NSCLC Flashcards
2 most common mutations in NSCLC
p53 and KRAS
how does smoking induce carcinogenesis
hydrocarbins and nitrosamines form DNA adducts by covalently binding to DNA, resulting in DNA misreplication and mutation
effect of screening for lung cancer
20% decrease in lung-cancer-specific mortality in this population, 7% decreased in overall mortality
who should be screened for lung cancer
current smokers or smokers who quit within the last 15 years. 55-77.
Subtypes of NSCLC
1) adenocarcinoma
2) squamous cell carcinoma
3) *large cell undifferentiated carcinoma
4) mixed histology tumors (eg. adenosquamous carcinoma)
paraneoplastic syndromes associated with NSCLC
1) Humoral hypercalcemia (pTHRP)
2) Hypercoagulable state (Trousseau syndrome)
3) Hypertrophic pulmonary osteoarthropathy (HPOA)
most critical decision making point during workup of NSCLC
presence or absence of sites of disease that would preclude primary surgery or cure
variables precluding surgery/cure
malignant effusion
distant mets
chest wall invasion
***N2 or N3 lymph nodes
negative prognostic markers in NSCLC
K-RAS
positive prognostic markers in NSCLC
EGFR
intent of therapy for stages I-III
cure
system for determining completeness of resection
R0 = complete
R1 = microscopic residual disease (positive margins)
R2 = macroscopic (gross) residual disease
surgical options
lobectomy, pneumonectomy, sublobar resection (wedge resection)
stage I management
Refer to CT surgery + preoperative PFTs
IF surgical candidate → Complete surgical resection
No role for adjuvant chemotherapy unless high risk with tumor diameter >4 cm
clinical features of stage III criteria
1) nodal involvement – N2 or N3 disease
2) Size – greater than 7 cm with or without nodal involvement
- greater than 5 cm with nodal involvement
3) some other criteria…
options for management of positive margins post-op
1) re-resect if possible
2) RT if re-resection not possible
3) concurrent chemo plus RT
regimens for use with concurrent RT
PLATINUM DOUBLETS
cisplatin + etoposide
carboplatin + etoposide
carboplatin + paclitaxel
Cisplatin/carboplatin + pemetrexed (adenocarcinoma only)
EGFR TKIs
- osimertinib
- erlotinib
- gefitinib
- afatinib
drug targeting ALK and ROS1
crizotinib
difference between nivolumab and pembrolizumab for NSCLC
- pembro is only approved for tumors that express PD-L1 >1%
- nivo doesn’t require PD-L1 testing
alimta generic name
pemetrexed
EGFR TKI’s
5 FDA approved: osimertinib, erlotinib, gefitinib, afatinib, dacomitinib
Major risk factors for non-small cell lung cancer
smoking, radon, asbestos, COPD,
Prevalence of sensitizing EGFR mutations?
10% in Western populations
evidence for beta-carotene in preventing lung cancer in current smokers
None, increased incidence of lung cancer in RCTs
First diagnostic step in patient with incidentally found solitary pulmonary node?
review of prior chest imaging
Clinical significance of ERCC1 biomarker
High expression = Resistance to platinum agents
Clinical significance of RRM1 biomarker
High expression = resistance to gemcitabine
Clinical significance of K-RAS mutation
confers resistance to EGFR-TKIs
when do you need to test for EGFR, ALK, ROS1?
Stage IV adeno or squamous if mixed histology or neversmoker (very low likelihood of finding in squamous)
Targets tested for in molecular testing
driver mutations (EGFR, ALK, ROS1, BRAF) + assess PDL1 expression
types of surgery
Lobectomy/pneumonectomy
sublobar resection/wedge resection
options for early stage NSCLC who are inoperable
SBRT
Stage II management
IF II or IB → surgery with adjuvant chemo
IF nonsurgical candidate → RT, SABR, or RFA w/ curative intent
Management of superior sulcus (pancoast tumors) stage IIB + A
Neoadjuvant concurrent chemo plus RT followed by resection
What is PCI?
prophylactic cranial irradiation
Management of stage IV NSCLC?
IF PS1-2: Targeted therapy if actionable mutation or immunotherapy
IF PS3-4: Palliative care
Management of solitary FDG-PET avid lymph nod in addition to mass
Biopsy – would preclude surgery, thus needs to be biopsied
Treatment of tumor harboring EGFR sensitizing mutation
EGFR-TKI’s (erlotinib, gefinitib, afatinib)
Treatment of tumor that is driver mutation negative, PD-L1 positive
Pembrolizumab
adjuvant chemo regimens in general
Platinum doublets
cisplatin vs carboplatin efficacy and toxicity
equivalent efficacy, but carbo is less toxic
Drugs not used with squamous cell histology + why
- Pemetrexed not indicated (lack of efficacy)
- Bevacizumab shouldn’t be used (excessive risk of hemoptysis)
Treatment of Stage III in general
*most = concurrent CRT followed by durvalumab
*select patients considered for surgery
Chest CT type
noncontrast adequate if tumor only involves lung parenchyma, need contrast if meldiastinal or other nodal involvement
difference in treatment between adeno and squamous
pemetrexed not used for squamous
Molecular targets tested for
ALK/elk
C-ros1/Ross riding elk
EGFR/vegetable garden
BRAF/Brad getting f’d by horse
PD-L1
MET
*RET
First step if spiculated nodule post op
PET/CT
Talk to IR about biopsing
When is molecular testing indicated in NSCLC
Stage IV, adeno, or squamous if mixed histology or never smoker
N3 disease in NSCLC
lymph node involvement in side contralateral to tumor
What is a platinum doublet?
carboplatin or cisplatin plus paclitaxel, docetaxel, pemetrexed, or gemcitabine
Positive prognostic biomarker in NSCLC
KRAS (wild type have longer survival)
BRAF mutation prevalence
rare, 1-2%
BRAF mutation clinical implications
1) sensitive to BRAF inhibitors
2) ***modest response to CPIs
Prevalence of ROS1 rearrangements
rare, 1-2%
clinical implications of ALK rearrangement
sensitive to ALK TKIs and *resistant to EGFR TKIS and CPIs
(ALK and EGFR are mutually exclusive)
General efficacy of targeted therapy in NSCLC
useful in a very low percentage of overall patients with lung cancer
molecular testing used to predict EGFR TKI response
POINT MUTATIONS, not EGFR expression via IHC
Treatment for metastatic NSCLC unresponsive to platinum-based therapy without driver mtuation
IO
Contraindications to surgery with Stage III
- Mediastinal involvement (confirm)
- Bulky multistation lymphadenopathy (widespread mediastinal or hilar lymph node involvement)
- chest wall invasion
When to test for activating mutations
Metastatic adeno (can test in squamous, but likelihood of finding an alteration is very low)
more common histology
adeno
adjuvant management of stage II
adjuvant platinum doublet chemo, NO radiation
Stage III management
chemoradiation (does not typically fare well with surgery, mediastinal involvement…)
Stage I criteria
- No nodal involvement
- tumor 4cm or smaller
Definition of stage II (some exceptions) =
- Peribronchial or perihilar lymph node involvement
- OR larger tumor
Stage III Generally (some exceptions) means
Mediastinal or supraclavicular nodal involvement OR large size
Stage I treatment generally
Gold standard is lobectomy, no adjuvant chemo
Management of Stage I patient who defers surgery or who is not surgical candidate?
SBRT (similar outcomes to surgery have been shown in trials) OR wedge resection
Only patients who seem to benefit from adjuvant chemo in stage I
Highly select Stage IB patients
Stage II treatment generally
Surgery with adjuvant chemo
Standard chemo for adjuvant treatment in general
Cisplatin-doublets
Standard chemo regimen for squamous cell histology NSCLC
Cisplatin + gemcitabine or docetaxel
Stage IIIA treatment generally
- IF surgical candidate and operable – chemo or CRT followed by surgery
- IF nonsurgical candidate – CRT followed by durvalumab consolidation
Stage IIIB treatment generally
CRT or surgery
Other contraindications for surgery
- Hoarse voice or elevated hemi-diaphragm
**most importantly – Inadequate cardiopulmonary reserve
Definition of adequate cardiopulmonary reserve in PFTs
- FEV 1 greater than 1.5 L (pre-op) for lobectomy
- FEV 1 greater than 2 L (pre-op) for pneumonectomy
- Goal is to have greater than 40% post-op predicted for FEV-1 and DLCO
N2 vs N1 lymph nodes in terms of digits
- Single digit LN’s are N2
- Double digit LN’s are N1
N1 refers to
peribronchial or perihilar lymph nodes (confirm)
Alternative options for lobectomy if medically inoperable
SBRT or wedge resection
Area that is critical for staging
Mediastinal staging (assessing for multilevel disease, contralateral disease)
Pemetrexed is only used for
Non-squamous histology
Role for post-operative radiation therapy in Stage II
- small OS benefit in IIA (N2) disease
*so refer these patients
Role for immunotherapy
1) induction, consolidation
2) Now promising data of immunotherapy in neoadjuvant setting
Management of Superior sulcus tumor
Neoadjuvant CRT, then proceed to surgery then adjuvant chemo
*local control is critical to reducing morbidity
Superior sulcus tumor presentation
Typically describe upper neck or shoulder pain
Management of chest wall invasion
ChemoRT
Who to not do surgery on in Stage III
- significant weight loss or PS 2 or greater
- borderline cardio-respiratory status
- multi-level N2 disease
- IF requiring pneumonectomy, should be more conservative
Management of unresectable stage III
- Concurrent CRT followed by durvalumab
Initial workup of stage IVA
- molecular testing (adeno)
- MRI
- PETCT
Management of brain mets in NSCLC
Stereotactic radiosurgery (SRS) alone
OR
surgical resection followed by WBRT
PD-L1 TPS stands for
PD-L1 tumor proportion score
What is concept of continuation maintenance?
Continuing the same drug as you gave in induction chemo as the maintenance drug
What is concept of switch maintenance?
Switching to a new drug for maintenance treatment
Role for chemo in stage IV
PS1-2 patients who no targetable mutations and ineligible for IO therapy
BSC is
best supportive care
PD means
progressive disease
Basic algorithm for management of non-squamous stage IV NSCLC
Targeted therapy if actionable mutation
IF no targetable mutation –> immunotherapy
IF no targetable mutation and contraindications to IO –> BEV (bevacizumab)
Role for targeted therapy in stage IV adeno
- EGFR and ALK inhibitors are first approved for first line
- Ros-1, BRAF, MET, and RET are approved for second LINE
Standard of care EGFR TKI for exon 19 mutation
osimertinib
Most commonly found targetable mutations
ALK and EGFR
Approved ALK inhibitors in first line setting
- Crizotinib
- Ceritinib
- Brigatinib
- Alectinib
- a few others
superior/first line ALK inhibitors
Alectinib
Brigatinib
Clinical utility of targeting other mutations at this point
There are FDA approved drugs but there is no clear consensus on which line of therapy to use these agents.(but a lot of experts use them in the first line setting if patient has a targetable mutation).
Drugs targeting ROS-1
Crizotinib
Entrectinib
Lorlatinib
Drug targeting RET fusion
Selpercatinib
Drug targeting MET exon 14 splice mutation
Capmatinib
First line for patients with metastatic NSCLC and no actionable mutation
Depends on PDL1 status
Immunotherapy drugs approved for NSCLC
Nivo (regardless of PD-L1)
Pembro (only if PDL-1 greater than 1%)
Atezolizumab (regardless of PD-L1)
Darvalumab
Correlation of PD-L1 and immunotherapy in NSCLC
Higher the PD-L1 score, the higher the likelihood of response (also holds for tumor mutational burden)
Duration of immunotherapy in advanced NSCLC
- up to 2 years
TPS vs CPS
CPS = number of PD-L1 positive TUMOR cells over viable tumor cells
TPS = number of PD-L1 positive TOTAL cells (including tumor cells, lymphocytes, macrophages) over viable tumor cells
KRAS drug
sotorasib
Stage IA management
- surgery alone, no adjuvant chemo
oligometastatic disease management with 1-3 brain mets
- SRS or surgery to brain met followed by definitive chemoRT (these patients can have long term survival)
First line for patient with advanced NSCLC and an ALK-EML4 rearrangement
ALK inhibitor
Characteristics of patients with ALK mutations
- young
- never-smokers
- adeno histology
- *mutually exclusive to having an EGFR mutation
crizotinib molecular targets
ALK + ROS1 + MET (multikinase inhibitor)
Drugs approved for ROS-1 mutations
- crizotinib
- entrectinib
Lorlatinib
Line of therapy of ALK inhibitors for stage IV + CNS penetration
- first line
- alectinib, brigatinib, lorlatinib
- good CNS penetration
adjuvant chemo in general for stage II-III + number of cycles
Cisplatin-based doublet for 4 cycles
T3 NSCLC means (in terms of tumor burden)
- separate nodule in primary lobe
T4 NSCLC means
- Tumor >7 cm in greatest dimension
- or associated with separate tumor nodule(s) in a different IPSILATERAL lobe than that of the primary tumor
- or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
M1a means
- nodule in a contralateral lung (make sure not a different primary)
Stage IIIC lung adeno management and regimen
IF nodal –> chemoRT with platinum doublet followed by consolidation with durvalumab
IF T4NO – primary surgery
staging significance of contralateral mediastinal or hilar lymphadenopathy
N3 disease
Stage III management in patient with EGFR mutation
chemoRT adjuvant osimertinib
approved EGFR targeted therapies
- erlotinib + minus ramucirumab
- osimertinib
- gefitinib
- afatinib
- dacomitinib
*there are a bunch but osimertinib is preferred per NCCN
efficacy of immunotherapy in patients with actionable mutation
generally doesn’t work well
Initial step in management of progression on EGFR targeted therapy
Given disease progression, will repeat biopsy with sequencing + continue osimertinib
*unless concern for visceral crisis, then carbo + pemetrexed
afatinib targets
EGFR + HER2 TKI
Drugs that are only indicated for non-squamous histology
1) bev (CONFIRM)
2) pemetrexed
pancoast tumor management
- pre-operative chemorads, followed by surgery, with adjuvant chemo
presentation of pancoast tumors
- severe shoulder pain
- hand muscle atrophy
- subclavian vein obstruction
- horner’s syndrome
Drug to avoid in second line setting for patients with actionable mutations
- immune checkpoint inhibitors
(this cohort fails to respond to immunotherapy for unclear reasons) (PD-1/PD-L1 is probably not the main escape route for this tumor type)
FDA approved drugs for patients with MET amplification
- crizotinib, capmatinib, tepotinib
Activity of ALK inhibitors
- very active in advanced NSCLC but still only approved for stage IV setting
Only situations in which wedge resection is preferred over lobectomy
1) poor pulmonary reserve or other comorbidity contraindicating lobectomy
2) **peripheral* nodule less than 2 cm with at least one of the following: Pure AIS histology, Nodule greater than 50% GGO on CT, or surveillance confirms a long doubling time
*just remember lobectomy done most of the time. Wedge resection has worse outcomes.
SE to know about with crizotinib
- hypogonadism
Preferred chemo regimens to give concurrently with radiation for Stage III squamous
1) weekly taxol and carboplatin
2) cisplatin/etoposide
Creatinine clearance that is contraindication for pemetrexed
less than 45 ml/min
regimen and number of cycles for extensive stage SCLC
4 cycles of carbo + etoposide with atezo **OR durvalumab maintenance
next step after finishing 6 cycles of carbo-etoposide for SCLC
Stop therapy and then let patient recover, rechallenge when cancer recurs
management of grade 1 pneumonitis from checkpoint inhibitors
- hold immunotherapy and reassess in 1-2 weeks
management of grade 2 pneumonitis from checkpoint inhibitors
- hold treatment, consult pulm, ID work-up, start steroids
most commonly observed genetic alterations in patients with EGFR resistance
- MET amplification
- C797S
Regimens approved for Stage IV lung adeno without actionable mutation
- carbo - pemetrexed + pembro
- carbo + taxol + bev + atezo
- carbo + abraxane + atezo
- nivo + ipi + pemetrexed + carbo
- nivo + ipi
- pembro monotherapy
second line for metastatic lung adeno EGFR+
IMpower 150
Stage III NSCLC management
chemorads followed by darvalumab consolidation
first line regimen for metastatic squamous cell lung cancer with 0% PDL1
pembro + carbo + taxol (or albumin-bound paclitaxel
PD-L1 level required for frontline pembro + carbo + taxol for stage IV squamous cell lung cancer
agnostic (doesn’t matter)
PD-L1 level required for second line immunotherapy in stage IV squamous cell lung cancer
pembro = 1%
others (nivo and atezo) are agnostic
first line ALK inhibitors + preferred ALK inhibitor + why preferred
alectinib (preferred given improved CNS penetration, and well tolerated)
brigatinib
lorlatinib
second line for ALK positive NSCLC
- switch to different ALK inhibitor (depends on what was previously received, active against resistant mechanisms)
- if started on crizotinib, switch to alectinib, brigatinib, or ceritinib
- if started on alectinib, brigatinib, ceritinib, or lorlatinib, offer lorlatinib (active against resistant mechanisms)
role for sotorasib (KRAS inhibitor)
- Second line for metastaic, previously treated with chemo (may change, trial in a few years)
Targeted therapy for BRAF mutant? line of therapy?
- combination BRAF/MEK (dabrafenib-trametinib)
- first line
biggest SE of MET inhibitors
peripheral edema
CNS penetration of targeted therapy generally speaking
Most have CNS penetration
KRAS targetable mutation
p.G12C
Response rate required for first line FDA approval
Response rate greater than 50%
abraxane vs. paclitaxel in terms of SE profile + action
- less neuropathy
- some evidence abraxane gets into tumor cells better
What is IMpower150 regimen
atezo + bev + taxol + carbo
ChemoRT regimens for Stage III
1) cisplatin + etoposide, followed by durvalumab
2) carbo/taxol
Management of stage II patient who is status post resection with R1 resection
- reresection if surgical candidate
- if not surgical candidate, then sequential or concurrent chemoRT
General treatment approach for superior sulcus or pancoast tumor
**neoadjuvant chemoradiation –> surgery –> adjuvant chemo
Preferred maintenance IO for carbo/etoposide in SCLC
Atezo or durvalumab
Role for EGFR TKI’s
1) Stage IV disease
2) Adjuvant setting
immunotherapy used as consolidation for stage III NSCLC after chemoRT
durvalumab
Diagnosis of pulmonary osteoarthropathy
- bone scan (highly sensitive). Shows diffuse, symmetrically increased uptake in diaphysis and metaphysis of tubular bone.
Most common lung cancer histologic subtype in non-smokers
invasive mucinous adenocarcinoma
Procedure used for mediastinal staging
Mediastinoscopy
Other drug you can’t give to squamous histology
Bev
KRAS line approval
Second line
Difference m
.
Drug approved for EXON 20 EGFR + line of therapy
- mobocertinib
- second line
Segmentectomy
- removal of part of one of the lobes of the lung
- Segmentectomy may be recommended over lobectomy (where one entire lobe of the lung is removed) if the patient already has a highly reduced lung reserve. Lobectomy is the most common and preferred type of procedure for NSCLC.
Size threshold for wedge resection
Less than 4 cm
Why never give IO second line for targeted mutations?
- won’t respond
- substantially increases risk of toxicity
NTRK mutation is druggable in which cancers
ALL, universally responsive
Only ALK inhibitor with an indication for ROS1
crizotinib
Management of R1 resection in NSCLC
CRT
Promising investigational approach to Stage III lung
Chemoimmunotherapy induction
High risk factors warranting adjuvant chemotherapy for stage I
tumor >4cm
Resistance mechanism to first and second generation EGFR TKI’s that led to development of osimertinib
T790 in exon 20
Drug approved for EGFR insertion 20 mutations + in what line
Mobicertinib, second line
Category 1 NCCN regimens for squamous and non squamous metastatic
squamous — carbo, taxol, pembro
nonsquamous – carbo, pem, pem
N2 disease is
Ipsilateral mediastinal OR subcarinal lymph node (confirm)
management of ILD from osimertinib
- stop osimertinib
- start steroids
IHC as good as a test as FISH for ALK
equivalent
First line for ROS1 mutant
entrectinib
adjuvant therapy for Stage II to IIIA
chemo for high risk features
atezo for 1 year if PD-L1 greater than 1%
***confirm this
Second line for stage IV adeno with excellent PS
ramucirumab + docetaxel
What is stage 1a in terms of disease burden?
no lymph node involvement
NCCN preferred first line for metastatic thymic carcinoma
Carboplatin/paclitaxel
lung cancer screening indication
IF 50-80 w/ 15 pack yr history AND current or quit <15 yrs ago, annual Low-dose chest CT
Platinum doublet adjuvant regimens
gemcitabine
docetaxel
vinorelbine.
IF nonsquamous -> pemetrexed
Neoadjuvant chemo approved for what indications?
N1 OR >4 cm
ROS-1 drugs
entrectinib
crizotinib
High risk features warranting adjuvant treatment
tumor >4 cm
Size at which you can’t do SRS alone in NSCLC
At a certain size threshold (?) you need conventionally fractioned radiation rather than SRS, which requires chemo for local control
T3 disease in NSCLC
1) Tumor >5 cm but ≤7 cm in greatest dimension
2) or associated with separate tumor nodule(s) in the same lobe as the primary tumor
3) or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, parietal pericardium
T4 disease
1) Tumor >7 cm in greatest dimension
2) or associated with separate tumor nodule(s) in a different IPSILATERAL lobe than that of the primary tumor
3) OR invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina
Clinical significance of separate tumor nodule in contralateral lobe
M1a disease
Indications for molecular lung panel
Given adeno OR squamous neversmoker (or light smoker) OR mixed histology, molecular lung panel
What is ALCHEMIST looking at?
- early stage with druggable mutations
- Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials – represents three integrated, precision medicine trials that are designed to identify people with early-stage lung cancer who have tumors that harbor EGFR and ALK gene alterations and evaluate whether drug treatments targeted against those molecular changes can lead to improved survival compared to current standard of care therapy alone
What are the sublobar surgery types?
Segmentectomy – removes larger piece of lung tissue
Wedge resection –
What is a pneumonectomy?
Removal of entire lung
Separate tumor nodule in a contralateral lobe indicates
M1a disease
Which number lymph node stations are N1 disease?
10-13
Which number lymph node stations are N2-3 disease?
1-9
T staging of satelite lesions
T3 = same ipsilateral lobe
T4 = different ipsilateral lobe
Term for response rate of CNS disease
Intracranial response rate
What are the types of sublobar resections?
1) segmentectomy 2) wedge
