pts):

• Phase 2: ORR 13.3%, mOS 11.4 mo (13)

Avelumab (PD-L1 inhibitor):

• Phase 1b: ORR 9.7% (2L), 9% (1L, maintainance); DCR 29% (2L), 57.3% (1L, maintainance) (14)

CTLA-4

Overexpression

CTLA-4

Tremelimumab (CTLA-4 inhibitor):

• Phase 2: ORR 5%, TTP 2.83 mo, mOS 4.83 mo (15)

Ipilimumab (CTLA-4 inhibitor):

• Phase 2: OS 12.7 vs. 12.1 mo with BSC (16)

Nivolumab + ipilimiumab (CTLA-4 inhibitor):

• Phase 1/2: ORR and OS

Nivo 3 mg/kg Q2W: 12% and 6.2 mo

Nivo 1+Ipi 3 mg/kg Q3W: 24% and 6.9 mo

Nivo 3+Ipi 13 mg/kg Q3W: 8% and 4.8 mo (17)

MSI-H; dMMR

Mutation

4 (13)

Pembrolizumab (PD-1 inhibitor) (FDA approved):

• ORR 56%; DOR^† range 5.4+, 21.1+ mo (9)

• Phase 2: ORR 57.1%, DCR 71.4% (13)

FGFR2b

Amplification

9 (20)

FPA144 (anti-FGFR2B antibody):

• Phase 1: ORR of 22%, DCR 55.6%, DOR 15.4 wk (18)

AZD4547 (FGFR1/2/3 inhibitor):

• PFS 1.8 vs. 3.5 mo with paclitaxel (19)

Actionable Target

Abnormality

Prevalence (%)

Clinical Experience with Targeted Agent

VEGFR-2

Overexpression

30-60

Apatinib (VEGFR2 inhibitor):

• Phase 3: OS 6.5 vs. 4.7 mo with placebo^* (20)

Regorafenib (VEGFR/multikinase inhibitor):

• Phase 2: OS 5.8 vs. 4.5 mo with placebo (21)

Claudin-18.2

N/A

48 (32)

IMAB362 (anti-claudin-18.2 antibody):

Phase 2: IMAB362 + EOX OS 13.2 vs. 8.4 mo with EOX (22)

Stat3

Amplification

N/A

Napabucasin (BBI608) (Stat3 inhibitor):

• Phase Ib/II: BBI608 + paclitaxel wkly, ORR 31%, DCR 75%, mOS 39.3 wk (23)

Matrix metalloproteinase 9 (MMP9)

Overexpression

N/A

GS-5745 (MMP9 inhibitor):

• Phase 1: GS-5745 + FOLFOX, ORR 50%, DOR 9.4 mo (24)

^† For FDA approval, the major efficacy outcome measures were ORR and DOR as assessed by blinded independent central radiologists’ (BICR) review according to RECIST 1.1^* Apatinib is approved only in China

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

AR

AR positivity

86% SDC, 26% Ac NOS, 15% AcCC, 5% MEC, 5% ACC (1)

Androgen deprivation therapy (ADT):

• mPFS 3.8 mo, mOS 4 mo (2)

• Phase 2 bicalutamide (anti-androgen) with leuprorelin (GnRH agonist): ORR 42%, mPFS 8.8 mo, mOS 30.5 mo (3)

• Bicalutamide (anti-androgen) alone or with goserelin (LHRH agonist) or leuprolide (LHRH agonist): ORR 25%-50% (4)

• Bicalutamide (anti-androgen) with triptorelin (LHRH agonist): ORR 65%, PFS 12%, 5-yr OS 19% (5)

NTRK

ETV6-NTRK3 fusion

15% AcCC (6), 30% mammary analogue secretory carcinoma of salivary glands (MASC) (7)

LOXO-101/larotrectinib (NTRK inhibitor):

• Phase 1: 1 MASC pt with ETV6-NTRK3 gene fusion with confirmed PR at 4 mo (8)

• Integrated study of Ph1 adult/Ph1 pediatric/Ph2 adult/adolescent: ORR 78% across all cancers (12 salivary pts of 55 total) (9)

ACC, adenoid cystic carcinoma; AcCC, acinic cell carcinoma; Ac NOS, adenocarcinoma not otherwise specified; MEC, mucoepidermoid carcinoma; SDC, salivary duct carcinoma.

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

PD-1/PD-L1

N/A

90% (all HNSCC)

Nivolumab (anti-PD-1 antibody) (FDA approved):

• Phase 3: ORR 13.3% with nivolumab vs. 5.8% with investigator’s choice, mOS 7.5 mo with Nivo vs. 5.1 mo investigator’s choice (10)

Pembrolizumab (anti-PD-1 antibody) (FDA approved):

• Phase 1b: ORR 18% (11)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

PD-1/PD-L1

N/A

N/A

Pembrolizumab (anti-PD-1 antibody):

• Phase 2: ORR 26% (12)

Actionable Target

Abnormality

Prevalence

Clinical Experience with Targeted Agent

c-MET

Mutation (increases transcription of angiogenesis and growth factor receptors)

In addition to MET mutations, copy number gain of chromosome 7 (containing loci of both the MET receptor gene, MET, and its ligand, HGF) is common, occurring in 45%-75% of sporadic PRCC cases, and copy number alterations of MET occur in 81% of type 1 and 46% of type 2 PRCCs

Savolitinib:

• Phase 2: RR 18% of papillary RCC pts with MET-driven disease vs. 0% with MET-independent disease, PFS 6.2 vs. 1.4 mo (1)

PD-1

Nivolumab (PD-1 inhibitor) (FDA approved):

• Phase 1: RR 27% (2)

• Phase 3: OS 25.0 mo with nivolumab vs. 19.6 mo with everolimus (3)

• With ipilimumab (CTLA4 inhibitor): RR 40.4%; ongoing responses in 42.1% and 36.8% of pts in the N3I1 and N1I3 arms, respectively; 2-yr OS 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively (4)

BMS-936559 (PD-L1 inhibitor):

• Phase 1: Responses in 2/17 pts (5)

VHL

Mutation

43% (90% in sporadic cancers)

Bevacizumab (VEGF inhibitor) (FDA approved):

• Phase 3: ORR 26%-31% with IFN-α vs. 10% IFN-α alone (6,7)

Sunitinib (VEGFR/PDGFR/RET/KIT/FLT3 inhibitor) (FDA approved):

• Phase 3: ORR 47% vs. 17% with IFN-α alone, OS 26.4 vs. 21.8 mo with IFN-α alone (8)

Sorafenib (VEGFR/PDGFR/RAF/RET) (FDA approved):

• Phase 3: ORR 10%, PFS 5.5 vs. 2.8 mo with placebo (9)

Pazopanib (VEGFR/PDGFR/c-KIT) (FDA approved):

• Phase 3: ORR 30%, PFS 9.2 vs. 4.2 mo with placebo (10)

Axitinib (VEGFR/PDGFR/c-KIT) (FDA approved):

• Phase 3: PFS 6.7 vs. 4.7 with single-agent sorafenib (11)

Trebananib (TIE2 inhibitor):

• Phase 1: ORR 29% (with sorafenib), 53% (with sunitinib) (12)

PT2385 (HIF-2α antagonist):

• Phase 1: CR 2%, PR 12%, SD 52% (13)

Cediranib (VEGFR inhibitor):

• Phase 2 (first-line treatment): ORR 38%, PFS 8.9 mo, OS 28.6 mo (14)

• Phase 2 (in advanced disease): ORR 34%, PFS 12.1 vs. 2.8 mo (with placebo) (15)

Everolimus (mTOR inhibitor) (FDA approved):

• Phase 3: ORR 2%, PFS 4.9 vs. 1.9 mo with placebo (16)

Temsirolimus (mTOR inhibitor) (FDA approved):

• Phase 3: ORR 9%, PFS 5.5 vs. 3.1 mo with IFN-α (17)

Actionable Target

Abnormality

Clinical Experience with Targeted Agent

FLT3

Internal tandem duplication (ITD)

Sorafenib (VEGFR inhibitor):

• Compassionate use, monotherapy: Median time from allo-SCT to relapse = 192 d (1)

• Phase 2, with idarubicin + cytarabine: CR 92%, CR with incomplete platelet recovery (CRp) 8% (2)

• Phase 2, with azacytidine: CR 16%, PR 3%, CR with incomplete count recovery (CRi) 27%; median duration of CR/CRi 2.3 mo (3)

Midostaurin (PKC-α/VEGFR2/c-KIT/PDGFR/FLT3 inhibitor):

• Phase 3, 7 + 3 ±midostaurin in pts with FLT3 mutated AML: CR rates similar (59% [mido] vs. 54%), but significant improvement in OS (p = 0.007) and EFS (p = 0.004) with midostaurin (4)

Quizartinib (FLT3 inhibitor):

• Phase 2: ≥18 yr: CR 46%, mOS 22.9 wk (in FLT3-ITD positive) (5); ≥ 60 yr: CR 50% (in FLT3-ITD positive) (6)

Gilteritinib (FLT3/AXL/ALK inhibitor):

• Phase 1/2, monotherapy in R/R AML: ORR 49% in FLT3 mutated and 12% in WT FLT3 (7)

PML-RARα

t(15;17)

All-trans retinoic acid (ATRA):

• Pilot study, with idarubicin: CR 90% (8)

• Phase 3, with arsenic trioxide (ATO), in pts with low-to-intermediate risk APL: CR 100%, at 2 yr, disease-free survival rate 97%; cumulative incidence of relapse 1%; EFS 97% (9)

NPM-RARα

t(5;17)

PLZF-RARα

t(11;17)

MEK

RAS activating mutation

Trametinib (MEK inhibitor):

• Phase 1/2: CR or CRp 12%, PR 2%; hematologic improvement 7% (10)

Cytogenetics

Inv(16), t(8;21)

Gemtuzumab ozogamicin (anti-CD33 antibody) + FLAG:

• Phase 1: CR/CRp 96%, relapse-free survival at 34 mo 83% (11)

IDH1

Mutation

AG-120 (IDH1 inhibitor):

• Phase 1/2 study as monotherapy in R/R AML: ORR 33%, CR 15.5%, CRi/CRp 15.5%, PR 2%; 60 d mortality 21%; mDOR 10.2 mo (12)

IDH305 (IDH1 inhibitor):

• Phase 1, as monotherapy in R/R AML/MDS: ORR 33%, CR or CRi 14.3%, PR 19% (13)

IDH2

Mutation

AG221 (IDH2 inhibitor):

• Phase 1/2, as monotherapy in R/R AML: ORR 41%, CR 26%, PR 15% (14)

BCL2

Overexpression

Venetoclax (BCL-2 inhibitor):

• Phase 2: As monotherapy in R/R AML: ORR 19%, additional 19% with PR and incomplete hematologic recovery. 33% CR rates in IDH-mutated AML (15)

• Phase 1b with azacytidine/decitabine in treatment naïve AML >65 yr: ORR 75% (venetoclax 400 mg), 80% (venetoclax 800 mg) (16)

• Phase 1, with low-dose cytarabine in treatment naïve AML >65 yr: CR or CRi 54%, 60 d mortality 15% (17)

MDM2

Overexpression

RG7112 (MDM2 inhibitor):

• Phase 1, as single agent in R/R AML: ORR 23%, CR with or without complete count recovery 10%, PR 13% (18)

CD33

Expression

SGN-33A (anti-CD33 antibody):

• Phase 1, single agent in treatment naïve AML: CR/CRi rates 60% (19)

• Phase 1/2, with azacytidine/decitabine in treatment naïve AML: CR/CRi rates 65%; mOS not reached for median of 13.5+ wk (20)

• Phase 1, with cytarabine and daunorubicin in ND AML: CR/CRi 76%; mOS in MRD negative CR/CRi pts, not reached (21)

Actionable Target

Type

Prevalence (%)

Clinical Experience with Targeted Agent

CD19

Precursor B cell

80

Blinatumomab (CD3-CD19 bispecific monoclonal antibody):

• Phase 2 in pts with R/R B-ALL: CR/CRh rate of 43%, median RFS 5.9 mo (22)

• Phase 3, blinatumomab vs. chemotherapy in R/R AML: Blinatumomab superior in complete remission rates (34% vs. 16%; p < 0.001) and OS (7.7 vs. 4.0 mo; p = 0.01) (23)

CD19

Precursor B cell

80

Tisagenlecleucel (murine anti-CD19 CAR T-cell therapy):

• Phase 2, single-arm ELIANA trial in pts with R/R B-ALL: Overall remission rates 82.5%; RFS 75% and 64% at 6 and 12 mo; OS 89% and 79% at 6 and 12 mo (pivotal Phase II global ELIANA trial)

CD20

Precursor B cell

40-50

Rituximab (CD20 monoclonal antibody):

• Phase 2, with hyper-CVAD: CR 96%, CR duration 70% at 3 yr, OS 75% at 3 yr (24)

Ofatumumab (CD20 monoclonal antibody):

• Phase 2, with hyper-CVAD: CR 94%, CR duration 100% at 1 yr, OS 95% at 1 yr (25)

CD22

Precursor B cell

>90

Inotuzumab ozogamicin (toxin conjugated CD22 monoclonal antibody):

• Phase 3 InO vs. standard salvage in pts with R/R B-ALL: Significantly higher CR rate (81% vs. 29%, p < 0.001); MRD rate (78% vs. 28%, p < 0.001); PFS (5 vs. 1.8 mo, p < 0.001); and OS (7.7 vs. 6.7 mo; p = 0.04) (26)

• Phase 2: ORR 58%, CR rate 19%, CR with no platelet recovery 30%, bone marrow CR with no recovery of counts 9%, mOS 6.2 mo, median remission duration 7 mo (27)

CRh, complete response with partial hematologic recovery.