Note on Drugs for Lung Cancer

Question 1

What type of Lung cancer are EGFR mutations typically associated with?

Answer 1

Adenocarcinomas

Question 2

What EGFR monoclonals are used to treat lung cancer?
• what type of lung cancer are they used to treat?
• MOA?

Answer 2

Necitumumab Panitumumab

• Indicated in SQUAMOUS NSCLC

MOA: Competitively block binding of EFT and TGF-alpha to EGFR inhibiting receptor autophosphorylation

Question 3

How is activity of Tyrosine Kinase Inhibitors, specifically EGFR, Blocked?

Answer 3

• Binding Site Mutation
• Increased activity of MET (phosphorylating enzyme)
• Binding of HGF to HGFR to kick of the PI3K/Akt path

Question 4

When TK inhibitors loose their efficacy in a patient, what mutations (2) are likely to have occured?
• How do these mutations differ in their ability to make TKIs less effective?

Answer 4

Mutations that change cell sensitivity to TK singaling:
• Exon 19 (in-fram deletion)
• Point mutation in exon 21 (L858R)

Mutations (or natural varients) with Mutated ATP binding site:
• T790M
**Note: T790M may naturally occur**

Question 5

What downstream mutations may be used to render anti-EGFR (mAbs or PKIs) drugs useless?

Answer 5

Mutatations in any downstream enzyme can render the drug ineffective

Question 6

Why is it bad when genes fuse to yeild fusion proteins with ALK?
• What is the primary mutation involving the ALK gene that leads to NSCLC?
• what pathway is kicked off?

Answer 6

Mutations involving the formation of ALK fusion proteins leads to the formation of constitutively activated Tyrosine Kinases
• EML4-ALK is the most common (seen in non-smokers, light smoking history, and pts. with adenocarcinomas)
• MEK/ERK, PI3K, JAK-STAT path is activated

Question 7

What is the relationship between VEGF, VHL, and HIF-1alpha?

Answer 7

VHL lets off of hypoxia inducible factor -1 (HIF-1) in hypoxic conditions typically so that HIF-1 can induce the transciption of growth factors including VEGF to reduce hypoxia

Question 8

What are the down sides to using and anti-VEGF drug?

Answer 8

1. Reduction in vasculature may reduce the distribution of concurrent chemotherapy
2. Selection for the most aggressive cells may occur

Question 9

What are some mutations that are seen more often in NSCLC in non-smokers than smokers?
• What is the most common in smokers?

Answer 9

Most common mutation in smokers:
• KRAS (30-40%)

Mutations more common among non-smokers:
• EGFR mutations
• EML4-ALK fusion
• HER2-mutations

Question 10

What lung cancer patients should undergo testing for EGFR and ALK rearrangments?

Answer 10

ALL adenocarcinomas should undergo testing for EGFR or ALK mutations (squamous cell carcinoma testing is not currently recommended)

Question 11

Why is Chemotherapy the only option in SCLC?

Answer 11

Metathesis occurs very early on so Chemotherapy and Radiation are the only good options

Question 12

What are the conventional drugs used to treat SCLC?

Answer 12

Etoposide and Cisplatin or Carboplatin or…

Cisplatin + irinotecan
Cisplatin + etoposide + ifosfamide
Cyclophosphamide + doxorubicin and/or etoposide ± vincristine

Question 13

What are the conventional treatment options for NSCLC?
• what is maintenance therapy for these pts?

Answer 13

CISPLATIN and Taxane (Paclitaxel, Docetaxel), Vinca alkaloid (vinorelbine), Gemcitabine (Ribonuc. reducase and DNA pols. inhibit), Irinotecan (topoisomerase inhibitor) or Pemtrexed (DHFR inhibitor - methotrexate analogue)

Maintainance via Pemtrexed

Question 14

What lung cancer patients can you give EGFR TKIs to?

Answer 14

NSCLC Patients with EGFR positive genetic test

Question 15

What lung cancer patients can get Bevacizumab?

Answer 15

Bevacizumab - NSCLC patients with non-squamous histology, no brain metastatses, or hemoptysis

Question 16

T or F: Toxicities of newer targeted drugs affect nearly every organ system in the body.

Answer 16

True, **The majority of these drugs are administered in a continuous fashion making cumulative toxicities a COMMON event**

Question 17

How do we minimize the toxicity of targeted drugs?

Answer 17

Surveillance and Early Management are key to minimizing treatment interruption

Question 18

Afatinib
• Target

Answer 18

Target:
• EGFR, exon 19 del or 21 subs

Question 19

Alectinib
• Target

Answer 19

Target
ALK

Question 20

Ceritinib
• Target
• Indication?

Answer 20

Target:
ALK

Indication:
Patients that are intolerant to crizotinib

Question 21

Crizotinib
• Target?

Answer 21

Target
• ALK, and HGFR

Question 22

Eroltinib
• Target

Answer 22

Target:
EGFR, exon 19 del or 21 subs

Question 23

Gefitinib
• Target

Answer 23

Target:
EGFR, exon 19 del or 21 sub

Question 24

Osimertinib
• Target

Answer 24

Target:
EGFR, 790M mutation positive

Question 25

What KEY toxicity is seen in patients receiving EGFR targeting drugs (mAb or TKI)? • Who typically experiences this effect? • Who doesn't?

Answer 25

SEVERE RASH - makes sense b/c you're inhibiting Epithelial Growth Factor * YOUNGER MALE patients are more likely to get this rash * Patient who smoke and have light skin pigmentation are more immune

Question 26

What KEY toxicity is seen in targeted therapies towards angiogenesis?

Answer 26

HYPERTENSION (20%)\*\*\*, Hemorrhage, Thrombosis, CARDIAC CONTRACTILE DYSFUNCTION- makes sense given that these are preventing new vessels from being formed Damage to Matrix is not repaired as well without VEGF and we see exposure of the underlying matrix leading to Thrombosis and Hemorrhage

Question 27

In patients using targeted therapies, especially TKIs, what should you advise them to do or not do?

Answer 27

Avoid Pregnancy - make sure they're using contraception Avoid Breastfeeding - concerns over neonatal drug toxicity Tell them to report and Dematologic, Cardiac, or Pulmonary symptoms since these are common

Question 28

Which tyrosine kinase inhibitors used in lung cancer target EGFR exon 19 del or 21 subs? • 790M mutations (exon 20)?

Answer 28

Exon 19 del or 21 subs: Afatinib Eroltinib Gefitinib 790M mutations: Osimertinib

Question 29

What Tyrosine Kinase Inhibitors used in lung cancer target ALK? • differentiate between these on the basis of other targets.

Answer 29

ALK TKIs: • Alectinib • Ceritinib (ppl. intolerant to crizotinib) • Crizotinib (also targets HGFR)

Question 30

What are some things you should consider by the fact that TKIs are taken orally?

Answer 30

Question 31

Some physicians use the rash induced by TKIs as an indicator that the drug is working. What should you do to ensure that the drug is staying at a constant level in their bloodstream?

Answer 31

To ensure consistent plasma levels advise against taking these drugs with Food or Grapefruit Juice

Question 32

Bevacizumab MOA Adverse Effects Contraindications

Answer 32

MOA **mAb that binds VEGF receptor** and prevents activation Adverse Effects **Hand-Foot syndrome,** HTN, hemmorhage, cardiac dysfuncton, Thormbosis, **Fistula formation** Contraindications **High Risk for Hemorrhage: • NSCLC (especially those with squamous histology), renal cell carcinoma, colorectal cancer** - causes central tumor necrosis leading to hemorrhage

Question 33

Ramucirumab MOA Contraindications

Answer 33

MOA Inhibits VEGF2 receptor Adverse Effects Neutropenia, HTN, Hemorrhage (monitor BP) Contraindications Unlike Bevicizumab, Ramucirumab is NOT contraindicated with Squamous Carcinoma NSCLC

Question 34

Why do patients with functional p53 probably not respond to VEGF inhibitors as dramatically as those with a p53 mutation?

Answer 34

* VHL binds HIF-1alpha under normal circumstance but lets it go under hypoxic circumstances * If hypoxia is induced then HIF-1 alpha will go ot the nucleus and transcribe VEGF HOWEVER... * In prolonged Hypoxia p53 represses HIF-1 alpha

Question 35

What is the idea behind PD-1 antibodies used in cancer treatment?

Answer 35

PD-1 is a receptor found on Tcells that downregulates their activity when bound to their ligand PD-1L. Many cancers upregulate PD-1L to avoid T cell recognition as foreign. Inhibiting this system is beneficial to allowing T cells "see" the cancer.

Question 36

What mAb drugs work by inhibiting PD-1 receptors? • what is the advantage to these drugs? • what major risk is associated with taking these drugs?

Answer 36

**Nivolumab Pembrolizumab** **\***compared to TKIs, these mAbs have pretty mild effects Major Risks: • May induce AUTOIMMUNE disease (like pneumonitis, hypo/hyperthyroidism)

Question 37

What happens when the phosphorylation step to EGFR is blocked?

Answer 37

Cell undergoes apoptosis \*\*Even with this resistance mechanisms like the binding of MET (aka HGFR) can come in a phosphorylate EGFR, or HGF can just kick off the pathway itself\*\*

Question 38

Carboplatin and Cisplatin MOA Toxicity Remedy

Answer 38

MOA Form DNA intrastrand crosslinks and adducts Toxicity: Carboplatin less toxic than cisplatin • Nephro- and ototoxicity • Peripheral Neuropathy Remedy • Amifostine is nephro-protective • Prophylax for SEVERE N/V \*\*Dose Limiting Toxicity in Cisplatin = nephro and ototoxicity\*\*\*

Question 39

Cyclophosphamide, Ifosphamide MOA Toxicity

Answer 39

MOA: Pro-drug of active alkylating moiety Toxicity: BMS, HEMORRHAGIC CYSTITIS from ACROLEIN •Mesna = renoprotective

Question 40

Docetaxel, Paclitaxel MOA Toxicity

Answer 40

MOA: • Microtubule Stabilizer inhibiting depolymerization Toxicity: • Mucositis, Peripheral neuropathy, Hypersensivity

Question 41

Doxorubicin MOA Toxicity Protection

Answer 41

MOA Intercalator, free radical generator, topo II inhibitor Toxicity: Red-Orange Urine, Acute cardiac arrythmia, Chronic cardiomyopathy (CHF) Dexrazoxan = protective chelator \*\*Cumulative-Dose cardiotoxicity = Dose limiting\*\*

Question 42

Etoposide, VP-16 MOA Toxicity

Answer 42

MOA: • DNA-topo II complex stabilizer Toxicity: BMS, N/V, HYPOTENSION, hypersensitivity

Question 43

Gemcitabine MOA Toxicity

Answer 43

MOA DNA pols inhibitor via incorporation of triphosphate form during DNA systhesis Toxicity INTERSTITIAL PNEUMONITIS, Peripheral Neuropathy, BMS, mucositis, etc.

Question 44

Irinotocan and Topotecan MOA Toxicity

Answer 44

MOA DNA-topo I complex stabilizer Toxicity: ASTHENIA, BMS, N/V

Question 45

Vincristine and Vinorelbine MOA Toxicity

Answer 45

MOA Microtubule inhibitor; tubules disintegrate into spiral aggregates/protofilaments Toxicity VINCRISTINE - SIADH!!! Peripheral neuropathy (less so with vinorelbine)