SACT: Systemic Anti-Cancer Therapies

Comprehensive flashcards covering drug mechanisms, indications, and hallmark toxicities; mostly from Dr Westerman's notes on Systemic Anti-Cancer Therapy.

Abemaciclib

MOA: CDK4/6 inhibitor that crosses the blood-brain barrier

Tumour: breast cancer

SE: diarrhoea, neutropenia, and increased LFTs/creatinine.

Abiraterone

MOA: selectively inhibits the $CYP17$ enzyme to reduce androgens

Tumour: prostate

Must be administered with prednisolone to offset mineralocorticoid excess.
(sx: hypokalaemia, hypertension, fluid retention) + liver tox, angina, arrhythmia

Abraxane (Nab-paclitaxel)

MOA: nanoparticle albumin-bound formulation of paclitaxel; promotes microtubule assembly and stabilisation - inhibiting mitosis and inducing apoptosis

Tumour: metastatic breast Ca, advanced NSCLC, metastatic pancreatic ca

Does not require steroid premedication, has a shorter infusion time ($30$ minutes), and is associated with fewer hypersensitivity reactions — due to not using Cremophor EL.

Afatinib / Dacomitinib

MOA: 2nd generation EGFR tyrosine kinase inhibitor (TKI), crosses BBB (also has activity on HER2/HER4)

Tumour: EGFR mut NSCLC (exon 19 del, exon 21 sub)

SE: high rates ($96\%$) of diarrhoea, rash, LVEF dysfunction, GI perforation, paronychia.

Alectinib

MOA: potent receptor tyrosine kinase inhibitor selective for $ALK$ and $RET$

Tumour: ALK-positive NSCLC

SE: myalgia, bradycardia (AV block), photosensitivity, vision disorders, liver tox

Alpelisib

MOA: selectively inhibits $PI3K$ in the $PI3K/AKT/mTOR$ pathway

Tumour: hormone-positive metastatic breast cancer

SE: significant risk of hyperglycaemia, rash/DRESS

! can increase warfarin concentrations !

Lorlatinib

MOA: $ALK$ TKI , high CNS activity

Tumour: ALK positive NSCLC

SE: CNS and psychiatric side effects - mood changes, speech disturbances, and hallucinations. Hyperlipidaemia.

Anastrozole

MOA: reversible, type 2, nonsteroidal aromatase inhibitor - stops oestrogen production in peripheral tissues, primarily fat.

Tumour: hormone-positive Breast Ca

SE: peripheral oedema, hot flush, osteoporosis, arthralgia/myalgia

Enzalutamide

MOA: potent androgen receptor inhibitor, crosses BBB

Tumour: Prostate Ca

SE: risk of seizures, cognitive deterioration, falls

! interacts with DOACs/warfarin, gemfibrozil

Apalutamide

MOA: androgen receptor inhibitor, crosses BBB

Tumour: prostate Ca

SE: higher rates of rash and hypothyroidism ($22\%$), fractures, seizures, rash, IHD

Atezolizumab

MOA: PD-L1 blockade immunotherapy
Tumour:

• NSCLC (monotherapy after complete resection PD-L1 >1% OR in chemo-naive metastatic setting)

• bladder cancer (if cisplatin unsuitable)

• TNBC with PDL>1% (combi with pacli)

• ES-SCLC 1L with EP

• HCC (1L).

monotherapy ~9% grade3/4 tox

Bevacizumab (Avastin)

MOA: monoclonal antibody that binds VEGF-A - inhibit angiogenesis

Tumour: mets colorectal Ca, Ovarian Ca, Cervical Ca, renal cell carcinoma, glioblastoma

SE: notable for risks of GI perforation, impaired wound healing, proteinuria, VTE/bleeding, and hypertension.

Axitinib

MOA: second-generation VEGFR inhibitor TKI with a short half-life

Tumour: second-line for RCC after dailure of 1L Rx (sunitinib or pazopanib) or a cytokine

SE: hypertension and dysphonia, DVT/PE, thrombocytopaenia/haemorrhages, cardiac tox, CRVO/CRAO, proteinuria, posterior leukoencephalopahty syndrome

Short half-life = rapid dose changes allowed

Bleomycin

MOA: anti-tumour antibiotic that binds to DNA to cause unwinding and single and double strand breaks through generation of free radicals —> inhibition of DNA synthesis and apoptosis

Tumours: BEP for germ cell, ABVD for Hodgkin’s lymphoma

SE: lung toxicity, hypersensitivity, skin/nail changes

* has a cumulative maximum lifetime dose of $400\,\text{units}$ due to pulmonary fibrosis risk.

Cabozantinib

MOA: multi-target TKI (VEGR 1-3, MET, AXL, RET, KIT, etc.) - reduces angiogenesis, tumour growth, invasion and mets; also overcomes resistance mechanisms to VEGFR inhibition

—> broad activity, good in bone mets, higher GI tox risk

Tumour:

• advanced RCC - 1L in intermediate/poor risk disease or after VEGFR-targeted therapy

• HCC - previously treated with sorafenib

• medullary thryoid carcinoma that is unresectable/metastatic

SE: HTN, diarrhoea, PPE, stomatitis, wound healing, GI perforation, liver tox, osteonecrosis of jaw

Capecitabine

MOA: oral prodrug of 5-FU that inhibits DNA/RNA synthesis in the S phase; antimetabolites - affect nucleotide production (no direct DNA damage, thus less issues with 2nd cancers)

^ key enzyme to activate - thymidine phosphorylase. Metabolised in the liver by DPD.

Tumour: breast and colorectal Ca mainly, sometimes pancreatic cancer

SE: PPE, diarrhoea, cardio tox (less than 5-FU), acute cerebellar syndrome

note: 5-FU preferred in renal disease or Cr <50 umol/L

Dihydropyrimidine dehydrogenase (DPD)

The key enzyme that metabolises fluoropyrimidines (capecitabine/5FU); deficiency leads to reduced drug clearance and life-threatening toxicities like severe mucositis and myelosuppression.

Inherited autosomal recessive; if partial deficiency can give fluoropyriomidines with 50% DR. (If complete then not to give)

Treatment: stop drug and supportive treatment + Uridine triacetate (early antidote)

Cetuximab

MOA: chimeric monoclonal antibody that blocks the extracellular domain of EGFR

Tumour: RAS wild-type metastatic colorectal cancer, and head and neck cancer.

SE: rash/folliculitis, hypoMg, interstitial lung disease

Cisplatin

MOA: platinum-based agent that forms DNA crosslinks

Tumours: various

SE: highly emetogenic and carries serious risks of nephrotoxicity, ototoxicity, and peripheral neuropathy. Can cause AML later in life. Azoospermia

*Carboplatin - used instead when concerns re: renal function, lower PS, or hearing loss.

Cyclophosphamide

MOA: nitrogen mustard alkylating agent and pro-drug that crosslinks DNA at the N7 guanine position, blocks DNA replication and RNA transcription

SE: myelosuppression, azoospermia, haemorrhagic cystitis and SIADH-like syndrome.

Doxorubicin

MOA: anthracycline and topoisomerase II inhibitor

SE: vesicant, cardio-tox

! cumulative maximum dose of $450\,\text{mg/m}^2$ due to dose-dependent cardiotoxicity from oxidative stress.

note: Epirubicin - different 3D structure —> less toxic and eliminated more quickly (cumul max dose 900 mg/m2)

Everolimus

MOA: oral inhibitor of mTORC1

Tumours: mHER2-neg breast cancer (combi with exemestane) and RCC (after progression on VEGF targeted therapy)

SE: associated with non-infectious pneumonitis, stomatitis, and hyperglycaemia.

Irinotecan

MOA: topoisomerase 1 inhibitor that causes double DNA strand breaks in the S phase (Topo-1 enzyme produces reversible single-strand breaks for normal DNA replication)

Tumour: colorectal mainly, sometimes upper GI/pancreas

SE: acute cholinergic syndrome (“on chair”), profound alopecia (quick), and early/late-onset diarrhoea. Need normal bili to treat - screen for Gilbert’s syndrome (as can increase toxicity).

metabolised to SN 38 – this causes diarrhoea through direct damage to GI mucosa

!UGT1A1 polymorphism increases toxicity

Methotrexate

A folate analogue and $DHFR$ inhibitor; it can accumulate in third-space fluids (ascites, pleural effusion) leading to life-threatening toxicity.

Mitomycin C

A blue-coloured anti-tumour antibiotic and vesicant that acts like an alkylating agent; carries risks of $HUS$ and delayed myelosuppression.

Olaparib

A $PARP$ inhibitor that blocks single-strand DNA break repair, leading to synthetic lethality in cells with $BRCA$ mutations.

Osimertinib

MOA: third-generation, irreversible EGFR TKI selective for sensitising mutations and the T790M resistance mutation; effectively penetrates the CNS.

Tumour: EGFRmut NSCLC

SE: Rash, diarrhoea, QT prolongation, ILD

Oxaliplatin

MOA: platinum agent, synergistic with 5-FU; cross-linking of DNA

Tumour: CRC

SE: cold-induced acute peripheral sensory neuropathy, pharyngolaryngeal dysthesiae, extravasation → warm compress.

Pemigatinib

MOA: oral selective fibroblast growth factor inhibitor (targets FGFR1, FGFR2, FGFR3)

Tumour: cholangiocarcinoma with FGFR2 fusions.

SE: severe hyperphosphataemia leading to soft tissue mineralisation, ocular toxicity such as central serous retinopathy, and severe gastrointestinal or hepatic adverse events.

Sacituzumab govitecan

MOA: antibody-drug conjugate (ADC) targeting Trop-2 coupled with the topoisomerase 1 inhibitor SN-38

Tumour: metastatic breast

SE: Hypersensitivity reactions

Sorafenib

MOA: multi-kinase inhibitor that targets RAF and VEGFR

SE:  PPE, hand foot syndrome, cardiac toxicity, HTN, GI perforation, diarrhoea, fatigue, haemorrhage (VEGF), yellow colouration of skin

Trastuzumab (Herceptin)

MOA: monoclonal antibody targeting HER2 receptor

Tumour: HER2+ve breast and HER+ve gastric/GOJ

SE: reversible cardiomyopathy

!overexpression of PI3K/AKT implicated in resistance

Vinca alkaloids

Eg. Vincristine, Vinorelbine, Vinblastine

MOA: binds to beta-tubulin to inhibit mitotic spindle formation through de-stablisation; they are vesicants uniquely managed with warm compresses and hyaluronidase.

Zoledronic acid

A nitrogen-containing bisphosphonate (stops osteoclast activity); only drug licensed for hypercalcaemia of malignancy; requires dental assessment to prevent osteonecrosis of the jaw.

Uridine triacetate

The emergency antidote for fluoropyrimidine (5-FU or capecitabine) overdose or life-threatening early-onset toxicity; must be started within 96 hours of the last dose.

Crizotinib

MOA: ALK, ROS1, MET TKI

Tumour: NSCLC ALK+ or ROS+

SEs: visual changes, oedema, nausea

Ceritinib

MOA: ALK TKI

Tumour: NSCLC ALK+

SE: GI toxicity, hepatotoxicity

Alectinib

MOA: ALK TKI - high CNS activity

Tumour: NSCLC ALK+ — mainly adjuvant setting

SE: myalgia, constipation, oedema

Brigatinib

MOA: ALK (anaplastic lymphoma kinase) TKI - high CNS activity

Tumour: NSCLC ALK+ —> particularly patients who progressed/intolerant on crizotinib

SE: early pulmonary toxicity, liver tox, bradycardia

Entrectinib

MOA: NTRK, ROS1, ALK TKI

Tumour: NTRK+ solid tumours, NSCLC ROS1+

SE: CNS effects, weight gain

Loratrectinib

MOA: NTRK TKI

Tumour: NTRK+ solid tumours

SE: fatigue, dizziness

Sunitinib, sorafenib, pazopanib, axitinib

MOA: VEGFR TKIs

SE: fatigue, confusion, rare PRES (CNS tox not common)

• Sunitinib → fatigue, mucositis, hypothyroidism, hand–foot syndrome.

• Pazopanib → LFT derangement, hair depigmentation

• Tivozanib → cleaner VEGFR inhibition, fewer off-target toxicities.

Darolutamide

MOA: Androgen receptor inhibitor - distinct scaffold, limits BBB crossing

Tumour: Prostate Ca

SE: fatigue, cardiac tox, arthralgia, hypertension

Avelumab

MOA: PDL1 blockade

Tumours:

• mets RCC in combi with axitinib

• untreated metastatic Merkel cell cancer

• Bladder: maintenance after 1L platinum-containing combi chemo

~9% grade3/4 tox

Busulfan

MOA: alkylating agent - selective action on blood cells

Tumour: CML and bone marrow transplant

SE: veno-occlusive disease, marrow aplasia, pulmonary fibrosis

Etoposide

MOA: inhibits DNA topiosomerase II - prevents DNA re-ligation, disrupting DNA replication process (mainly in S & G2 phase) —> DNA damage —> apoptosis

Tumour: BEP in germ cell, carbo-etop in small cell lung Ca

SEs: myelosuppression, alopecia, rash, LFTs, temporary bluish sclera/urine/nails

Palbociclib

MOA: CDK4/6 inhibitor

Tumour: ER-pos, HER2-neg breast Ca (metastatic setting)

SEs: neutropaenia, fatigue, nause, alopecia, stomatitis

Ribociclib

MOA: CDK4/6 inhibitor

Tumour: ER-pos, HER2-neg breast Ca

SEs: neutropaenia, hepatotoxicity, QT prolongation

CDK4/6 mechanism of resistance?

Loss of Rb1

Also: ESR1 mutations —> use elacestrant

Gemcitabine

MOA: antimetabolite - pyrimidine nucleoside analogue; works by mimicking natural building blocks of DNA, disrupting replication, affects ribonucleotides production, inhibits self-metabolism. “dirty drug”

Tumour: NSCLC, ovarian, breast, pancreatic (more active in solid tumours than ARA-C)

SEs: liver toxicity/transaminitis (if no bili rise, no need for DR), pulmonary syndrome, myelosuppression, flu-like symptoms, HUS

! NOT to be given with thoracic radiotherapy

Cytarabine

MOA: Antimetabolites - pyrimidine analogue - affect nucleotide production, no direct damage to DNA

Tumour: AML

SE: myelosuppression, neurotox (crosses BBB) - namely cerbellar neurotox, blurry vision (steroid eyedrops), cholestatic jaundice, pulmonary syndrome

Caelyx (pegylated liposomal doxorubicin)

MOA: doxorubicin encapsulated in pegylated liposomes - prolonged circulation time and preferential tumour acculation via enhanced permeability and retention (EPR) effect. Reduces peak plasma concentrations —> slower action but less toxicity, less hair loss, nausea, and cardiotox.

Tumour: recurrent ovarian, metastatic breast, Kaposi sarcoma (1L)

SE: more PPE, secondary malignancies, cardiomyopathy, more hypersensitivity reactions than doxorubicin

Erlotinib / Gefitnib

MOA: reversible EGFR TKIs (1st generation)

Tumour: NSCLC with EGFRmut (exon 19 del or L858R)

SE: rash, diarrhoea

Tucatinib

MOA: HER2 selective TKI - good CNS penetration

Tumour: HER2+ metastatic breast cancer (in combi with Trastuzumab and capecitabine)

SE: diarrhoea, hepatotox

Lapatinib / Neratinib

MOA: TKIs targeting HER2, EGFR

Tumour: HER2+ breast cancer

SE: diarrhoea, (and lapatinib has rash/hand-foot syndrome)

Eribulin

MOA: microtubule dynamics inhibitor - prevents formation of mitotic spindles

Tumour: metastatic breast, unresectable liposarcoma previously treated with anthracycline

SE: QT prolongation, neuropathy, myelosuppression

FOLFOX

5-FU, leucovorin, and oxaliplatin.

MOA: targeting DNA synthesis and repair;

• Oxaliplatin = platinum analogue, causes DNA crosslinking, leading to inhibition of DNA replication and cell death.

• 5FU = pyrimidine analogue that inhibits thymidylate synthase, thereby blocking DNA synthesis.

• Leucovorin enhances the binding of 5FU to its target enzyme, increasing cytotoxicity.

Tumours: colorectal and upper GI

SE: PSN (oxaliplatin - also cold induced dysaesthesia), coronary vasospasm with 5FU, diarrhoea, PPE (milder than cape)

Ifosfamide

MOA: alkylating agent - nitrogen mustards; Interstrand crosslinks, bifunctional electrophiles, prefer to react with guanine

SE: neuro-toxicity - treat with methylene blue, haemorrhagic cystitis - treat with mesna, Fanconi syndrome with renal tubular damage

Ipilimumab

MOA: CTLA-4 immunotherapy blockade

Given as combo Ipi/Nivo in: melanoma, NSCLC, RCC (int/poor risk), mesothelioma, MSI-H/dMMR mCRC after chemo

^ Grade 3 toxicities ~55-59%

Pembrolizumab

MOA: PD-1 immunotherapy blockade

monotherapy ~18% grade3/4 tox

Nivolumab

MOA: PD-1 immunotherapy blockade

~16% monotherapy grade3/4 tox

Durvalumab

MOA: PD-L1 immunotherapy blockade

~30% grade3/4 tox

Relatlimab

MOA: LAG-3 immunotherapy blockade

Given in combi with Nivo (Opdualag) ~18.9% grade3/4 tox

Tremelimumab

MOA: CTLA-4 immunotherapy blockade, IgG2

Pemetrexed

MOA: antimetabolites (no direct DNA damage);

• Inhibits thymidine synthase

• Inhibits dihyrofolate reductase

• Inhibits GARFT

Tumour: NSCLC - adenocarcinoma

SE:   Must be given with folic acid and B12 to decrease haematological and GI toxicity (High levels of homocysteine at baseline are a marker of endogenous B12 deficiency and also predict pemetrexed toxicity)

Docetaxel

MOA: Taxane, inhibits microtubular disassembly; binds β-tubulin subunit, preventing depolymerisation and thus blocking mitotic spindle disassembly

SE: PSN, skin + nail changes, neutropaenia, fluid retention

Temozolamide

MOA: Alkylating agent – triazenes. Mono-alkylating at 06, does not required CYP metabolism; crosses BBB

*NB: dacarbazine requires CYP metabolism

06 methylation is removed by MGMT enzyme

Tumour: GBM, metastatic uveal melanoma as 2^nd line treatment after IO
^ Works best in MGMT methylated GBM

SE: predominately lymphopenia, hepatic toxicity, photosensitive rash

Tebentafusp

MOA: bispecific, fusion protein - binds gp100 peptide x CD3

Tumour: Licensed for HLA-A*2010 (Uveal melanoma)

Enfortumab Vedotin

MOA: ADC targeting Nectin-4 → cytotoxic payload intracellularly when MMAE released —> microtubule disruption

Tumour: Urothelial carcinoma (high nectin-4 expression)

SE: PSN, hyperglycaemia, ocular irritation, GI symptoms

Calvert formula

Dose = target AUC x (GFR + 25)