Lung Cancer

Question 1

KRAS Mutation (EGFR) (HER-1, erb-B1)

If a patient has KRAS mutation what is it associated with

Kras is what type of Protien

MOA of G Protien

Most common Mutation in Kras for Lung Cancer

What does it signifies to have KRAS Point Mutation G12C

KRAS mutation will predict resistance to what tpye of medicaiton?

Answer 1

KRAS mutations in adenocarcinoma are strongly associated with smokers

1.KRAS is a G-protein with intrinsic GTPase activity, which result in unregulated signaling through the MAP/ERK pathway.

2.Mutations in KRAS (proto-oncogene) are most commonly at codon 12, although other
mutations can be seen in NSCLC.
3.Presence of a KRAS point mutation G12C is associated with responsiveness to an oral KRAS
G12C inhibitor, sotorasib,
4.Predicts primary resistance to EGFR tyrosine kinase inhibitors (TKIs)

5.KRAS predicts for patients who are unlikely to benefit from further molecular testing

Question 2

Adenosarcoma

Answer 2

A tumor that is a mixture of an adenoma (a tumor that starts in the gland-like cells of epithelial tissue) and a sarcoma (a tumor that starts in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue). An example of an adenosarcoma is Wilms tumor.

Question 3

EGFR mutations (HER-1, erb-B1)

What is the MOA of EGFR Mutation?

What population will you see this mutation?

3. Most common mutation in EGFR are that are associated with responsibeness in oral EGFR TKI medicaiton?
4. What are the less common observed mutation in EGFR ?

Answer 3

1. activate the ERK MAPK pathway, leading to increased cell proliferation, motility, and invasion
2. Common in Females vrs male, Asian, and Light to never smoker
3. Exon 19 deletions and p.L858R point mutation in exon 21)
4. Less commonly observed alterations in EGFR include exon 19 insertions, L861Q, G719X, S768I are also associated with responsiveness to EGFR TKI therapy, although the number of patients studied is low

Question 4

EGFR exon 20 mutations

What Is the mutation that does not respond to TKI Therapy?

What are the two exceptions

NCI Guideline for EGFR gene mutation testing?

Answer 4

1.Are a heterogeneous group and response to targeted therapy require knowledge of the specific alteration

T790M Generally associated with lack of response to EGFR TKI therapy with the following exceptions:

1. A763_Y764insFQEA is associated with TKI therapy sensitivity
2. A763_Y764insLQEA may be associated with TKI therapy sensitivity
   b) It is best to further clarify EGFR exon 20 insertions found on some assays as the sequence found may have additional therapy options.
   e. Real-time PCR, Sanger sequencing, and next generation sequencing (NGS) are the most commonly used methods for examining EGFR mutation status.
   f. Testing for EGFR gene mutations is recommended with patients on diagnostic biopsy or surgical resection so results are available for adjuvant treatment decisions with stage IIB-IIIA or high-risk stage IB-IIA as well as metastatic nonsquamous NSCLC. (NCCN© Category 1)
   g. Testing for EGFR gene mutations should be considered in squamous cell NSCLC.10

Question 5

KRAS and EGFR

Answer 5

KRAS and EGFR mutations are mutually exclusive.

Question 6

Anaplastic Lymphoma Kinase (ALK) Rearrangement

3. NCCN guideline recommendation of what type of cancer for ALK Rearrangement testing?

Answer 6

MOA: Inversion in chromosome 2 that links the 5’ end of the echinoderm microtubule- associated protein-like 4 (EML4) gene with the 3’ end of the anaplastic lymphoma kinase 12,13 3. Results in fusion oncogene EML4-ALK, which is an independent driver of cancer cell proliferation

This leads to activation of downstream signaling pathways (through the RAS pathway) and inhibition of apoptosis

Question 7

ALK Features :

Answer 7

Clinical features include :

adenocarcinoma histology (97%)

no/light smoking history,

younger age (median age of ALK + patients = 52 years)

Question 8

ALK Testing

Answer 8

FISH testing for ALK rearrangement was the first testing method used. IHC can be used and has an FDA-approved IHC test (ALK [D5F3] CDx Assay) to detect ALK without requiring confirmation by FISH. 15 Next generation sequencing methods can be used to detect ALK fusions, real-time PCR can be used however it is unlikely to detect fusions with novel partners

Question 9

Testing for ALK is what catergory for NCCN Guideline

Answer 9

Testing for ALK rearrangements is recommended with patients found to have metastatic nonsquamous NSCLC. (NCCN© Category 1)

Question 10

ROS1 Rearrangement MOA and Histology

Answer 10

Overall frequency in NSCLC = 1-2% 2.

The ROS1 oncogene encodes a tyrosine kinase related to ALK.16 3. Rearrangement leads to fusion of the portion of ROS1 that includes the tyrosine kinase domain with 1 of 12 different partner proteins.

Fusion kinases are constitutively active which drives cellular transformation.

4. Clinical features include adenocarcinoma histology and no/light smoking history.

Question 11

What is ROS frequency and in which cancer

Answer 11

Overall frequency in NSCLC = 1-2%

Question 12

ROS1 NCCN Guidelines Recommendation

Answer 12

5. Numerous NGS methods can detect ROS1 fusions, although DNA-based NGS may under-detect ROS1 fusions.
6. NCCN© guidelines recommend testing for ROS1 gene rearrangements prior to first line therapy in the metastatic setting for NSCLC

Question 13

What is the NCCN guideline rommendation for testing ROS1 rearrangement?

Answer 13

NCCN© guidelines recommend testing for ROS1 gene rearrangements prior to first line therapy in the metastatic setting for NSCLC

Question 14

BRAF V600E19 What does it stand

What is the most common mutation

Answer 14

BRAF (v-Raf murine sarcoma viral oncogene homolog B) V600E: most common of the BRAF mutations

Question 15

BRAF NCCN guideline

Answer 15

Testing for BRAF mutations prior to first line therapy in the metastatic setting for NSCLC is recommended (NCCN Category 2A), but no testing is recommended for SCLC

Question 16

NTRK (neurotrophic tyrosine receptor kinase) gene fusions

Answer 16

Testing for this mutation would be suggested for advanced/metastatic non-squamous cell carcinoma and considered for squamous cell carcinoma

Question 17

Mesenchymal-epithelial transition (MET) exon 14 skipping variants4

Answer 17

1. Presence of MET exon 14 skipping mutation is associated with responsiveness to oral MET targeted therapy
2. More frequently observed in older women who are nonsmokers2

Question 18

MET Exon 14 NCCN Guideline

Answer 18

NCCN© guidelines recommend testing for MET exon 14 skipping mutation in the advanced/metastatic NSCLC patient population

Question 19

Rearranged during transfection (RET) gene rearrangements

is associated with

Answer 19

1. RET is a receptor tyrosine kinase which can be rearranged in NSCLC.
2. Presence of RET rearrangement is associated with responsiveness of oral RET targeted therapy, regardless of the fusion partner.

Question 20

NCCN guideline recommondation for RET Reaggangement

Answer 20

NCCN© guidelines recommend testing for RET rearrangements in the advanced/metastatic NSCLC patient population.

Question 21

PD-L1 (program cell death-ligand 1) Expression Levels MOA

Answer 21

PD-L1 binds to the PD-1 receptors found on activated cytotoxic T-cells

Question 22

NCCN Guideline for testing of PD-L1

Answer 22

IHC testing for PD-L1 expression is recommended before first-line treatment in patients with metastatic NSCLC. (NCCN© Category 1)

Testing for PD-L1 expression is not recommended for SCLC at this time

Question 23

Postinve PD-L1 Expression with Unique IHC Assay has been developed for ?

Answer 23

Patients with oncogenic drivers can have elevated PD-L1 expression; however, treatment with targeted therapy takes precedence over treatment with an immune checkpoint inhibitor.

Positivity of PD-L1 expression is variable and unique IHC assays have been developed for each of the PD-1 and PD-L1 inhibitors currently on the market

Question 24

Emerging Biomarkers

Answer 24

High-level MET amplification and ERBB2 (HER2) mutations are genetic alterations which may have available therapies with activity against the driver

Question 25

Prevention for NSCLC

and Smoking Cessation decrease what ?

Answer 25

No known effective method of chemoprevention at this time.

Smoking cessation – decreases risk of second primary cancer, improves tolerance and possible response to treatment

Question 26

Summary of Guidelines for Lung Cancer Screening

Answer 26

U.S. Preventive Services Task Force

Adults aged 50-80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years

Annual screening with low dose CT

NCCN© Lung Cancer Screening Recommentations

High Riskb • Age ≥ 50 years and ≥ 20 pack-year history of smoking Annual low dose CTc (NCCN Category 1)

1) Low riskb • Age < 50 years and/or < 20 pack year history of smoking

Not recommended to do Annual Low Dose CTc

Question 27

Summary of Screening for LUNG Cancer with CXR and Spiral CR and PET

Answer 27

Screening impacts lung cancer survival, and to date CXR, regular spiral CT, and PET scans have not consistently improved mortality.

Annual low dose CT scans in patients similar to those evaluated in the NLST data may be employed at qualified centers in patients where cost is not an issue.3

Question 28

Lung cancer symptoms

Answer 28

Cough that won’t go away

Coughing up blood

Difficulty breathing

Chest pain

Repeated bronchitis and/or pneumonia.

Question 29

Small cell lung cancer General points

Answer 29

a. Very sensitive to radiation and chemotherapy
b. Systemic chemotherapy is the backbone of treatment at all stages in eligible patients.
c. Surgery only has a limited role

Question 30

SCLC Surgery has two limited points

Answer 30

1) Option in T1-2 (stage I-IIA) disease without mediastinal pathology (<5% of patients)
a) Select patients with T3 (based on size), N0 SCLC may also be considered for surgery
2) Preferred operation: Lobectomy with mediastinal lymph node dissection

Question 31

Two stages in SCLC

Answer 31

Limited and Extensive

Question 32

Limited Intent in SCLC is accociated with a cure Rate of

Answer 32

a. Curative intent with associated cure rate of 20%

Question 33

Treatment: Concurrent chemoradiotherapy for SCLC in Limited Stage

NCCN Preferred recommendation

How many Cycles

Radiontherapy and PCI ( prophylactic cranial irradiation )

Answer 33

I Cisplatin-etoposide with concurrent radiation has the best supporting clinical data (NCCN© category 1).

Preferred, NCCN Category 1 Recommendations:

1. Cisplatin 60 mg/m2 IV D1, etoposide 120 mg/m2 IV D1-3 Q21-28 days x 4 cycles or cisplatin 75 mg/m2 IV D1, etoposide 100 mg/m2 IV D1-3 Q21-28 days x 4 cycles WITH radiation
2. Four cycles of chemotherapy are recommended. Maintenance therapy has not shown any improvement in disease-free survival or overall survival (OS)
3. Thoracic radiotherapy Should begin early in the course of treatment, preferably with cycle or 2
4. Prophylactic cranial irradiation (PCI) should be offered for patients attaining a CR or PR. (NCCN© Category 2A recommendation).

Question 34

Other chemo Recommended Regimens, NCCN Recommendations for limited stage SCLC

Answer 34

Cisplatin 25 mg/m2 IV D1-3, etoposide 100 mg/m2 D1-3 Q21-28 days x 4 cycles WITH radiation

Question 35

Cisplatin can Casue what syndrome

How do you treat it

what can be used instead of Cisplatin

Answer 35

low sodium (SIADH paraneoplastic syndrome)

Treatment is aggressive hydration to prevent nephrotoxicity. SIADH necessitates fluid restriction to prevent further reduction in sodium.

Can utilize carboplatin in this situation, and other situations when cisplatin is contraindicated

Carboplatin AUC 5-6 IV D1, etoposide 100 mg/m2 IV D1-3 Q21-28 days x 4 cycles WITH radiation (Other Recommended Regimen, NCCN Recommendation

Question 36

Prophylactic cranial irradiation (PCI) should be offered for patients attaining a CR or PR. (NCCN© Category 2A recommendation).

PCI is recommended for patients with what Performance Status ?

When should we use PCI in patients?

Patient equal or older to 60, what should be discussed with them about PCI?

Answer 36

1. A meta-analysis showed improved 3 year survival (15% vs 21%).

b) PCI is not recommended for patients with a poor performance status or baseline impaired neurocognitive function
c) The benefit of PCI is unknown in patients who undergo complete resection for pathologic stage I-IIA SCLC. Consider PCI or brain MRI surveillance for N0

. d) Patients ≥ 60 years old have demonstrated increased cognitive decline after PCI. The risks and benefits should be discussed with older adults

Question 37

Sotorasib (Lumarkras) MOA

Answer 37

Lumakras (sotorasib) is an inhibitor of KRASG12C- which is a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS.

Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRASG12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS.

Sotorasib blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines.

Question 38

Sortorasib (Lumakras)

Indication and Dosing

Answer 38

Lumakras -indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received at least one prior systemic therapy.

Recommended Dose is 960 mg (eight 120 mg tablets) orally QD until disease progression or unacceptable toxicity.

Take at the same time each day with or without food.

Swallow whole.

If a dose is missed by more than 6 hours, take the next dose as prescribed the next day.

Do not take 2 doses at the same time for miss dose

If vomiting occurs after taking Lumakras, do not take an additional dose. Take the next dose as prescribed the next day.

Question 39

Sotorasib Lumakras

Adverse Efects

Answer 39

diarrhea

musculoskeletal pain

nausea

fatigue

hepatotoxicity

cough

laboratory abnormalities,

decreased -lymphocyte & hemoglobin & Calcium & Sodium

increased _aspartate aminotransferase &alanine aminotransferase, & alkaline phosphatase & urine protein

Question 40

Oral topotecan

Answer 40

Second-line therapy for recurrent SCLC

Regimen of 2.3 mg/m2 PO daily x 5 days Q21 days superior to best supportive care

Grade IV neutropenia = 32%

Question 41

Lurbinectedin (Zepzeleca)

Indiciation:

Dose

Pre medicaiton

Dose reduction

MOA

AE

Drug Drug Interaction

Answer 41

Patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy

Lurbinectedin 3.2 mg/m2 IV every 21 days until disease progression

Consider administering the following pre-infusion medications to antiemetic prophylaxis:

Corticosteroids (intravenous dexamethasone 8 mg or equivalent)

Serotonin antagonists (intravenous ondansetron 8 mg or equivalent)

First and second dose reduction

2.6 mg/m2 every 21 days

Second dose reduction

2 mg/m2 every 21 days

An alkylating agent and selective inhibitor of oncogenic transcription which preferentially binds to guanine residues in the minor groove of DNA. This leads to bends in the DNA helix and affects the activities of DNA binding proteins, including some transcription factors and DNA repair pathway

Treatment-related adverse events (TRAEs): neutropenia (12% resulted in dose delays, and 16% resulted in dose reductions)

Drug-Drug Interactions: Minor substrate of CYP3A4, avoid coadministration with strong or moderate CYP3A inducers and inhibitors
Chemotherapy-induced nausea/vomiting risk: Moderate

Question 42

Nivolumab (Opdivio)

Do not use in SCLC or NSCLC

Answer 42

Bristol Myers Squibb announcement shared that in consultation with the FDA, they have decided to withdraw the indication of nivolumab for treatment in patients with small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least one other line of therapy. Additional phase 3 trials failed to prove overall survival benefit.

Question 43

Cosela

Answer 43

COSELA is indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC).