Novel Anticancer Agents

Authors: Richard Thomas, Katherine Krajewski, Atul Shinagare

Date: January 11, 2021

VEGF Inhibitors

Indications

  • Axitinib – RCC
  • Bevacizumab – colorectal cancer, NSCLC, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, RCC and glioblastoma. Off label use in retinal vein occlusion, diabetic macular edema and age-related macular degeneration
  • Sunitinib – RCC, GIST, pancreatic neuroendocrine tumor
  • Sorafenib – RCC, HCC, metastatic differentiated thyroid carcinoma
  • Pazopanib – RCC, advanced soft tissue sarcoma
  • Cabozantinib – RCC, HCC
  • Regorafenib – GIST, HCC, colorectal cancer
  • Ponatinib – BCR-ABL positive CML and AL

ALK Inhibitors

Indications

  • Crizotinib – ALK positive NSCLC, ROS-1 positive lung cancer
  • Ceritinib, Alectinib, Brigatinib, Lorlatinib – ALK positive NSCLC
  • Entrectinib – ROS-1 positive NSCLC and NTRK gene fusion positive solid tumors

ROS Inhibitors

Indications

  • Crizotinib – ALK positive NSCLC, ROS-1 positive lung cancer
  • Lorlatinib – ALK positive NSCLC
  • Entrectinib – ROS-1 positive NSCLC and NTRK gene fusion positive solid tumors

BCR-ABL Inhibitors and PDGFR i\Inhibitors

Indications

  • Imatinib – BCR-ABL mutated CML and ALL; and GIST
  • Dasatinib, Nilotinib, Ponatinib – BCR-ABL mutated CML and ALL
  • Bosutinib – BCR-ABL mutated CML
  • Regorafenib – GIST, HCC, colorectal cancer
  • Sorafenib – RCC, HCC, metastatic differentiated thyroid carcinoma
  • Pazopanib – RCC, advanced soft tissue sarcoma

PARP Inhibitors

Indications

  • Olaparib – BRCA mutated breast cancer, BRCA mutated ovarian cancer, BRCA mutated pancreatic cancer
  • Rucaparib, Niraparib – BRCA mutated ovarian cancer
  • Talazoparib – BRCA mutated breast cancer
  • Veliparib – in clinical trials

EGFR Inhibitors

Indications

  • Gefitinib, erlotinib, icotinib, dacomitinib, osimertinib – EGFR mutated NSCLC
  • Afatinib – squamous cell lung cancer and EGFR mutated NSCLC
  • Brigatinib – ALK mutated NSCLC
  • Neratinib, Lapatinib – HER2 positive breast cancer
  • Vandetanib – medullary thyroid cancer
  • Cetuximab – metastatic colorectal cancer, metastatic head and neck cancer
  • Panitumumab – ‘wild-type RAS’ metastatic colorectal cancer
  • Rociletinib, Naquotinib – in clinical trials

RET, MET, KIT, PI3K inhibitors

Indications

  • Idelalisib, duvelisib – chronic lymphocytic leukemia, lymphoma
  • Copanlisib – relapsed follicular lymphoma 
  • Alpelisib – breast cancer 
  • Umbralisib – breakthrough therapy status for marginal zone lymphoma
  • Gedatolisib and Apitolisib – in clinical trials

Indications for RET, MET and KIT inhibitors are discussed under other targets

RAF Inhibitors

Indications

  • Dabrafenib and vemurafenib – BRAF V600E mutation positive Melanoma (frequently used in combination with MEK inhibitor)
  • Vemurafenib – BRAF V600E mutation positive Erdheim-Chester disease
  • Dabrafenib – BRAF V600E mutation positive non small cell lung cancer and anaplastic thyroid cancer
  • Encorafenib in combination with Binimetinib – BRAF V600E mutation positive melanoma

MEK Inhibitors

Indications

  • Trametinib and Cobimetinib (alone or in combination with MEK inhibitors)- advanced melanoma
  • Binimetinib in combination with Encorafenib – BRAF V600E mutation positive melanoma
  • Trametinib in combination with Dabrafenib – BRAF V600E mutation positive non small cell lung cancer, melanoma and anaplastic thyroid cancer

mTOR Inhibitors

Indications

  • Everolimus – renal cell cancer, pancreatic/gastrointestinal/lung neuroendocrine tumor, breast cancer, tuberous sclerosis complex (TSC)-associated partial-onset seizures, TSC-associated subependymal giant cell astrocytoma, TSC-associated renal angiomyolipoma
  • Temsirolimus – renal cell cancer
  • Sirolimus – lymphangioleiomyomatosis, coating of coronary stents
  • Ridaforolimus, gedatolisib, apitolisib – in clinical trials

BTK Inhibitors

Indications

  • Ibrutinib – Mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia, marginal zone lymphoma, chronic graft versus host disease

Hedgehog Pathway Inhibitors

Indications

  • Vismodegib – Basal cell carcinoma

CDK Inhibitors

Hedgehog Pathway Inhibitors

Indications

  • Palbociclib, abemaciclib, ribociclib – HR+/HER2 advanced or metastatic breast cancer (used in combination with hormonal agent)
  • Trilaciclib – in clinical trials

HER2 Inhibitors

Indications

  • Trastuzumab – HER2 positive breast cancer and HER2 positive gastric cancer
  • Pertuzumab, Ado-trastuzumab emtansine – HER2 positive breast cancer
  • Neratinib, Lapatinib – HER2 positive breast cancer

Methyl Transferase Inhibitor

Indications

  • Tazemetostat – advanced epitheloid sarcoma
  • In clinical trials for mesothelioma, non-hodgkin’s lymphoma, soft tissue sarcomas

Immune Checkpoint Inhibitors

Indications

  • Ipilimumab alone – advanced melanoma, reduce risk of recurrent melanoma after surgery
  • Nivolumab – melanoma, NSCLC, SCLC, RCC, HCC, Hodgkin’s lymphoma, head and neck cancer,  urothelial carcinoma, microsatellite instability high (msi-high) or DNA mismatch repair deficient (mmr-d) colorectal cancer and solid tumors
  • Ipilimumab with Nivolumab –  melanoma, RCC, msi-high or mmr-d colorectal cancer
  • Pembrolizumab – melanoma, NSCLC, SCLC, RCC, HCC, Hodgkin’s lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL),  head and neck squamous cell cancer,  urothelial carcinoma, msi-high or mmr-d colorectal cancer and solid tumors, gastric cancer, esophageal cancer, cervical cancer, Merkel cell carcinoma, endometrial carcinoma
  • Cempilimab – advanced cutaneous squamous cell carcinoma
  • Atezolizumab – triple negative breast cancer, urothelial cancer, small cell lung cancer, non-small cell lung cancer
  • Avelumab – merkel cell carcinoma, urothelial carcinoma, RCC
  • Durvalumab – Bladder cancer, non small cell lung cancer

Anti-lymphocyte Antibodies

Anti CD 20 (B lymphocytes)

  • Rituximab – CLL, NHL, waldenstrom’s macroglobulinemia, granulomatosis with polyangiitis, microscopic polyangiitis, pemphigus vulgaris, rheumatoid arthritis
  • Obinutuzumab – CLL, follicular lymphoma
  • Ofatumumab – CLL
  • Ibritumomab tiuxetan (antibody conjugated Y-90 or In-111 ) – NHL. 

Anti CD52 (Mature B and T lymphocytes)

  • Alemtuzumab – multiple sclerosis

Anti CD30 (activated T and B cells)

  • Brentuximab Vedotoxin – Hodgkin’s lymphoma, systemic/cutaneous anaplastic large cell lymphoma, CD30-expressing peripheral T-cell lymphomas (PTCL)

Hormonal Agents

Selective estrogen receptor modulator (SERM)

  • Tamoxifen – HR+ breast cancer

Selective Estrogen Degrader

  • Fulvestrant – HR+ breast cancer as monotherapy or in combination with abemaciclib

Aromatase inhibitor

  • Letrozole, Anastrozole, exemestane – post-menopausal women with HR+ breast cancer

LHRH agonists

  • Leuprolide, Goserelin, Triptorelin, Histrelin – prostate cancer, endometriosis

LHRH antagonists

  • Degarelix  – prostate cancer

CYP17A1 inhibitor

  • Abiraterone – prostate cancer

Androgen receptor antagonist

  • Flutamide, Nilutamide, Bicalutamide, enzalutamide, apalutamide, darolutamide – prostate cancer 

Targets and Toxicities

Drug Class Drugs Additional Targets Toxicities
VEGF inhibitors

Kinase inhibitor – axitinib, cabozantinib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib
Antibodies – ziv-aflibercept, bevacizumab

Cabozantinib – RET, MET and KIT
Pazopanib – KIT and PDGFR Ponatinib – BCR-ABL, RET, KIT and PDGFR
Regorafenib – BCR-ABL, RET, KIT, PDGFR and RAF
Sorafenib – RET, KIT, PDGFR and RAF
Sunitinib – RET, KIT and PDGFR

 hemoptysis, GI bleed, CNS hemorrhage, GI pneumatosis, perforation, fistula, arterial and venous thromboembolic events, delayed wound healing, hypertension, PRES
ALK inhibitors (+ROS inhibitors) crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib Crizotinib, Lorlatinib, Entrectinib – ROS pneumonitis, arterial and venous thromboembolic events, hepatitis, pleural effusion, Crizotinib associated renal cysts.
BCR-ABL inhibitors (+PDGFR inhibitors) Imatinib, dasatinib, bosutinib, nilotinib, ponatinib, regorafenib, Nilotinib – BCR-ABL, PDGFR
Imatinib, Dasatinib – BCR-ABL, KIT, PDGFR
Ponatinib – BCR-ABL, RET, KIT, PDGFR, VEGF
Regorafenib – BCR-ABL, RET, KIT, PDGFR, VEGF, RAF
Pazopanib – PDGFR, VEGF, KIT
Sorafenib – PDGFR, RET, KIT, RAF
Sunitinib – PDGFR, RET, KIT		 Imatinib – fluid retention, QTc prolongation, cardiac failure, hepatotoxicity, cytopenia.
Dasatinib – fluid retention, cytopenia, hemorrhage, diarrhea , pneumonitis.
Bosutinib – cytopenia, diarrhea
Nilotinib – arterial occlusive disease, Raynaud’s phenomenon, pulmonary hypertension.
Ponatinib, Regorafenib, Pazopanib, Sunitinib and Sorafenib – toxicities seen with VEGF inhibitors
PARP inhibitors Olaparib, Rucaparib, Niraparib, Talazoparib, Veliparib   Cytopenia, Diarrhea, Pneumonitis, Myelodysplastic syndrome, Acute myeloid leukemia
EGFR inhibitors

Kinase inhibitors:

  • First generation – gefitinib, erlotinib, icotinib
  • Second generation – afatinib, dacomitinib
  • Third generation – osimertinib, rociletinib, olmutinib, naquotinib
  • Others – brigatinib, neratinib, lapatinib, dacomitinib, vandetanib
Antibodies: cetuximab, panitumumab

Brigatinib – EGFR and ALK
Neratinib, Afatinib, Lapatinib, Dacomitinib – EGFR and HER2
Vandetanib – EGFR, VEGF and RET

Skin rash, Hepatitis, Diarrhea, Pneumonitis
RET, MET, KIT inhibitors

RET inhibitors:
Cabozantinib, alectinib, ponatinib, regorafenib, sorafenib, sunitinib, vandetanib
MET inhibitors:
Cabozantinib, crizotinib, trametinib
KIT inhibitors:
Cabozantinib, dasatinib

Cabozantinib – VEGF
Alectinib – ALK
Ponatinib – VEGF, BCR-ABL, PDGFR
Regorafenib, Sorafenib – VEGF, BCR-ABL, PDGFR, RAF
Sunitinib – VEGF, PDGFR
Vandetanib – VEGF, EGFR
Crizotinib – ALK, ROS
Trametinib – MEK
Dasatinib – BCR-ABL, PDGFR

 see sections for the additional targets
PI3K inhibitors Idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, gedatolisib, apitolisib Gedatolisib, Apitolisib – mTOR

Hyperglycemia/hypoglycemia, hypertension, hepatitis, colitis, pneumonitis, autoimmune dysfunction
RAF inhibitors

Dabrafenib, Vemurafenib, Encorafenib, Regorafenib
PDGFR, RET, KIT, RAF – Sorafenib

Regorafenib – BCR-ABL, RET, KIT, PDGFR, VEGF, RAF.
Sorafenib – PDGFR, RET, KIT, RAF

Cutaneous toxicities: cutaneous squamous-cell carcinoma, hyperkeratotic lesions, Grover’s disease (transient acantholytic dermatolysis), keratosis pilaris-like reactions, and photosensitivity
Diarrhea, hepatitis, pneumonitis
Regorafenib and Sorafenib – toxicities associated with VEGF inhibitors
MEK inhibitors Trametinib, cobimetinib, binimetinib Trametinib – MET Diarrhea, colitis, gastrointestinal perforation, hypertension, cardiomyopathy
BTK inhibitor Ibrutinib    Atrial fibrillation, diarrhea, rash, Pneumonitis, hypertension, neutropenia
mTOR inhibitors sirolimus, temsirolimus, everolimus, ridaforolimus, gedatolisib, apitolisib Gedatolisib, Apitolisib – mTOR, PI3K

Pneumonitis, hyperglycemia, hyperlipidemia, mucositis
Hedgehog pathway inhibitors Vismodegib   Nausea, vomiting, diarrhea, dysgeusia, hair loss
CDK inhibitors Palbociclib, abemaciclib, ribociclib, trilaciclib   Leukopenia, diarrhea, QTc prolongation, hepatitis
HER2 inhibitors

Monoclonal antibodies: Trastuzumab, Pertuzumab, Ado-trastuzumab emtansine (trastuzumab conjugated with emtansine).  
Small molecule kinase inhibitors: Neratinib, Afatinib, Lapatinib, Dacomitinib

 Neratinib, Afatinib, Lapatinib, Dacomitinib – EGFR Cardiotoxicity – left ventricular dysfunction and heart failure, diarrhea, rash, cytopenia, hepatitis
Methyl transferase inhibitor Tazemetostat  

Cardiotoxicity – left ventricular dysfunction and heart failure.

Diarrhea, rash, cytopenia, hepatitis
Immune checkpoint inhibitors

CTLA4 inhibitor – Ipilimumab
PD1 inhibitor – Nivolumab, Pembrolizumab, Cempilimab
PDL1 inhibitor – Atezolizumab, Avelumab, Durvalumab

   Colitis, Hepatitis, Pancreatitis, Hypophysitis, endocrine gland inflammation and insufficiency, Pneumonitis, myocarditis, vasculitis, accelerated atherosclerosis, Sarcoid like reaction, myofasciitis, arthritis, periarthritis
Anti-CD20 Obinutuzumab, Ofatumumab, Rituximab, Ibritumomab tiuxetan  

Cytokine release syndrome (Fever, cytopenia, headache, confusion, tachypnea, tachycardia, myalgia, arthralgia, rash, hepatitis, splenomegaly).  

Pneumonitis, Progressive multifocal leukoencephalopathy, HBV reactivation, Opportunistic infections
Anti-CD52 Alemtuzumab   Infections, cardiac failure, arrythmia, vomiting, rash
Anti-CD30 Brentuximab Vedotoxin   Infection, peripheral neuropathy, diarrhea
Selective estrogen receptor modulator (SERM) Tamoxifen, Toremifene   Fatty liver, endometrial hyperplasia, endometrial cancer, uterine sarcoma, thromboembolic events, hot flashes, depression, vaginal bleeding
Selective estrogen degrader Fulvestrant  

Hepatitis, thromboembolism, bone pain, arthralgia, hot flashes, vomiting, anorexia, constipation
Aromatase inhibitor Letrozole, Anastrozole, Exemestane   Osteoporosis, bone pain, hot flashes, vomiting, anorexia, constipation
Luteinizing hormone-releasing hormone (LHRH) agonists Leuprolide, Goserelin, Triptorelin, Histrelin  

Osteoporosis, hot flashes, nausea, diarrhea, constipation, vaginal bleeding, fluid retention
Luteinizing hormone-releasing hormone (LHRH) antagonists Degarelix   QT prolongation, hot flashes, weight gain
CYP17A1 inhibitor Abiraterone, Ketoconazole   Hepatitis, cardiac failure, hypertension, myopathy, gynecomastia
Androgen receptor antagonist Flutamide, Bicalutamide, Nilutamide, Enzalutamide, Apalutamide, Darolutamide   Gynecomastia, hepatitis, hot flashes, osteoporosis
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