Biomarker-Driven Targeted Therapies in Solid Tumor Malignancies

JHOP - April 2021 Vol 11, No 2 - Review Article, Biomarkers, Targeted Therapies
Hanjie Mo, PharmD, BCOP; Catherine Renna, PharmD, BCOP
Dr Mo is Hematology/Oncology Clinical Pharmacy Specialist, and Dr Renna is Hematology/Oncology Clinical Pharmacy Specialist, Department of Pharmacy, Cleveland Clinic, Cleveland, OH.
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BACKGROUND: The discovery of actionable biomarkers in solid tumor malignancies continue to expand rapidly. Predictive biomarkers, including somatic and germline mutations, are used to determine the probability of a response to specific therapies and can guide the selection of best treatment to optimize patients’ survival and quality of life.

OBJECTIVE: To review the information related to US Food and Drug Administration (FDA)-approved targeted therapies and indications based on predictive biomarkers in solid tumor malignancies, through December 1, 2020.

DISCUSSION: In the past few decades, many targetable biomarkers for malignant tumors have been uncovered, which enabled the development of many targeted therapies that have now been approved by the FDA for the treatment of various types of solid tumor malignancies associated with specific gene mutations, translocations, and other gene rearrangements. This article provides a quick overview of the targeted therapies that have been approved by the FDA through December 1, 2020, and are currently available for the treatment of patients with various solid tumor cancers in the United States.

CONCLUSION: Testing for targetable biomarkers is critically important to guide the choice of best available treatment options. Targeted therapies that are driven by predictive biomarkers will continue to expand and provide new options for patients with cancer, with the goal of improving patient outcomes and treatment safety.

Key Words: biomarkers, genetic mutations, genetic testing, predictive biomarkers, targeted therapies

J Hematol Oncol Pharm.
Disclosures at end of text

The discovery of predictive biomarkers in the development of targeted therapies has revolutionized cancer treatment. A predictive biomarker is a measure characteristic that provides information on the probability of response to specific therapies. Predictive biomarkers include various germline or somatic mutations, gene rearrangements, proteins, and other molecules, and may be detected through a US Food and Drug Administration (FDA)-approved companion diagnostic test or another method. Using predictive biomarkers to guide therapeutic decisions is necessary to optimize patient outcomes; predictive biomarkers are an essential component of clinical practice guidelines.1,2

By contrast, prognostic biomarkers influence patient survival or disease recurrence outcomes, regardless of any therapeutic intervention. Some prognostic biomarkers are also predictive biomarkers, but this review is focused exclusively on predictive biomarkers.

The goal of this review article is to describe the current FDA-approved targeted therapies and their indications in solid tumor malignancies through December 1, 2020, based on predictive biomarkers (Table).


ALK Inhibitors

Anaplastic lymphoma kinase (ALK) gene alterations were first discovered in anaplastic large-cell lymphoma.3 ALK gene rearrangements, also known as ALK fusions, are usually an inversion on chromosome 2 that creates ALK oncogenic fusion proteins, which lead to increased tumor proliferation.4 In 2007, ALK alterations were discovered for the first time in a solid tumor malignancy, namely, non–small-cell lung cancer (NSCLC), which led to significant advances in the treatment of NSCLC in the metastatic setting.4

Alectinib, crizotinib, ceritinib, brigatinib, and lorlatinib all inhibit the phosphorylation of ALK, which decreases tumor-cell growth in ALK-positive tumors.3 Crizotinib, a first-generation ALK inhibitor, has poor central nervous system penetration compared with later-generation ALK inhibitors. All the ALK inhibitors may be used for the treatment of ALK-positive metastatic NSCLC; ALK mutations occur in 3% to 5% of patients with NSCLC and are usually associated with being a nonsmoker and adenocarcinoma histology.3

The side effects associated with ALK inhibitors include bradycardia, gastrointestinal (GI) toxicity, visual disturbances, and pulmonary adverse events.5

ALK tyrosine inhibitors have been shown to improve overall survival, progression-free survival, and quality of life in patients with metastatic NSCLC.6-8

BRAF Inhibitors

The mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway plays an essential role in cell proliferation.9 Alterations in the MAPK/ERK pathway, such as activating mutations in receptor tyrosine kinase (RTK) or mutations in the kinase rapidly accelerating fibrosarcoma (RAF), can lead to cancer-cell growth.9

BRAF is a kinase that activates the MAPK/ERK-signaling pathway. Mutations in BRAF can lead to uncontrolled cell proliferation, which is seen in approximately 40% to 60% of patients with cutaneous melanoma.10 The most common BRAF mutations are BRAF V600E (80%) and BRAF V600K (10%-30%).10,11

BRAF inhibitors (ie, dabrafenib, encorafenib, and vemurafenib) are frequently used in combination with mitogen-activated protein kinase (MEK) inhibitors (ie, trametinib, binimetinib, and cobimetinib). MEK is another protein downstream of BRAF, and the inhibition of these 2 targets has been shown to improve overall survival and progression-free survival compared with monotherapy BRAF inhibition; for example, the use of dabrafenib monotherapy versus dabrafenib plus trametinib; encorafenib monotherapy versus encorafenib plus binimetinib12; and vemurafenib monotherapy versus vemurafenib plus cobimetinib.13

The combination of dabrafenib and trametinib is FDA-approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation, as well as for the treatment of metastatic NSCLC with BRAF V600E mutation or locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation.

Encorafenib plus binimetinib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation; encorafenib is also approved in combination with cetuximab for the treatment of metastatic colorectal cancer (CRC) with BRAF V600E mutation.

Patients with metastatic CRC and BRAF V600E mutation are unlikely to respond to the epidermal growth factor receptor (EGFR) cetuximab without the addition of a BRAF inhibitor.14 BRAF is downstream of EGFR; thus, the lack of BRAF inhibition bypasses EGFR inhibition through the constitutive activation of BRAF mutation, which leads to continued tumor growth.14 By contrast, the combination of cobimetinib plus vemurafenib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation.

The drug class–related side effects of BRAF inhibitors, with or without MEK inhibitors, include dermatologic adverse events, fevers, secondary cutaneous malignancies, hemorrhage, cardiomyopathy, and ocular toxicities.15

Other than cutaneous melanoma, BRAF mutations also occur in anaplastic thyroid cancer (20%-50%), colon cancer (5%-15%), and NSCLC (3.5%-4%), among other tumor types.16-18

BRCA1 and BRCA2 Mutations

BRCA1 and BRCA2 are tumor-suppressor genes that help to repair breaks in DNA. Mutations in these genes lead to uncontrolled cell proliferation. BRCA1 and BRCA2 mutations can be germline or somatic, and poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in treating various germline BRCA1 and BRCA2 mutation–positive solid-tumor malignancies.19

PARP enzymes are involved in DNA repair and DNA transcription. PARP inhibitors are particularly active in tumors with BRCA1 or BRCA2 mutations, because these tumors lack the ability to repair DNA strand breaks as a result of a deficiency in homologous recombination repair (HRR).20

PARP inhibitors are approved for the treatment of ovarian, breast, pancreatic, and prostate cancers. The incidence rates of BRCA1 or BRCA2 mutations in these tumor types are 5% to 15%, approximately 5%, 4% to 7%, and 0.9% to 5.3%, respectively.20-25 The PARP inhibitors class includes olaparib, talazoparib, niraparib, and rucaparib, and the PARP inhibitor class side effects include bone marrow suppression, fatigue, rash, GI toxicities, and secondary malignancies.26

Estrogen and Progesterone Receptors

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common (87%) female breast cancer subtype.27 Patients are considered to have HR-positive disease if estrogen receptor (ER) or progesterone receptor (PR) is expressed in 1% to 100% of the cells evaluated.28

The use of endocrine therapies is the standard of care for the treatment or prevention of recurrent HR-positive breast cancer because these therapies have shown to improve overall survival or disease-free survival. Limited data are available to support the benefits of endocrine therapy in ER-low–positive (1%-10% expression) and ER-negative, PR-positive breast cancer than in ER-positive (>10% expression) breast cancer.28

The use of a specific endocrine therapy depends on several factors, including patient age, menopause status, tolerability, and survival benefit.29 Patients may be receiving selective ER modulators, such as tamoxifen and/or aromatase inhibitors, for up to 10 years. Tamoxifen inhibits ERs on breast cancer tumor cells, resulting in decreased cell proliferation.29 By contrast, aromatase inhibitors, such as letrozole, anastrozole, or exemestane, ultimately prevent the generation of estrogens.30 Selective ER modulators and aromatase inhibitors may lead to hot flashes, mood changes, bone mineral density changes, and cardiovascular complications.29

Patients with ER- or PR-positive and HER2-negative breast cancer may be candidates for treatment with cyclin-dependent kinase (CDK)4/6 inhibitors. CDK4/6 inhibitors block CDK4 and CDK6 from binding to cyclin D1 and subsequently preventing retinoblastoma protein phosphorylation and gene transcription.31

Cyclin D1 is more frequently overexpressed and amplified in ER-positive breast cancer compared with ER-negative breast cancer.32 It has been shown that ER-positive breast cancer, regardless of HER2 status, is the most sensitive breast cancer subtype to CDK4/6 inhibition.31,32

The use of CDK4/6 inhibitors (ie, palbociclib, ribociclib, or abemaciclib) with endocrine therapy is currently the preferred first-line regimen in patients with advanced or metastatic HR-positive, HER2-negative breast cancer, because this combination has been shown to improve overall survival.28,33-35

The drug-class adverse events for CDK4/6 include bone marrow suppression, GI toxicities, corrected QT prolongation (ie, ribociclib), and rarely pulmonary side effects.36

EGFR Inhibitors

EGFR is an RTK located on the epithelial cells and is amplified in a variety of malignancies. EGFR mutations lead to constitutive activation and cancer growth. Therefore, multiple EGFR inhibitors have been developed to hinder this signaling process. Approximately 50% of Asian patients and 10% of Caucasian patients with NSCLC have disease associated with EGFR mutations.37 Treatment with oral EGFR inhibitors, including erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib, in patients with EGFR-positive NSCLC has been shown to improve overall survival and/or progression-free survival.38

Specific EGFR mutations, such as exon 20 insertions and T790M, lead to resistance to most EGFR inhibitors, except osimertinib, which has been shown effective in these patients.6,38,39 In addition, osimertinib and dacomitinib are FDA-approved for the treatment of patients with metastatic NSCLC and EGFR exon 19 deletion or exon 21 L858R substitution mutation.

The drug-class adverse events include GI side effects, cardiotoxicity, rashes, ocular side effects, and pulmonary side effects.40

FGFR Inhibitors

Fibroblast growth factor receptor (FGFR) is a transmembrane and is part of the RTK family. When the kinase is bound by its ligand, fibroblast growth factor, the downstream activation of RAS/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways occur.41

Genetic alterations and dysregulation in FGFR can lead to tumor-cell proliferation.41

Several mechanisms may cause excessive FGFR signaling, including upregulated FGFR or FGFR expression, mutations, or chromosomal rearrangements in the genes encoding FGFR, impaired termination of FGFR signaling, or defective degradation of FGFR.41

FGFR genetic alterations occur in approximately 21% of patients with bladder cancer and in approximately 15% to 20% of patients with cholangiocarcinoma.42-44

Two FGFR inhibitors were approved by the FDA by December 1, 2020. Erdafitinib is a pan-FGFR1-4 tyrosine kinase inhibitor that is approved for the treatment of urothelial carcinoma with FGFR2 or FGFR3 gene alterations, whereas pemigatinib is an FGFR kinase inhibitor approved for the treatment of cholangiocarcinoma that expresses FGFR2 fusions or rearrangements.

The adverse events associated with FGFR inhibitors include hyperphosphatemia and ocular adverse events.45

Homologous Recombination Deficiency/Homologous Recombination Repair

Patients with homologous recombination deficiency (HRD)-positive status (which involves a deleterious or suspected deleterious BRCA mutation or genomic instability) have a decreased ability to conduct normal DNA repair, which makes the tumor more susceptible to PARP inhibition.46 PARP inhibitors, such as olaparib and niraparib, are also effective (in addition to targeting BRCA mutations) for the treatment of patients with genomic instability. Therefore, patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer and HRD-positive status are eligible for treatment with olaparib plus bevacizumab or with niraparib monotherapy.46,47

Based on the PAOLA-1 clinical trial evaluating olaparib, HRD scores of at least 42 are considered positive results.46 Olaparib is FDA approved for the treatment of metastatic castration-resistant prostate cancer in patients with germline or somatic HRR gene mutations after receiving enzalutamide or abiraterone treatment, based on the results of the PROfound clinical trial.48

The 15 HRR gene mutations in the PROfound clinical trial included ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. Gene mutations that affect DNA damage repair, such as those listed above, can occur in up to 30% of patients with prostate cancer.48 HRR gene mutations are involved in DNA repair, and PARP inhibitors work synergistically, by disrupting tumor-cell repair.48

HER2 Inhibitors

HER2 is a transmembrane RTK that belongs to the EGFR family and functions by stimulating growth factor–signaling pathways, such as the PI3K/Akt pathway.49 The overexpression of HER2 leads to the constitutive activation of this pathway and subsequent cell proliferation.49 Thus, the inhibition of HER2 mutation leads to antitumor activity via decreased downstream cell-proliferation signaling.49 In 1998, trastuzumab was the first anti-HER2 monoclonal antibody to be approved by the FDA for the treatment of solid tumors.50 Trastuzumab is routinely used for the treatment of HER2-expressing cancers and is most frequently seen in breast cancer, gastric cancer, and esophageal or esophagogastric junction cancers, based on its benefits in overall and/or progression-free survival.28,51,52

In addition to trastuzumab, many anti-HER2 agents have been approved by the FDA, but only in the breast cancer setting. These agents include pertuzumab, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, lapatinib, neratinib, and tucatinib. The various anti-HER2 agents may differ in specific binding location (eg, intracellular, extracellular, and particular epitopes).

Cardiomyopathy, such as decreased left-ventricular ejection fraction, infusion reactions, and pulmonary adverse events are important monitoring points for most anti-HER2 therapies, especially intravenous agents. Although associated with intravenous agents, diarrhea and hepatotoxicity may occur more often with oral anti-HER2 agents, such as neratinib and lapatinib.53 In addition, ado-trastuzumab emtansine and fam-trastuzumab deruxtecan are antibody–drug conjugates that bind HER2, but they ultimately release a cytotoxic component (ie, DM1 and DXd, respectively), leading to bone marrow suppression.54,55

KIT Oncogene

The KIT proto-oncogene encodes the transmembrane RTK.56 KIT is activated through the binding of its ligand, stem-cell factor, which initiates downstream signaling via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), PI3K/Akt, and MAPK/ERK pathways.56,57 KIT mutations lead to the constitutive activation of downstream pathways, resulting in spontaneous proliferation and uncontrolled growth of tumor cells.56,57 KIT mutations are common driver mutations in gastrointestinal stromal tumors (GIST; 80%) and in melanoma (10%-15%).58,59

Mutations in KIT mainly affect the exons that encode the functional domains of the RTK, including exon 9, exon 11, exon 13, and exon 17.57 KIT exon 11 and exon 13 mutations have a high level of sensitivity to KIT inhibition, whereas KIT exon 9 and exon 17 mutations and KIT amplification have minimal or no sensitivity to KIT inhibitors.56,58

Imatinib, a BCR-ABL inhibitor, targets KIT and is FDA approved for the treatment of KIT (CD117)-positive GIST in the adjuvant or metastatic setting. The common adverse events associated with imatinib when used for the treatment of GIST include diarrhea, nausea, edema, and fatigue.60

KRAS Mutations

In contrast to NSCLC, EGFR testing is not recommended in patients with CRC, because it currently has no proved predictive value in determining a response to anti-EGFR monoclonal antibodies.61 Instead, the Kirsten rat sarcoma (KRAS) mutational status is used to identify appropriate patients to receive anti-EGFR monoclonal antibodies.61 KRAS mutations are strong, independent negative predictors of response to anti-EGFR monoclonal antibodies therapy.62 Approximately 40% of CRC cases are linked to KRAS mutations.63,64

In patients with KRAS wild-type advanced CRC, anti-EGFR monoclonal antibody therapy, such as cetuximab or panitumumab, may be added to standard chemotherapy to improve efficacy.65 These agents bind to EGFR, preventing phosphorylation and the activation of downstream kinases, which leads to tumor apoptosis.62

The common adverse events of cetuximab and panitumumab include hypersensitivity or infusion reactions, rashes or skin toxicities, and GI side effects.66

MET Inhibitors

The MET proto-oncogene encodes for the MET protein, a transmembrane RTK. MET RTK is activated via the binding of hepatocyte growth factor, leading to the downstream induction of the PI3K/Akt and MAPK/ERK pathways.67 Mutations and amplifications of MET and the overexpression of MET lead to the constitutive and prolonged activation of MET.68

The incidence of MET mutations is 5.6% in patients with NSCLC, 9% in patients with breast cancer, and up to 100% in papillary thyroid cancers.68,69 MET inhibition prevents the phosphorylation of RTK, thereby inhibiting the activation of those downstream pathways.70

Currently, the only FDA-approved MET-selective inhibitor is capmatinib, which is indicated for the treatment of metastatic NSCLC with MET exon 14 skipping mutation. Treatment with capmatinib may lead to peripheral edema and nausea most often; rare but serious side effects, including pneumonitis and hepatotoxicity, have been linked to treatment with capmatinib.71

Neurotrophic Tyrosine Receptor Kinase

The tropomyosin receptor kinase (Trk) family of receptors TrkA, TrkB, and TrkC are encoded by the neurotrophic tyrosine receptor kinase (NTRK)1, NTRK2, and NTRK3 genes. Trk proteins are transmembrane receptors, and through activation via ligand binding, signal transduction pathways leading to the modulation, proliferation, differentiation, and apoptosis of normal and neoplastic neuronal cells.72 The pathways involved include MAPK/ERK, PI3K/Akt, and phosphoinositide phospholipase C/protein kinase C (PLC/PKC).73,74

NTRK gene fusions are the most common genetic alteration with known oncogenic potential that lead to constitutively activated or overexpressed Trk.73,74 Chromosomal rearrangements involving the NTRK1, NTRK2, or NTRK3 genes occur in approximately 1% of all solid-tumor cancers.75 Entrectinib and larotrectinib inhibit Trk and are indicated for the treatment of solid tumors that express an NTRK gene fusion.75

Entrectinib and larotrectinib have favorable safety profiles. The common side effects of these drugs include fatigue and GI adverse events.76 In addition, on-target adverse events, such as dizziness, weight gain, and cognitive changes, can occur secondary to Trk inhibition in normal tissues.76

PIK3CA Mutations

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are the oncogenic driver in a variety of cancers.77 Alterations in this pathway most frequently result from somatic mutations in the PIK3CA coding p110α or PIK3CA amplification and can lead to enhanced cell growth, antiapoptosis, cell-cycle progression, and translation.77,78

The PIK3CA-activating mutations occur in approximately 40% of HR-positive breast cancer.79 Alpelisib, a PI3K inhibitor, is approved, in combination with fulvestrant, after disease progression during or after receiving an endocrine-based regimen, for the treatment of postmenopausal women with HR-positive advanced or metastatic breast cancer and PIK3CA mutation. This approval was based on data demonstrating a progression-free survival benefit with alpelisib compared with placebo.79 The adverse events associated with alpelisib include rash, GI adverse events, hyperglycemia, hypersensitivity reactions, and pulmonary side effects.79

PDGFRA Mutations

Platelet-derived growth factor receptor alpha (PDGFRA) mutations are oncogenic drivers in 5% to 10% of GIST cases.80 The specific PDGFRA mutation D842V occurs in 5% to 6% of GIST cases and is resistant to currently available tyrosine kinase inhibitors that target PDGFRA other than avapritinib.81 Avapritinib was approved in January 2020 for the treatment of patients with GIST and a PDGFRA exon 18 mutation, including PDGFRA D842V mutations.81

Avapritinib inhibits PDGFRA, which prevents the autophosphorylation of PDGFRA, thus preventing tumor proliferation. The adverse events of avapritinib may include cognitive changes, nausea, vomiting, diarrhea, and edema.81

RET Oncogene

The rearranged during transfection (RET) is a proto-oncogene that encodes a transmembrane protein that is involved in cell growth via multiple pathways, including MAPK/ERK, PI3K/Akt, JAK/STAT3, and PLC/PKC. RET mutations and fusions are oncogenic drivers in NSCLC and in thyroid cancer.82

Approximately 1% to 2% of patients with NSCLC have RET fusions, with KIF5B-RET being the most common.82 RET fusions occur in 20% to 40% of papillary thyroid cancers.83 In addition, RET mutations occur in 43% to 71% of patients with sporadic medullary thyroid cancer, whereas germline RET mutations occur in 88% of familial medullary thyroid cancers and 95% of multiple neoplasia type 2A cases.83,84

The first 2 FDA-approved RET inhibitors were selpercatinib and pralsetinib, which are indicated for the treatment of patients with advanced or metastatic medullary thyroid cancer and RET mutation, advanced or metastatic thyroid cancer with RET fusion, and metastatic NSCLC with RET fusion.

The drug-class adverse events include hepatotoxicity, hypertension, hemorrhage, and GI adverse events.85,86

ROS1 Oncogene

The rearrangement of the ROS1 gene leads to a constitutively activated RTK, which results in dysregulation and inappropriate cell signaling via the MAPK/ERK pathway.87 ROS1 rearrangements were initially identified in glioblastoma cells; in 2007 ROS1 rearrangements were first discovered in NSCLC.88,89

ROS1 rearrangements occur in 1% to 2% of patients with NSCLC, and the incidence is higher in nonsmokers and in patients with adenocarcinoma histology.87,90,91

Because of the structural similarities between ROS1 and ALK within the kinase domain and the ATP-binding sites, many agents that inhibit ALK rearrangements also inhibit the ROS1 mutations.92,93 ALK inhibitors (crizotinib) and NTRK inhibitors (entrectinib) have been approved by the FDA for patients with metastatic NSCLC and ROS1 mutation and have improved the overall response rate, progression-free survival, and/or overall survival.93-95


As the number of actionable biomarkers continues to increase, testing patients with solid tumors for targetable biomarkers is critically important, to guide the selection of available treatment options. Predictive biomarker-driven targeted therapies will continue to expand to provide new treatment options for patients, which will subsequently improve patient outcomes and treatment safety. A potential targeted therapy class that may soon be approved by the FDA is KRAS G12C inhibitors, which shows promising efficacy in patients with KRAS G12C mutations. In addition, the indications of the currently approved treatments may be expanded in the future. Within this rapidly growing clinical area, oncology pharmacists are essential in managing the treatment selection, drug interactions, and treatment side effects.

Author Disclosure Statement
Dr Mo and Dr Renna have no conflicts of interest to report.


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