Sweatman - Lung Cancer Rx Flashcards
Why is the division between NSCLC and SCLC no longer used?
- Histologic subtype of NSCLC now has to be reported due to advent of targeted therapy
- EGFR mutations are extremely rare in large cell, small cell, and pure squamous carcinomas
1. Evident in significant # of adenocarcinomas - Bevacizumab associated w/high risk of bleeding in squamous lung cancers -> only approved for use in non-squamous NSCLC
About what % of NSCLC are squamous vs. adenocarcinoma?
- 50% adenocarcinoma
- 30% squamous
How does the EGF receptor work? How does it “malfunction?”
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Normal cell (A): ligand-induced receptor activation leads to receptor dimerization and trans-phosphorylation of 2 tyrosine residues
1. Transduced to nucleus via signalling, and nuclear transcription can lead to cell growth, proliferation, and avoidance of apoptosis -
Cancer cells (B): proliferative pathway gains func via 1) receptor amplification, 2) mutation, or 3) trans-location
1. Chromosome rearrangement can lead to: the transcriptional activation of proto-oncogenes or creation of fusion genes encoding chimeric proteins w/transforming properties
How do TKI’s INH EGFR? What are the 4 NSCLC resistance mechs?
- TKI INH the phosphorylation step, and absence of proliferative signal leads to apoptosis -> this should lead to a clinical anti-tumor response
- Resistance mechs (see attached image):
C. Drug binding site (T790M) mutation
D. Amplified MET (hepatocyte growth factor receptor, HGFR) phosphorylates ERBB3 (circumventing drug presence)
E. HGF activates P13K/Akt via MET, independent of ERBB3 and EGFR
What is an anti-apoptotic IC mech of resistance to TKI’s?
- Polymorphisms in apoptosis genes: downstream of EGFR
1. Example: BIM polymorphism -> absence of pro-apoptotic BH3 domain in 15% of East Asians (predictive of significantly shorter survival than patients with “normal” BIM)
What is a pro-proliferative IC mech of resistance to TKI’s?
- KRAS and BRAF muts can render anti-EGFR drugs (Mab’s or TKI’s) ineffective due to proliferative path constitutively active DOWNSTREAM of drug-induced blockade
- Genotyping for mutation can be a deciding factor NOT to treat with Mab, e.g., Cetuximab
What is the EML4-ALK translocation?
- Family of abnormal (pro-malignant) fusion genes
1. Echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes
2. Activates the MEK/ERK pathway and cell proliferation (drug for it now) - 2-7% of NSCLC -> more prevalent in non-smokers, pts w/hx of light smoking, & pts w/adenocarcinomas
Why can blocking VEGF be helpful? Problematic?
- Proliferating tumors need blood supply, which is maintained by cells sensing oxygenation via HIF-1, and the release of VEGF
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Potential downsides:
1. Reduce distribution of concurrent chemo
2. Induce proliferation of more aggressive cells (green in image) that have capacity to spread to other organs
Why is human variation so critical when it comes to anti-cancer drugs, like TKI’s?
- Metabolism may be influenced by several host factors, including bioavailability and host pharmaco-genetics
- Variation in the germline constitution of individual patients can have significant impact on response to tx and degree of toxicity
- By inhibiting their target kinases, these agents extinguish crucial downstream signalling pathways involved in normal cell growth
- Host tissues can also influence efficacy of kinase inhibitors by secreting factors, e.g., HGF, in a paracrine fashion
Which mutations are more common in non-smokers?
- EGFR (45%)
- EML4-ALK
- HER2
- hMSH2 (40%)
- Not only smokers get lung cancer
Why is genetic testing of adenocarcinomas so important?
- Actionable mutation in 60% of patients
- Data used to either:
1. Treat according to guidelines based on EGFR results (KRAS and ALK too)
2. Offer enrollment in clinical trials targeting other ID’d mutations (BRAF, MET)
What are the existing genetic testing guidelines?
- Routine testing recommended for EGFR muts and ALK rearrangements in ALL ADENOCARCINOMAS
1. Not recommended in pure squamous cell tumors due to very low diagnostic yield - DNA sequencing is the method used in most EGFR studies -> discordance of up to 28% b/t 1o tumors and distant metastases
- Fluorescence in situ hybridization (FISH) preferred and FDA-approved choice for ALK gene rearrangement testin
What is the current recommendation for preventive scans for smokers?
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Smokers (55-80 y/o) with >30-pack history and those who have quit in the last 15 years should get low-dose CT scans of lungs to look for possible tumors
1. 2 previous reviews found insufficient evidence to support annual screenings - Small risk of radiation exposure from low-dose scans outweighed by benefits of detecting abnormal growths early and intervening w/tx
What are the standard tx plans for SCLC and NSCLC?
- SCLC: metastasis early, so radiation/chemo the only option
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NSCLC: sx resection if no metastasis (early stage)
1. Chemo/radiation used in adjuvant, neo-adjuvant or maintenance role to:
a) reduce bulk of the tumor (facilitating sx) and eradicate early micrometastases OR
b) prevent growth or metastasis
2. Pre-op chemo may delay potentially curative sx -> metastasize very early, most commonly spreading to adrenals, liver, brain, and bone
What are the standard tx options for SCLC?
- Etoposide + Cisplatin or Carboplatin
OR
- Cisplatin + Irinotecan
- Cisplatin + Etoposide + Ifosfamide
- Cyclophosphamide + Doxorubicin + Etoposide
- ”” + Vincristine
- Cyclo + Doxo + Vincristine
- Cyclo + Etoposide + Vincristine
What are the standard tx options for NSCLC?
- Cisplatin AND Paclitaxel, Gemcitabine, Docetaxel, Vinorelbine, Irinotecan, or Pemetrexed (commonly a taxane)
- Pemetrexed maintenance: for pts w/stable or responding disease after 4 cycles of nonpemetrexed-platinum combo therapy)
- Based on appropriate genetic markers, TKI’s and VEGF inhibitors may also be used:
1. EGFR TKI’s for pts w/EGFR+ genetic test
2. Bevacizumab (pts w/non-squamous histo, no brain metastases, and no hemoptysis)
3. Erlotinib: first-line tx for locally advanced or metastatic NSCLC after failure of at least 1 prior chemo regimen, or for maintenance tx of “” that has not progressed after 4 cycles of platinum-based first-line chemo
What is the MOA for Cisplatin and Carboplatin?
Form DNA intrastrand crosslinks and adducts
What is the MOA for Cyclophosphamide?
Pro-drug of active alkylating moiety
What is the MOA for Docetaxel?
Microtubule stabilizer inhibiting depolymerization
What is the MOA for Doxorubicin?
Intercalator, free radical generator, topo II INH
What is the MOA for Etoposide/VP-16?
DNA-topo II complex stabilizer
What is the MOA for Gemcitabine?
DNA polymerase inhibitor via incorporation of triphosphate form during DNA synthesis
What is the MOA for Ifosfamide?
Intra- and interstrand crosslinker
What is the MOA for Irinotecan?
DNA-topo I complex stabilizer
What is the MOA for Paclitaxel?
Microtubule stabilizer inhibiting depolymerization
What is the MOA for Pemetrexed?
DHFR inhibitor
What is the MOA for Topotecan?
DNA-topo I complex stabilizer
What is the MOA for Vincristine/Vinorelbine?
Microtubule inhibitor; tubules disintegrate into spiral aggregates/protofilaments
What is a big clinical issue, and often the dose-limiting toxicity for most of the anti-cancer drugs?
Myelosuppression
What are the Carboplatin AE’s?
- Allergic (platinum) reactions
- Dose-related myelosuppression; cumulative anemia
- Dose-related N/V
- Blood chemistry dyscrasia, INC hepatic enzymes, BUN, and creatinine
What are the Cisplatin AE’s?
- Allergic (platinum) reactions
- Dose-related, severe nephrotoxicity, myelosuppression and N/V
- Significant ototoxicity (tinnitus and occasionally deafness) reported in children
What are the Cyclophosphamide AE’s?
- Blood dyscrasias -> anemia, infection
- Renal compromise, hemorrhagic cystitis (Mesna is protective), N/V, rashes
- Amenorrhea, infertility
- Monitor for 2o malignancies
- Pulmonary fibrosis
What are the Docetaxel AE’s?
- INC mortality in NSCLC
- Edema (give steroids)
- Contraindicated with INC bilirubin/ALK/phos, AST/ALT
- Dose-limiting neutropenia
- Sensory neuropathy
What are the Doxorubicin AE’s?
- Myelosuppression, CHF (cumulative dose exposure manner: 450 mg/sq m max cumulative dose), hepatic disease
- 2o malignancies
- Extravasational necrosis
- N/V
What are the Etoposide/VP-16 AE’s?
- Myelosuppresion, infection
- Dose-limiting hematologic toxicity
- N/V, diarrhea
- Alopecia
What are the Gemcitabine AE’s?
- Myelosuppression, infection
- Arthralgia, drowsiness, fatigue
- N/V
- Alopecia
- Sensory peripheral neuropathy (10%)
What are the Ifosfamide AE’s?
- Alopecia
- N/V
- Blood dyscrasia -> infection
- Neurotoxicity
- Hematuria renal failure (<10%)
What are the Irinotecan AE’s?
- Myelosuppression
- Diarrhea
- Asthenia
- Fever, pain
- Weight loss
What are the Paclitaxel AE’s?
- Taxane hypersensitivity
- Myelosuppression
- Myalgia/arthralgias
What are the Pemetrexed AE’s?
- Myelosuppression and GI toxicities, esp. when combined with Cisplatin vs. NSCLC
- Elevated LFT’s and serum creatinine
What are the Topotecan AE’s?
- Myelosuppression and GI toxicities
- Hyperbilirubinemia
What are the Vinblastine/Vinorelbine AE’s?
- Myelosuppression
- Neuropathic toxicity (less so w/Vinorelbine)
- Neutropenia (Vinorelbine)
- Intrathecal admin of Vinca alkaloids is fatal
What are the TKI’s approved for treating NSCLC?
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ALK
1. Crizotinib: + HGFR
2. Ceritinib: ALK intolerant to Crizotinib -
EGFR
1. Afatinib
2. Erlotinib
3. Gefitinib
What are some of the pitfalls associated with the oral route of administration of the TKI’s?
- Food may impact bioavailability: reflected in dosing instructions
- Extensive hepatic metabolism (except Afatinib), and predominantly fecal elimination
- Substrates for CYP3A4/5 and P-gp (except Crizotinib)
1. Other isoforms vary by drug - Inhibitors of CYP3A, and to varying degrees, other isoforms
- Drug-drug interactions are possible
What are some of the (un)common TKI side effects?
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Common:
1. EGFR: diarrhea, N/V, dermatologic, elevated hepatic enzymes, opthalmic (except Afatinib)
1. ALK: constipation, diarrhea, N/V -
Uncommon:
1. Gefitinib - renal
2. Ceritinib - fatigue, DEC hemoglobin, hyperglycemia (but no opthalmic, unlike Crizotinib)
What are the rare AE’s with the TKI’s? How should pts be counseled about these?
- Bradyarrhythmia and/or QT prolongation
- Severe rash and Steven Johnson Syndrome (SJS)
- GI hemorrhage or perforation
- Hepatotoxicity and hepatic failure
- Interstitial lung disease, pneumonia, PE
- Corneal ulceration, perforation, keratitis
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Counseling:
1. Avoid pregnancy -> use appropriate contraception
2. Immediately report new CV or pulm sxs
3. Immediatley report bullous, blistering, or exfolative dermatologic symptoms
What do you see here?
- EGFR-induced rash: common and potentially severe AE
- May necessitate specific txs with steroids, antimicrobials, and oatmeal lotions
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What should you do if your lung cancer pt on TKI’s presents with a rash?
What 2 things do these graphs tell you?
- Erlotinib produces a significant survival effect, especially in the short-term
- This effect is dependent on the molecular target, in this case, EGFR overexpression by the tumor
How is TKI resistance related to ATP affinity?
- Muts in TK domain of EGFR can have profound effect on drug sensitivity (ATP binding site highly conserved among TKI’s)
1. About 10-25% of NSCLS from E. Asia have somatic activating muts -> in-frame deletions in exon 19 (point mutation that substitutes Leu-858 w/arginine; L858R)
A. Compromises ATP affinity and INC initial sensitivity to TKI’s: erlotinib/afatinib (opens the therapeutic window)
- Secondary mut (T790M) closes window -> restores ATP affinity to wild-type levels)
A. Detection of this mut in naive pts indicates resistance; may reflect outgrowth of resistant clones (can be in pts who’ve never had TKI’s)
What is the theoretical resistance mutation to Crizotinib?
- G2032R ROS1: has been shown to reduce drug activity in in vitro kinase activity assays
- Emergence of resistance most likely reflects an outgrowth of pre-existing tumor clones with inherent resistance at this site
What is PD-1?
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Programmed cell death protein: one of the co-stimulatory signals that serve to modulate the signal (signal 1) in T-cells after initial binding of an Ag-presenting cell (APC)
1. Binding of PD-1 receptors by PDL1 or PDL2 leads to an INH or (-) regulatory impact on signal 1
2. Primary role is to regulate inflammatory responses in tissues by effector T cells recognizing Ag in peripheral tissues
3. Activated T cells upregulate PD-1 and continue to express it in tissues -> inflammatory signals in tissues induce expression of PD1 ligands that downregulate the activity of T cells, limiting colateral damage in response to a microorganism in that tissue
Nivolumab
- Very recent approval -> metastatic disease after failure of platinum therapy
- Toxicity profile limited (for now) -> common AE’s similar to those for TKI’s
1. Pruritis/rash, hyperkalemia/hyponatremia, DEC appetite, constipation, N/V, elevated LFT’s, cough, musculoskeletal pain, respiratory infection, fatigue - Less common AE’s: endocrine dysfunction, immune-mediated organ destruction
- Pt counseling: use reliable contraception, promptly report new sxs of dermatologic, hepatic, renal, or endocrine dysfunction
Bevacizumab
- Humanized Ab given IV; binds VEGF and prevents receptor activation
- Common AE’s similar to those of TKI’s:
1. HTN, hand-foot, endocrine, GI, or neuro dysfunction, hemorrhage, infections, proteinuria, fatigue -
Less common effects: arterial thromboembolism, CHF, DVT, cerebral artery occlusion, pulm HTN
1. Impaired wound healing
2. Fistula formation in tracheoesophagus/GI tract, liver, renal pelvis, F genital tract, bronchopleural tissue
What is the downside of Bevacizumab?
- INH blocks endo cell regeneration leading to underlying matrix exposure, and thrombosis/hemorrhage
- INH also promotes non-physiologic apoptosis of endo cells and DEC deposition of sub-endothelial matrix, making vasculature more susceptible to bleeding
- Life-threatening, severe bleeding is possible
- Gastric perforation and impaired wound healing may also contribute to hemorrhage in some cases
Can you use Bevacizumab in the tx of squamous NSCLC?
- NO -> contraindicated in these patients due to increased risk of bleeding bc located near major blood vessels, and necrose and cavitate
- Baseline cavitation was the main risk factor of high-grade bleeding for patients with NSCLC
- Drug causes central necrosis and enlarged tumor cavitation in these patients -> this combo w/immature blood vessels in the cavity leads to INC risk of bleeding
How does clinical staging of lung cancer affect genetic testing?
