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STEP Pharm II > Lung Cancer Tx > Flashcards

Lung Cancer Tx Flashcards

1
Q

What drug is only approved for treatment of non-squamous NSCLCs? Why?

A

Bevacizumb because it is associated with a high risk of bleeding

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2
Q

Drugs that end in ‘nib’ are what?

A

tyrosine kinase inhibitors

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3
Q

How do EGF receptors work?

A

In the normal cell, binding of a ligand to the receptor results in dimerization and tyrosine residue trans-phosphorylation. This initial event is transduced to the nucleus where effects upon nuclear transcription canlead to cell growth, proliferation and the avoidance of apoptotic events.

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4
Q

What the EGFR IgG monoclonals approved for treatment of SQUAMOUS NSCLC?

A

-Necitumumab-Panitumumab

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5
Q

How do EGFR monoclonals work?

A

competitively block binding of EGF and TGF-a to EGFR, thereby inhibiting receptor autophosphorylation

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6
Q

What step in the signaling pathway do TKIs inhibit? Result?

A

the phosphorylation step isinhibited and the absence of proliferative signal leads to an apoptotic response.

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7
Q

How can resistance to TKIs arise?

A

-Drug binding site mutation (T790M!!!), -Compensatory phosphorylation of the tyrosine residues (ERBB3) via MET, also known as hepatocyte growth factor receptor (HGFR) which itself possesses tyrosine kinase activity, or -By HGF assuming an independent role in the proliferative signaling process independent of ERBB3 or EGFR

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8
Q

Where do TKIs bind?

A

the tyrosine kinase domain of EGFR at the ATP binding site

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9
Q

What are some common drug site mutations to TKIs that make them MORE effective?

A

-in-frame deletions at exon 19 or point mutations in exon 21 (L858R) in NSCLC

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10
Q

What are some common drug site mutations to TKIs that make them LESS effective?

A

A T790M (exon 20) mutation reduces the drug activity by preventing correct orientation of drug binding on the active site. The T790M mutation (part of ATP binding site) maysimply be an outgrowth of pre-existing clones that are inherently resistant, because such mutations can be determined in patients who have never received one of theTKIs.

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11
Q

What happens when the EGFR is phosphorylated?

A

KRAS, BRAF, MEK, to ERK/MAPK that promotes proliferation, angiogenesis, survival etc in the nucleus via transcription

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12
Q

Describe the EML4-ALK oncogene mutation.

A

Translocations pair these two to produce constitutive tyrosine kinase activity independent of EGF which produce activation of the MEK/ERK, P13K, and JAK-STAT pathways and cell proliferation

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13
Q

What patient population commonly has a EML4-ALK mutation?

A

nonsmokers, light smokers, and in adenocarcinomas

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14
Q

When is VEGF released normally?

A

lack of O2 stimulates HIF-1 to release VEGF to stimulate angiogenesis

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15
Q

What is a large supply of VEGF important for?

A

solid tumor growth

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16
Q

What are some of the downsides of using VEGF inhibitors?

A

-reducing the distribution of concurrent chemotherapy without a blood supply-induces accumulation /selection of more aggressive cells

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17
Q

What mutations are more common in smokers?

A

-Tp53 mutations-G:C to T:A mutations-KRAS-STK11-p16 and APC methylation

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18
Q

What mutations are more common in NON-smokers?

A

-EGFR mutations-EML4-ALK-HER2 mutations-hMSH2 expression

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19
Q

What are the most common mutations in lung adenocarcinoma?

A

-KRAS (25%)-EGFR (23%)-ALK rearrangements recommend routine testing for EGFR and ALK rearrangements in all adenocarcinomas

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20
Q

What is the most commonly used method in most EGFR studies?

A

DNA sequencing

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21
Q

What is the preferred method of testing for ALK rearrangements?

A

FISH

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22
Q

T or F. The USPSTF recommends that all heavy smokers with a 30+ pack-year history undergo routine low-dose CT scans for small (and thus very treatable) tumors

A

T.

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23
Q

What is the best treatment for solid tumor?

A

surgical resection with drugs neo- or adjuvantly

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24
Q

Does metastasis occur earlier in SCLC or NSCLC cancers?

A

SCLC (so chemo/radiation is usually the only option)

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25
Q

What is the standard treatment of SCLC?

A

Etoposide + cisplatin+ carboplatin

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26
Q

What is the standard treatment of NSCLC?

A

Cisplatin AND paclitaxel, docetaxel, irinotecan, gemcitabine, vinorelbine, or pemetrexed

27
Q

What is the preferred maintenance drug for NSCLC?

A

Pemetrexed, a DHFR inhibitor

28
Q

When is pemetrexed maintenance indicated?

A

For patients with stable or responding disease following 4 cycles of nonpemetrexed-platinum combo chemo

29
Q

When is Bevacizumab indicated?

A

for patients with non-squamous histology, no brain metastases, and no hemoptysis

30
Q

What is a common reason for toxicity of targeted cancer drugs?

A

they are given frequently so toxicity occurs in a cumulative fashion

31
Q

What are some targeted TKIs for EGFR, exon 19 del or 21 subs in NSCLC?

A

-Afatinib-Erlotinib-Gefitinib

32
Q

What is Alectinib used for?

A

NSCLC with ALK rearrangement

33
Q

What is Ceritinib used for?

A

NSCLC with ALK arrangement that is intolerant to crizotinib

34
Q

Uses of Crizotinib?

A

-ALK-HGFR in NSCLC

35
Q

What drug is indicated for EGFR with 790M mutation positive in NSCLC?

A

Osimertinib

36
Q

Common toxicities with targeted drugs like TKIs, BRAF inhibitors, and angiogenesis inhibitors?

A

-rash (SEVERE in EGFR TKIs)-HTN (SEVERE in angiogenesis inhibitors)-thrombus formation (VEGF inhibitors)-diarrhea-mucositis-hypothyroidism, hypogonadism, hypopituitarism

37
Q

Counseling for patients taking small molecular weight drugs like TKIs (note these are taken orally)?

A

-avoid pregnancy and breastfeeding-report new CV, derm, or pulmonary symptoms immediately

38
Q

Things to consider with small PO molecule drugs like TKIs

A

-most are substrates for CYP3A4 and P-gp-some interact with food-some depend on acidic environment for absorption

39
Q

What is a fair inhibitor of CYP3A4?

A

Imatinib

40
Q

Note on the dermatologic effects of EGFR TKIs

A

Patients who smoke orwho have a naturally lighter skin pigmentation do not appear to experience as severe a rash from EGFR TKIs as do others, whereas younger and male patients correlatewith increased rash caused by the EGFR monoclonals.Some use the appearance of rash as an indication that the drug is working

41
Q

AEs of VEGF inhibitors?

A

originally thought that the adult vasculature is mostly independent of VEGF, BUT inhibition blocks endothelial cell regeneration leading to exposed underlying matrix (promotes thrombus formation) AND bleeding (even in the GI)

42
Q

Why do VEGF inhibitors affect the CV system?

A

they are involved in cardiac contraction as well as endothelial cell survival and vasodilation

43
Q

What are some Monoclonals against VEGF?

A

-Bevacizumab -Ramucirumab

44
Q

How does Bevacizumab work?

A

binds and neutralizes all free human VEGF forms via recognition of binding sites for the two human VEGF receptor types (flt-1 and flk-1).

45
Q

How does Ramucirumab work?

A

a VEGF receptor 2 antagonist that blocks binding of VEGF-A, VEGF-C, and VEGF-D to the VEGF receptor.

46
Q

How is Bevacizumab given?

A

IV

47
Q

AEs of Bevacizumub?

A

-HTN, hemorrhage-hand-foot syndrome-endocrine, neurologic, and GI dysfunction -infectious disease

48
Q

What patients have the greatest risk of serious bleeding with Bevacizumab?

A

all NSCLC with squamous histology, renal cell carcinoma, and colorectal cancer

49
Q

Why is bleeding increased in these patients?

A

the drug is believed to cause central necrosis and to enlarge the tumor cavity

50
Q

AEs of Ramucirumab?

A

-neutropenia-HTN and bleeding not increase in bleeding risk for squamous tumorsNOTE: only increased survival by 1.4 months

51
Q

What are some TKIs against VEGF?

A

-Sunitinib-Sorafenib

52
Q

Which patients have been shown to experience less benefit from anti-angiogenesis approaches?

A

those with normal TP53 function

53
Q

Why would normal TP53 function limit the effectiveness of anti-angiogenesis therapy?

A

“Normal” TP53 functions in a repressive role and would suppress VEGF activity and importance as a consequence of this action. However, “mutant” TP53 would likely lose the repressive role, thereby assigning more importance to the VEGF pathways and, in consequence, a greater treatment effect with the inhibitors.

54
Q

How can tumors suppress the immune system?

A

Tumor cells can serve as APCs and induce PD-1 expression on T cells. Tumor cells can also expressed PD-L1 which essentially turns off T cells

55
Q

What are some PD-1 receptor binders (compete with tumor cells with PD-1 for binding)?

A

-Nivolumab-Pembrolizumab

56
Q

AEs of PD-1 receptor binders?

A

By blocking repression of T cell function, there is the possibility that such agents could initiate autoimmune diseases. This causes endocrinopathies (consider adrenal insufficiency)many of these effects are self-limiting except pituitary damage

57
Q

What is the first step in determining whether targeted testing is needed in lung cancer?

A

Assess clinical stage:1-2: molecular testing not indicated; consider tissue banking3-4: assess histologic type

58
Q

What if histologic testing yields adenocarcinoma (or non-squamous)?

A

perform EGFR mutation analysis

59
Q

What if histologic testing yields squamous carcinoma?

A

molecular testing not indicated; consider tissue banking

60
Q

What is EGFR is positive?

A

consider erlotinib/afatinib

61
Q

What is EGFR is negative?

A

performs FISH assay for EML4/ALK fusion oncogene

62
Q

What is the EML4/ALK translocation is positive?

A

consider crizotinib

63
Q

What is the EML4/ALK translocation is negative?

A

standard cytotoxic chemotherapy indicated

STEP Pharm II (42 decks)

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