Targeted and Immunotherapy Agents

Targeted and Immunotherapy Agents

Color Key

image Agents in early-stage clinical trial investigations first in man, phase 1

image Agents in late-stage clinical trial investigations (phases 2 and 3)

image FDA-approved agents

image FDA-approved agents being repurposed for cancer


• 17-AAG:


• 2HG:


• 5FU:



antibody-dependent cell-mediated cytotoxicity


aminoimidazole carboxamide ribonucleotide formyltransferase

• ALK:

anaplastic lymphoma kinase

• ALT:

alanine transaminase

• AML:

acute myelogenous leukemia

• AR:

androgen receptor

• AST:

aspartate aminotransferase

• ATM:

ataxia telangiectasia-mutated


aurora A kinase


aurora B kinase


breast cancer resistance protein

• BNP:

brain natriuretic peptide


BReast CAncer susceptibility gene

• BTK:

Bruton tyrosine kinase

• CAR:

chimeric antigen receptor

• CBP:

CREB-binding protein

• CCR4:

CC chemokine receptor 4

• CD:

cytosine deaminase

• CDK:

cyclin-dependent kinase

• CLL:

chronic lymphocytic leukemia

• CMV:


• CPK:

creatine phosphokinase


cAMP response element-binding protein


cutaneous T-cell lymphoma

• CTLA4:

cytotoxic T-lymphocyte associated antigen 4


dihydrofolate reductase

• DOE:

dyspnea on exertion

• DPD:

dihydropyrimidine dehydrogenase

• DVT:

deep vein thrombosis

• EF:

ejection fraction


epidermal growth factor receptor

• EKG:


• ERK2:

extracellular signal-related kinase 2

• Fc:

fragment crystallizable


FGF receptor

• FKBP-12:

FK-binding protein-12

• FLT3:

FMS-related tyrosine kinase receptor-3


folinic acid/fluorouracil/irinotecan

• FOLR1:

folate receptor 1


folylpolyglutamate synthetase


glycinamide ribonucleotide formyltransferase

• GE:



• GGT:

gamma-glutamyl transferase

• GI:



granulocyte-macrophage colony-stimulating factor

• HCC:

hepatocellular carcinoma


histone deacetylase

• HER2:

human epidermal growth factor receptor 2

• HSV:

herpes simplex virus

• IDH:

isocitrate dehydrogenase

• IGF-1R:

insulin-like growth factor-1 receptor

• Ig:


• ITD:

internal tandem duplication

• ITP:

immune thrombocytopenic purpura

• JAK:

Janus kinase

• KDR:

Kinase insert domain receptor

• KLF4:

Kruppel-like factor 4


Kirsten rat sarcoma

• LD:

lactate dehydrogenase


left ventricular ejection fraction

• mAb:

monoclonal antibody

• MEK1:

mitogen-activated protein kinase kinase 1


mitogen-activated protein kinase

• MCL:

mantle cell lymphoma

• mCRC:

metastatic colorectal cancer

• MDS:

myelodysplastic syndrome

• MET:

mesenchymal epithelial transition

• MM:

multiple myeloma

• MTC:

medullary thyroid carcinoma

• MTF-1:

metal-regulatory transcription factor 1

• mTOR:

mammalian target of rapamycin

• MWF:

Monday, Wednesday, Friday

• NHL:

non-Hodgkin lymphoma


neuroblastoma ras viral oncogene homolog


non-small-cell lung cancer


neurotropic tropomyosin receptor kinase

• PAP:

prostatic-acid phosphatase


poly (ADP-ribose) polymerase


platelet-derived growth factor receptor

• PD-L1:

programmed death ligand 1

• PEG:

polyethylene glycol

• PFS:

progression-free survival

• PI3K:

phosphatidylinositol 3-kinase

• PIP3:


• PKC:

protein kinase C

• pNET:

pancreatic neuroendocrine tumor


: patched


peripheral T-cell lymphoma


receptor activator of nuclear factor χ-β ligand

• RAS:

rat sarcoma virus

• RET:

rearranged during transfection

• RFC-1:

reduced folate carrier

• RTKs:

receptor tyrosine kinases


stress-activated protein kinase


squamous cell carcinoma of the head and neck

• scFv:

single-chain variable fragment


small-cell lung cancer

• SMO:

small-molecule smoothened

• STAT3:

signal transducer and activator of transcription 3

• STS:

soft tissue sarcoma

• SYK:

spleen tyrosine kinase

• TAA:

tumor-associated antigen

• TCR:

T-cell receptor

• TEN:

toxic epidermal necrolysis

• TGF:

transforming growth factor

• TLS:

tumor lysis syndrome

• Trk:

tropomyosin receptor kinase

• TS:

thymidylate synthase

• URI:

upper respiratory infection


vascular endothelial growth factor


vascular endothelial growth factor receptor

• XRT:


Abiraterone Acetate (Zytiga)

  • Alias: CB7630

  • Selectively and irreversibly inhibits 17-α-hydroxylase/C17,20-lyase (CYP17), an enzyme required for androgen biosynthesis. The inhibition of CYP17 results in increased mineralocorticoid production by the adrenals.

  • FDA approved for castrate-resistant prostate cancer

  • Dose: 1,000 mg PO daily with prednisone. Give on a fasting stomach 1 hour before and 2 hours after meal

  • Half-life: 14.4 to 16.5 hours

  • Metabolism: Potent CYP3A4 substrate

  • Side effects: Peripheral edema, fatigue, hypertension, hyperglycemia/hypertriglyceridemia, lymphopenia

Acalabrutinib (Calquence)

  • Aliases: ACP-196; BTK inhibitor

  • An orally available inhibitor of BTK preventing the activation of the B-cell antigen receptor signaling pathway

  • FDA approved in October 2017 for MCL patients who have had one prior therapy.

  • Recommended dose: 100 mg PO Q 12 hours until progression

  • Metabolism: Avoid concomitant use with potent CYP3A4 inducers or inhibitors. May dose-adjust with moderate inhibitors of CYP3A4.

  • Half-life: 0.6 to 2.8 hours; ACP-5862 (active metabolite) ˜6.9 hours

  • Side effects: Headache, fatigue, skin rash, diarrhea, bruise, neutropenia, myalgias, anemia, rare increase in serum creatinine

Ado-Trastuzumab Emtansine (Kadcyla)

  • Alias: T-DM1

  • A HER2-antibody-drug conjugate that incorporates the HER2 targeted actions of trastuzumab with the microtubule inhibitor DM1 (a maytansine derivative). The conjugate, which is linked via a stable thioether linker, allows for selective delivery into HER2 overexpressing cells, resulting in cell cycle arrest and apoptosis.

  • FDA approved for HER2-positive metastatic breast cancer patients who have previously had trastuzumab

  • Recommended dose: 3.6 mg/kg IV every 3 weeks over 90 minutes with first dose, then may decrease to 30 minutes if tolerated

  • Half-life: ˜4 days

  • Common side effects: Fatigue, headache, neuropathy, skin rash, nausea, abdominal pain, muscle pain, arthralgias, cough, fever

Afatinib Dimaleate (Gilotrif)

  • Alias: BIBW2992

  • Orally bioavailable EGFR and HER2 inhibitor

  • FDA approved on June 12, 2013, for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test

  • Currently in phase 2 trials for breast cancer with overexpression of HER2 growth receptor

  • Recommended dose: 40 mg once daily. May be taken 1 hour before or 2 hours after meals

  • Half-life: 34 hours

  • Metabolism: BCRP and P-glycoprotein substrate

  • Common side effects: Diarrhea, acne/rash/pruritus, stomatitis, paronychia, dry skin, decreased appetite


  • Alias: GSK2110183

  • Orally bioavailable inhibitor of the serine/threonine protein kinase AKT (protein kinase B)

  • Currently no clinical trials open for cancer in the United States; previously showed efficacy in patients with MM

  • Recommended dose: 125 mg PO daily

  • Half-life: 1.7 days

  • Common side effects: Nausea, diarrhea, dyspepsia, fatigue, anorexia, GI reflux disease, neutropenia

(Spencer et al., 2011)

Alectinib (Alecensa)

  • Aliases: AF802; CH5424802; RG7853; RO5424802

  • A tyrosine kinase receptor inhibitor that inhibits ALK and RET resulting in decreased tumor cell viability. Alectinib is more potent than crizotinib against ALK and can inhibit most of the clinically observed acquired ALK resistance mutations to crizotinib. FDA approved for metastatic NSCLC with ALK-positive mutation or who have progressed on, or are intolerant to, crizotinib.

  • Recommended dose: 600 mg twice daily with food

  • Half-life: 33 hours (37% bioavailability under fed condition)

  • Common side effects: Edema, bradycardia, fatigue, headache, rash, hyperglycemia, hypophosphatemia, transaminitis, hyperbilirubinemia, muscle pain, increased CPK, increased SCr, constipation

Alemtuzumab (Campath-1h)

  • Aliases: MoAb CD52, anti-CD52 monoclonal antibody, humanized IgG1 anti-CD52 monoclonal antibody

  • As of September 4, 2012, alemtuzumab (Campath) is no longer commercially available in the United States (or Europe).

  • Campath remains accessible (free of charge) through the Campath Distribution Program for the treatment of B-cell CLL and select unlabeled uses.

  • In February 2014, alemtuzumab was launched under a different trade name of Lemtrada for use in multiple sclerosis with lower doses.

  • Recommended dose: 3 mg IV on day 1; if no reaction, increase to 10 mg IV on day 3; again if no reaction, increase to full dose 30 mg IV TIW for a total of 12 doses

  • Half-life: 11 hours (following first 30-mg dose); 6 days (following last 30-mg dose)

  • Common side effects: Black box warning: Potentially life-threatening cytopenias, opportunistic infections, infusion reactions, hypotension/hypertension, fevers, chills, lymphopenia, rash


  • Alias: MLN8237

  • Second-generation, orally bioavailable, selective AURKA inhibitor that has >200-fold higher selectivity for Aurora A than Aurora B

  • Currently under investigation in phase 3 trial for treatment of relapsed or refractory PTCL (failed to meet primary endpoint in May 2015, therefore study terminated). Continue phase 2 in SCLC and in high-risk AML

  • Recommended phase 3 dose: 50 mg twice daily for 7 consecutive days of the 21-day cycle (10 mg enteric coated tablet). Fast 2 hours before and 1 hour after dosing.

  • Half-life: 19 to 23 hours

  • Metabolism: Excreted primarily unchanged

  • Common side effects: Fatigue, neutropenia, nausea, stomatitis

(Cervantes et al., 2012; Dees et al., 2012)


  • Alias: BYL719

  • An orally bioavailable PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations; inhibits the PI3Kα isoform and much less strongly the β, δ, and γ isoforms

  • Phase 3 in combination with fulvestrant in PIK3CA-mutated advanced breast cancer (SOLAR-1 study); phase 1b/2 clinical trials in combination studies for ovarian cancer, SCCHN, hormone receptor-positive breast cancer, RAS-or RAF-positive colorectal cancer, and NSCLC

  • Recommended dose: 300 mg orally once daily until disease progression

  • Half-life: ˜8.5 hours

  • Side effects: Hyperglycemia, erythematous rash, stomatitis, nausea/vomiting, diarrhea, fatigue, anorexia, and increased lipase

(Juric et al., 2016)


  • Alias: YN968D1; Rivoceranib (international nonproprietary name)

  • Orally bioavailable VEGFR2 (KDR) inhibitor; also mildly inhibits RET, KIT, and SRC

  • FDA-granted orphan drug status for treatment of gastric cancer

  • Recommended phase 3 dose: 850 mg daily

  • Half-life: 9 hours

  • Metabolism: Extensively by CYP3A4

  • Common side effects: Hypertension, hand-foot syndrome, diarrhea, anemia, thrombocytopenia, proteinuria

(Zhang et al., 2017)

Atezolizumab (Tecentriq)

  • Alias: MPDL3280A, RO5541267

  • Fully humanized, mAb directed against the protein ligand PD-L1 expressed on activated T cells which, in turn, will enhance the T-cell-mediated immune response to neoplasms and reverse T-cell inactivation.

  • FDA approved for locally advanced or metastatic urothelial carcinoma with PD-L1 expression or metastatic NSCLC

  • Recommended dose: 1,200 mg IV every 3 weeks

  • Half-life: 27 days

  • Common side effects: Peripheral edema, fatigue, skin rash, hyponatremia, decreased appetite, transaminitis, hyperbilirubinemia, infection

Avelumab (Bavencio)

  • Alias: MSB0010718C

  • Fully human mAb that binds to PD-L1 to selectively prevent the interaction between the PD-1 and 7.1 receptors, resulting in the restoration of antitumor T-cell function

  • FDA approved for metastatic Merkel cell carcinoma and locally, advanced, or metastatic urothelial carcinoma following platinum therapy

  • Recommended dose: 10 mg/kg IV over 60 minutes every 2 weeks until disease progression; should premedicate with acetaminophen and diphenhydramine for the first four infusions

  • Half-life: 6.1 days

  • Side effects: Peripheral edema, hypertension, fatigue, dizziness, skin rash, nausea, diarrhea, hyponatremia, decreased appetite, abdominal pain, transaminitis, arthralgia, infusion-related reaction with chills, fevers

Axicabtagene Ciloleucel (Yescarta)

  • Alias: KTE-C19 CAR

  • A preparation of autologous peripheral blood T-lymphocytes that have been transduced with a gamma-retroviral vector expressing a CAR consisting of an anti-CD19 scFv coupled to the costimulatory signaling domain CD28 and the zeta chain of the TCR/CD3 complex (CD3 zeta), resulting in immunostimulation.

  • FDA approved on November 8, 2017 for adults with relapsed/refractory large B-cell lymphoma such as diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, or high-grade B-cell lymphoma

  • Recommended dose: A treatment course consists of lymphodepleting chemotherapy with fludarabine and cyclophosphamide on the fifth, fourth, and third day prior to
    axicabtagene ciloleucel infusion (confirm availability of autologous axicabtagene ciloleucel prior to initiating lymphodepleting chemotherapy). Ensure tocilizumab and emergency equipment are available prior to axicabtagene ciloleucel infusion and during recovery period. Premedicate with acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV or orally ˜60 minutes prior to axicabtagene ciloleucel infusion. Avoid prophylactic systemic corticosteroids because they may interfere with the axicabtagene ciloleucel activity. IV: Target dose: 2 × 106 CAR-positive viable T cells per kg body weight; maximum dose: 2 × 108 CAR-positive viable T cells.

  • Duration: Anti-CD19 CAR T cells displayed an initial rapid expansion followed by a decline to near baseline levels by 3 months after axicabtagene ciloleucel infusion. Peak level of anti-CD19 CAR T cells occurred within the 7 to 14 days after infusion.

  • Side effects: Cytokine release syndrome, tachycardia; neurologic toxicities, such as cerebral edema, ataxia, blurry vision, headaches; hypotension; hypogammaglobulinemia; fatigue; nausea; and abdominal pain

Axitinib (Inlyta)

  • Alias: AG-013736

  • Selective second-generation, orally bioavailable inhibitor of VEGFRs (VEGFR-1, VEGFR-2, and VEGFR-3), as well as platelet-derived growth factor receptor (PDGFR), and KIT

  • FDA approved for renal cell carcinoma

  • Recommended dose: 5 mg twice daily. May be taken regardless of food. No grapefruit or grapefruit juice

  • Half-life: 2 to 6 hours

  • Metabolism: CYP3A4 substrate

  • Common side effects: Diarrhea, hypertension, fatigue, decreased appetite, nausea/vomiting

  • Clinical pearls: Dysphonia (hoarseness) may occur while taking. Advise patients to avoid irritants and to drink plenty of fluids.

Anetumab Ravtansine

  • Alias: BAY94-9343

  • Fully human IgG1 monoclonal antibody against the cell surface glycoprotein mesothelin

  • Mesothelin is selectively overexpressed in many human tumors (e.g., pancreas 80%-100%, ovary 80%, mesothelioma 100%, and lung 40%).

  • The mAb moiety of antimesothelin antibody-drug conjugate BAY 94-9343 targets and binds to the TAA mesothelin; when internalized, the DM4 moiety binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells.

  • Currently in phase 1 clinical development

  • Potential cancer targets: Mesothelioma, ovarian cancer, pancreatic cancer, NSCLC

  • Starting dose: 5.5 mg/kg IV once a week and continue to escalate

  • Phase 1 half-life: 4 to 5 days

  • Common side effects: Fatigue/weakness, nausea/vomiting, anorexia

(Bendell et al., 2013)


  • Alias: MK-1775

  • Small-molecule WEE1 inhibitor that is a key regulator of cell cycle progression. WEE1 inhibits CDK1, which effects G2/M cell cycle checkpoint and therefore the regulation of cell size and DNA damage.

  • Phase 2 in combination with gemcitabine in recurrent ovarian, primary peritoneal, or fallopian tube cancer; phase 2 in combination with olaparib, AZD5363 (AKT-inhibitor), AZD2014 (mTOR inhibitor) in advanced solid tumors

  • Recommended dose: Intermittent dosing twice weekly to three times weekly with dose ranging from 200 to 325 mg with chemotherapy

  • Half-life: 7.6 to 12.2 hours

  • Common side effects: Nausea/vomiting, fatigue, leukopenia, neutropenia, diarrhea, hypokalemia

(Mahajan et al., 2013; Schellens et al., 2009)


  • Aliases: ISIS 481464, ISIS-STAT3rx (tentative US brand name)

  • An antisense oligonucleotide targeting STAT3, leading to apoptosis and reduced tumor cell growth

  • Currently under investigation in phase 1/2 clinical trial with advanced cancers

  • Recommended phase 2 dose: 2 mg/kg IV LD on MWF, then Q weekly

  • Proposed tissue half-life: 20 days

  • Possible side effects: Thrombocytopenia, liver dysfunction

(Furqan et al., 2013)

Belinostat (Beleodaq)

  • Alias: PXD101

  • A novel hydroxamic acid-type HDAC inhibitor that targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis

  • FDA approved for relapsed, refractory, PTCL

  • Recommended dose: 1,000 mg/m2 IV over 30 minutes on days 1 to 5 every 21 days until disease progression. NOTE: If the patient is homozygous for UGT1A1*28 allele, reduce the initial dose to 750 mg/m2.

  • Half-life: 1.1 hours

  • Side effects: Peripheral edema, prolonged QT, fatigue, chills, headache, rash, pruritus, hypokalemia, anemia, thrombocytopenia, dyspnea, fevers, hypotension, elevated SCr

Bevacizumab (Avastin)

  • A recombinant humanized mAb directed against the VEGF, a proangiogenic cytokine

  • Binds to VEGF and inhibits receptor binding, thereby preventing the growth and maintenance of tumor blood vessels

  • FDA approved for colon, lung, and renal carcinomas and glioblastoma multiforme

  • Recommended dose: 5 to 10 mg/kg IV every 2 weeks or 15 mg/kg IV every 3 weeks

  • Half-life: 20 days

  • Common side effects: Hypertension, severe or fatal hemorrhage (GI bleed, hemoptysis, CNS bleed), bowel perforation, fistulas/abscess formation, proteinuria

  • Clinical pearls: Have patients monitor blood pressure and bring the log to appointments. Avoid use in patients with serious hemorrhage or recent hemoptysis (˜2.5 mL blood). Bevacizumab should be discontinued at least 28 days prior to elective surgery and should not be reinitiated for at least 28 days after surgery and until wound is fully healed. Withhold treatment for ˜2 g proteinuria/24 hours and resume when proteinuria is 2 g/24 hours; discontinue in patients with nephrotic syndrome.

BI 811283

  • AURKB inhibitor

  • Currently no active clinical trials in the United States

  • Recommended dose: 230 mg as 24-hour continuous infusion on day 1 of 21-day cycle

  • Half-life: 12 to 26 hours

  • Common side effects: Neutropenia, leukopenia, febrile neutropenia

(Golfier et al., 2014; Mross et al., 2010)

Bicalutamide (Casodex/Cosudex)

  • Nonsteroidal AR inhibitor

  • FDA approved for treatment of prostate cancer and hirsutism. Clinical trials have shown minimum activity in AR-positive breast cancer.

  • Recommended dose: 50 mg PO daily

  • Half-life: 6 days

  • Metabolism: Substrate of CYP3A4

  • Common side effects: AST and ALT increase, hyperbilirubinemia, ALP increase, nausea, pain (bone, back, pelvis), anorexia, fatigue, diarrhea, hot flashes, limb edema


  • Alias: ARRY-162; MEK162; ARRY-43162

  • An orally available inhibitor of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling. This may eventually lead to an inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines, including interleukin-1, -6, and tumor necrosis factor.

  • Phase 1/2 in combination with palbociclib in KRAS-mutated NSCLC; phase 3 in combination with irinotecan, encorafenib, cetuximab, and 5FU in BRAF V600E mutant mCRC

  • Recommended phase 2 dose: 45 mg PO b.i.d. until disease progression

  • Metabolism: Major CYP3A4 and CYP1A2 substrates

  • Half-life: 6 to 8 hours

  • Common side effects: Rash, fatigue, dermatitis acneiform, peripheral edema, diarrhea, nausea, elevated CPK, anemia

(Cho et al., 2017)

Blinatumomab (Blincyto)

  • Aliases: MEDI-538; MT-103; AMG-103

  • A recombinant, single-chain, anti-CD19/anti-CD3 bispecific mAb that possesses two antigen-recognition sites, one for the CD3 complex, a group of T-cell surface glycoproteins that complex with the TCR, and one for CD19, a TAA overexpressed on the surface of B cells

  • FDA approved for relapsed or refractory B-cell acute lymphoblastic leukemia

  • Recommended dose: Each induction and consolidation treatment cycle consists of 4 weeks of continuous infusion followed by a 2-week treatment-free interval (allow at least 2 weeks treatment-free between cycles). Each continued therapy cycle consists of 4 weeks of continuous infusion followed by an 8-week treatment-free interval. Therapy involves up to two induction cycles followed by three additional cycles for consolidation and up to four additional cycles of continued therapy (a total of up to nine cycles).

  • For patient ≥ 45 kg (fixed dose): (1) Cycle 1: 9 micrograms daily administered as a continuous infusion on days 1 to 7, followed by 28 micrograms daily as a continuous infusion on days 8 to 28 of a 6-week treatment cycle. (2) Cycles 2 through 5: 28 micrograms daily administered as a continuous infusion on days 1 to 28 of a 6-week treatment cycle. (3) Cycles 6 through 9: 28 micrograms daily administered as a continuous infusion on days 1 to 28 of a 12-week treatment cycle.

  • For patient <45 kg (dose based on BSA): (1) Cycle 1: 5 µg/m2/day (maximum: 9µg/day) administered as a continuous infusion on days 1 to 7, followed by 15µg/m2/day (maximum: 28 µg/day) as a continuous infusion on days 8 to 28 of a 6-week treatment cycle. (2) Cycles 2 through 5: 15 µg/m2/day (maximum: 28 µg/day) administered as a continuous infusion on days 1 to 28 of a 6-week treatment cycle. (3) Cycles 6 through 9: 15 µg/m2/day (maximum: 28 µg/day) administered as a continuous infusion on days 1 to 28 of a 12-week treatment cycle

  • Half-life: ˜2 hours

  • Side effects: Edema, hypertension, cardiac arrythmia, headache, rash, headache, pyrexia, tremors, fatigue, lymphopenia, cytokine release syndrome, infusion-related side effects, fever


  • High-affinity, fully human, PD-L1-specific IgG4 monoclonal antibody that inhibits the binding of PD-L1 to both PD-1 and CD80

  • No active clinical trials for cancer in the United States; previous studies in melanoma and hematologic malignancies were withdrawn.

  • Recommended dose: 0.3 to 10 mg/kg as 60-minute infusion every 2 weeks

  • Half-life: ˜15 days

  • Common side effects: Rash, hypothyroidism, hepatitis, diarrhea

(Brahmer et al., 2012)

Bortezomib (Velcade)

  • Alias: PS-341

  • Reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquitinated protein with an unusual boron “backbone”

  • Inhibits nuclear factor NFχB, a protein that is constitutively activated in some cancers, thereby interfering with NFχB-mediated cell survival, tumor growth, and angiogenesis

  • FDA approved for MM

  • Recommended dose: 1.3 mg/m2 IV twice weekly for 2 weeks followed by a 10-day rest period. New recommendation for subcutaneous route

  • Half-life: 9 to 15 hours

  • Metabolism: Major substrate of CYP3A4 and CYP2C19

  • Common side effects: Peripheral neuropathy, neutropenia, thrombocytopenia, GI effects, asthenia

  • Clinical pearls: Clinicians should consider using antiviral medications when treating patients with bortezomib, because the reactivation of herpes zoster or simplex can occur. Pulmonary toxicity has been noted, including pneumonitis, interstitial pneumonia, lung infiltrates, and acute respiratory distress syndrome. Promptly evaluate new or worsening cardiopulmonary symptoms.

Bosutinib (Bosulif)

  • Aliases: SKI-606

  • BRC-ABL inhibitor with activities against SRC family (including SRC, LYN, and HCK)

  • Very minimal activity in KIT and PDGFR

  • Activity in 16 of 18 imatinib-resistant BCR-ABL mutations, with exceptions being the T315I and V299L mutants

  • FDA approved for Ph+ chronic myelogenous leukemia

  • Recommended dose: 500 mg orally once daily with food

  • Half-life: 22 hours

  • Metabolism: Major CYP3A4 substrate and P-glycoprotein

  • Common side effects: Nausea/vomiting, diarrhea, edema, myelosuppression, rash, abdominal pain, pyrexia, transaminitis

  • Clinical pearls: Do not take proton pump inhibitors while on bosutinib. Short-acting
    antacids and H2 antagonists may be taken as long as the medication is not taken within 2 hours of the dose of bosutinib. Take this medicine with food and a glass of water. Do not crush, break, or chew the tablets. The median time to the onset of side effects is typically 2 days.

Brentuximab Vedotin (Adcetris)

  • Aliases: SGN-35, cAC10-vcMMAE

  • CD30-directed (chimeric) antibody-drug conjugate that targets CD30, a protein expressed on the surface of certain cancer cells

  • FDA approved for anaplastic large cell lymphoma, CD30-expressing mycosis fungoides, or Hodgkin lymphoma

  • Recommended dose: 1.8 mg/kg up to a maximum of 180 mg as IV infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity (1.2 mg/kg for mild hepatic impairment)

  • Metabolism: Major CYP3A4 and P-glycoprotein substrate

  • Common side effects: Myelosuppression, fatigue, infusion-related side effects, nausea/vomiting, diarrhea, peripheral sensory/motor neuropathy, pyrexia, upper respiratory tract infection (cough), rash, progressive multifocal leukoencephalopathy (rare) (US box warning)

  • Clinical pearls: Peripheral neuropathy is generally cumulative. Dose interruption, reduction, or discontinuation may be recommended.

Brigatinib (Alunbrig)

  • Alias: AP26113

  • A broad-spectrum multikinase inhibitor with activity against ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR deletion and point mutations. ALK autophosphorylation and ALK-mediated phosphorylation of downstream signaling proteins STAT3, AKT, ERK1/2, and S6 are inhibited by brigatinib.

  • FDA approved for metastatic NSCLC with ALK(+) who have progressed on, or are intolerant to, crizotinib.

  • Recommended dose: 90 mg PO daily for 7 days. If tolerated, may continue to full dose at 180 mg PO daily until disease progression. If therapy is interrupted for 14 days or greater, need to start therapy back at 90 mg PO daily for days and then increase

  • Metabolism: Major CYP3A4 substrate. Avoid all potent inhibitors and inducers of CYP3A4.

  • Half-life: 25 hours

  • Side effects: hypertension, fatigue, headache, peripheral neuropathy, skin rash, hyperglycemia, transaminitis, constipation or diarrhea, nausea, anemia, lymphocytopenia, cough

Brivanib Alaninate

  • Alias: BMS-582664

  • The alaninate salt of a VEGFR2 inhibitor that strongly binds to and inhibits VEGFR2 and FGFR tyrosine kinases

  • Currently in phase 3 trials for HCC; phase 2 trials under way for colorectal cancer, pancreatic cancer, NSCLC, gastric and GE junction cancer, pancreatic cancer, bladder cancer, and STS

  • Recommended phase 2 dose: 800 mg PO daily

  • Half-life: ˜13.8 hours

  • Common side effects: Nausea/vomiting, diarrhea, constipation, fatigue

(Mekhail et al., 2010)


  • Alias: BKM120

  • Orally bioavailable pan-class I PI3K inhibitor

  • Currently under investigation in phase 3 trials with hormone receptor-positive, HER2-negative metastatic breast cancer

  • Recommended phase 3 dose: 100 mg PO daily in combination with fulvestrant. Take dose 1 hour after breakfast and fast for 2 hours after dosing.

  • Half-life: ˜40 hours

  • Metabolism: moderate/reversible inhibitor of CYP3A4

  • Common side effects: Rash, anorexia, mood alteration, diarrhea, hyperglycemia

(Baselga et al., 2017)

Cabozantinib (Cometriq)

  • Alias: XL-184

  • Potent inhibitor of RTKs, including AXL, FLT-3, KIT, MET, RET, TIE-2, TRKB, and VEGFR-1, -2, and -3

  • FDA approved in 2013 for MTC

  • Dose: 140 mg twice daily without food

  • Half-life: ˜55 hours

  • Metabolism: Potent CYP3A4 substrate

  • Common side effects: Hemorrhage, perforation/fistula (US box warning), hypertension, stomatitis, palmar-plantar erythrodysesthesia, decreased appetite, weight loss, nausea/vomiting, diarrhea, tiredness and weakness, change in hair color, liver dysfunction (hyperbilirubinemia,
    transaminitis), dysphonia (hoarseness)

  • Clinical pearls: May affect the rate of wound healing; patients should notify doctor prior to surgery or dental work

Carfilzomib (Kyprolis)

  • Alias: PR-171

  • Irreversible, epoxomicin-related proteasome inhibitor of the ubiquitin-proteasome pathway that potently binds to and specifically inhibits the chymotrypsin-like 20S proteasome (ChT-L) and immunoproteasome activities leading to cell cycle arrest and apoptosis

  • FDA approved for MM

  • Recommended dose: 20 mg/m2 IV on days 1 and 2 of each week for 3 weeks of a 28-day cycle; may increase dose in subsequent cycles if tolerated to 27 mg/m2 IV on days 1 and 2 of each week for 3 weeks of a 28-day cycle. All dosing on cycle 1 should have hydration and steroids premedication to prevent infusion-related side effects (chills, fevers, myalgia, flushing).

  • Half-life: <1 hour on cycle 1 day 1 dose. Proteasome inhibition effect can last up to 48 hours.

  • Metabolism: Mainly extrahepatic elimination, insignificant CYP450 metabolism

  • Common side effects: Fatigue, myelosuppression, nausea/vomiting, diarrhea, pyrexia, increased creatinine, back pain, upper respiratory infection (cough, pneumonia, DOE)


  • Aliases: AZD 2171, Recentin (tentative trade name)

  • Highly potent VEGFR inhibitor, which may inhibit VEGF-A)-driven angiogenesis

  • Phase 3 clinical trials with recurrent glioblastoma ongoing; currently under investigation in phase 2 clinical trials for newly diagnosed glioblastoma, thyroid cancer, and ovarian and triple-negative breast cancer

  • Recommended phase 2 dose: 30 or 45 mg orally daily (20 mg when combined with cytotoxic chemotherapy)

  • Half-life: ˜22 hours

  • Common side effects: Fatigue, diarrhea, nausea, dysphonia, hypertension (proteinuria)

(Drevs et al., 2007; Ryan et al., 2007)

Ceritinib (Zykadia)

  • Alias: LDK378

  • An orally available inhibitor of the RTK activity of ALK that binds to and inhibits wild-type ALK kinase, ALK fusion proteins, and ALK point mutation variants. Inhibition of ALK leads to both the disruption of ALK-mediated signaling and the inhibition of cell growth in ALK-overexpressing tumor cells.

  • FDA approved for metastatic NSCLC with ALK-positive mutation.

  • Recommended dose: 750 mg daily on empty stomach, 1 hour before or 2 hours after meal. Avoid grapefruit and grapefruit juice.

  • Metabolism: Major CYP3A4 substrate

  • Half-life: 41 hours

  • Common side effects: QT prolongation, nausea/vomiting, abdominal pain, diarrhea, neuropathy, fatigue, skin rash, hyperglycemia, increased lipase, transaminitis, hyperbilirubinemia, visual impairment

Cetuximab (Erbitux)

  • A recombinant human/mouse chimeric mAb that binds specifically to EGFR (HER1, c-ErbB-1) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands

  • FDA approved for KRAS wild-type colorectal cancer and squamous cell head and neck sarcoma

  • Recommended dose: 400 mg/m2 as 120-minute IV infusion as an initial dose, followed by 250 mg/m2 infused over 30 minutes weekly

  • Half-life: 114 hours

  • Common side effects: Infusion reactions (US box warning), nausea/vomiting, diarrhea, skin problems (acneiform rash, pruritus), hypomagnesemia, stomatitis, lung disease (dyspnea, cough), cardiopulmonary arrest (US box warning)

  • Clinical pearls: Severity of acne-form rash can be minimized with the use of topical steroid cream, topical antibiotic gel, and doxycycline.


  • Alias: IMC-A12, CIX

  • A fully human IgG1/λ monoclonal antibody directed at the IGF-IR

  • Has a dual action of inhibiting the binding of IGF-1 and IGF-2 ligands to the IGF-1R and inducing the rapid internalization of the receptor

  • Currently under investigation in phase 1/2 clinical trials in breast cancer, rhabdomyosarcoma, Ewing sarcoma, NSCL, pancreatic, adrenocortical carcinoma, metastatic prostate cancer, and HCC

  • Phase 1/2 dose: 6 to 10 mg/kg IV Q 1 to 2 weeks

  • Half-life: 148 to 209 hours

  • Common side effects: Hyperglycemia, rash, pruritis, fatigue, nephrotoxicity

(Higano et al., 2007)

Cobimetinib (Cotellic)

  • Aliases: GDC-0973, XL518

  • An orally bioavailable small-molecule inhibitor of MAP2K1 or MEK1 that specifically binds to and inhibits the catalytic activity of MEK1, resulting in the inhibition of ERK2 phosphorylation and activation and reduced tumor cell proliferation

  • FDA approved for unresectable or metastatic melanoma with BRAF V600E or V600K mutation in combination with vemurafenib

  • Recommended dose: 60 mg daily for 21 days out of the 28-day cycle.

  • Metabolism: Major CYP3A4 substrate

  • Half-life: Average 44 hours (range 23-70 hours)

  • Common side effects: Decreased LVEF, hypertension, photosensitivity, acneiform eruption, hypophosphatemia, increased GGT, nausea/vomiting, diarrhea, anemia, transaminitis, visual impairment, increased SCr

Combretastatin Disodium

  • Aliases: Fosbretabulin tromethamine; NSC-348103; NSC-600168; SureCN19956; AC1L7IJ7

  • Binds to the β-subunit of tubulin at the colchicine site, thereby inhibiting the tubulin polymerization, resulting in the prevention of cancer cells from producing microtubules

  • Phase 1b/2 studies are under way for ovarian cancer, SCLC, esophageal cancer, and melanoma.

  • Recommended phase 2 dose: 45 mg/m2 IV over 10 minutes every week for 3 weeks, 1 week off in anaplastic thyroid cancer.

  • Half-life: ˜1.9 hours

  • Common side effects: Pain, lymphopenia, fatigue, hypertension/hypotension, diarrhea, nausea/vomiting, visual disturbance, tachycardia

(Mooney et al., 2009)

Copanlisib (Aliqopa)

  • Alias: BAY 80-6946

  • An orally potent, highly selective, reversible pan-class I PI3K inhibitor

  • FDA approved in September 2017 for relapsed follicular lymphoma

  • Recommended dose: 60 mg IV over 1 hour every week for 3 weeks, 1 week off of a 28-day cycle

  • Metabolism: Avoid concomitant use of potent CYP3A4 inhibitors. If it cannot be avoided, decrease the dose of copanlisib to 45 mg.

  • Half-life: 39.1 hours (range 14.6-82.4 hours)

  • Common side effects: Hyperglycemia, nausea/diarrhea, mucositis, fatigue, hypertension, skin rash, hypertriglyceridemia, hypophosphatemia

Crizotinib (Xalkori)

  • An inhibitor of RTKs, including ALK, MET, ROS1, and RON

  • FDA approved for locally advanced or metastatic ALK-positive NSCLC

  • Recommended dose: 250 mg orally twice daily

  • Half-life: 42 hours

  • Metabolism: Major CYP3A4 substrate and P-glycoprotein

  • Common side effects: Vision problems (diplopia, blurred vision), nausea/vomiting, diarrhea, dysphagia, GE reflux disease, reflux esophagitis, swelling of hands or feet, fatigue, dizziness, transaminitis (ALT increase)

  • Clinical pearls: Advise patients to exercise caution when driving or operating machinery because of the risk of developing visual changes such as floaters, blurred vision, light sensitivity, or flashes of light.

Dabrafenib (Tafinlar)

  • Alias: GSK2118436

  • Selectively binds to and inhibits the activity of BRAF, which may inhibit the proliferation of tumor cells that contain a mutated BRAF gene

  • FDA approved for the treatment of (1) unresectable or metastatic malignant melanoma in patients with the BRAF V600E mutation, and (2) in combination with trametinib, for BRAF-V600E-mutated metastatic NSCLC

  • Recommended dose: 150 mg orally twice daily on fasting stomach at least 1 hour before or 2 hours after meals

  • Half-life: Parent drug 8 hours; hydroxy-dabrafenib (active metabolite) 10 hours; desmethyl-dabrafenib (active metabolite) 21 to 22 hours

  • Metabolism: Major CYP2C8 and CYP3A4 substrates

  • Common side effects: Keratoacanthoma and squamous cell carcinoma, fatigue, arthralgias, pyrexia, papilloma, hyperglycemia, hyperkeratosis

  • Clinical pearls: Corticosteroids may be used as an effective fever prophylaxis when fever occurs.


  • Alias: PF-00299804

  • A second-generation small-molecule RTK inhibitor that irreversibly blocks multiple EGFR family receptors (EGFR, HER2, and HER4)

  • Phase 3 studies in metastatic or locally advanced NSCLC with activating EGFR mutations ongoing

  • Recommended phase 3 dose: 45 mg orally once daily

  • Terminal half-life: 51 hours

  • Metabolism: CYP2D6 substrate

  • Common side effects: Diarrhea, dermatitis acneiform (dry skin), stomatitis, paronychia, liver dysfunction (increased bilirubin, ALT/AST), palmar-plantar erythrodysesthesia

(Bello et al., 2012; Ramalingam et al., 2012)


  • Aliases: BEZ235, NVP-BEZ235

  • Orally bioavailable imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTORC1 kinase activity by binding to the ATP-binding cleft of these enzymes

  • Currently under investigation in phase 1/2 trials for renal cell carcinoma and for pancreatic, prostate, and breast cancer

  • Recommended phase 2 dose: 1,200 mg PO daily or 400 to 800 mg PO daily (in combination with chemotherapy). Taken with food/breakfast. No Seville orange juice or grapefruit juice

  • Half-life: ˜4 to 8 hours

  • Common side effects: Nausea/vomiting, fatigue/asthenia, anemia, anorexia, diarrhea

(Burris et al., 2010)

Daratumumab (Darzalex)

  • Aliases: Anti-CD38 monoclonal antibody; JNJ-54767414

  • A fully human mAb directed against the cell surface glycoprotein CD-38 that is found on the surfaces of hematopoietic cells, including MM cells.

  • FDA approved for the treatment of patients with MM previously treated with at least three prior regimens, including a proteasome inhibitor and an immunomodulatory agent and are refractory to it.

  • Recommended dose: 16 mg/kg (diluted) IV once every week for 8 weeks, once every 2 weeks for 16 weeks, then once every month thereafter. Need premedications with IV corticosteroids, oral acetaminophen, and IV diphenhydramine or an equivalent H1 antagonist

  • Half-life: ˜18 days

  • Side effects: Fatigue, headache, nausea, diarrhea, lymphocytopenia, neutropenia, thrombocytopenia, back pain, arthralgias, anemia, cough, upper respiratory tract infections, hypertension.

Dasatinib (Sprycel)

  • Alias: BMS-354825

  • Multityrosine kinase inhibitor that was specifically designed to inhibit SRC, which acts as a signal transducer in several molecular pathways within the cell, but was also found to inhibit BCR-ABL and imatinib-resistant mutations of BCR-ABL, except the T315I and F317V mutants; also inhibits KIT, EPHA2, and PDGFRβ

  • FDA approved for chronic or accelerated myeloid leukemia and Ph+ acute lymphoblastic leukemia

  • Recommended dose: 100 to 140 mg orally once daily (preferably with food)

  • Terminal half-life: 3 to 5 hours

  • Metabolism: Major CYP3A4 substrate

  • Common side effects: Myelosuppression, fluid retention (edema, pleural effusion), nausea/vomiting, diarrhea, headache, musculoskeletal pain, rash, fatigue

Denosumab (Xgeva)

  • Alias: AMG 162; Prolia (osteoporosis trade name)

  • A novel, fully human, highly specific, mAb against the RANKL. The protein is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

  • Blocks osteoclast activation, thereby resulting in reduced bone resorption (less bone breakdown)

  • FDA approved for postmenopausal women with a risk of osteoporosis (Prolia) and for the prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva)

  • Recommended dose: 120 mg Sub Q every 4 weeks. Calcium and vitamin D need to be administered in conjunction to avoid hypocalcemia.

  • Half-life: 28 days

  • Common side effects: Fatigue/asthenia, hypophosphatemia, nausea, diarrhea, hypocalcemia, weakness, arthralgia

  • Clinical pearls: Poor dental hygiene, ill-fitting dentures, or certain dental procedures may increase the risk for developing osteonecrosis.


  • Alias: TKI258, CHIR-258

  • A multitargeted RTK inhibitor, mostly for class III (FLT3/KIT), and also potent to class IV (FGFR1/3) and class V (VEGFR1-4) RTKs; less potent to EGFR, MET, EphA2, TIE2, IGF-1R, and HER2

  • Currently under investigation in phase 2 and 3 studies for GI stromal tumors, and FGFR-amplified breast cancer

  • Recommended phase 3 dose: 400 to 500 mg orally once daily (5 days on/2 days off)

  • Half-life: ˜13 hours

  • Metabolism: CYP1A2 substrate

  • Common side effects: Fatigue, diarrhea, nausea

(Kim et al., 2011)

Durvalumab (Imfinzi)

Sep 29, 2018 | Posted by in ONCOLOGY | Comments Off on Targeted and Immunotherapy Agents
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