test - RAD-ASSIST

Mechanisms of Action and Indications

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

VEGF inhibitors

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

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