Metastatic NSCLC Flashcards
1
Q
What are the risk factors for lung cancer?
A
Smoking Exposure to Asbestos Arsenic Radon Non-tobacco-related polycyclic aromatic hydrocarbons
2
Q
What is the standard testing for detecting ALK fusion?
A
Break-apart fluorescence-in-situ-hybridization (FISH) test
PCR may be successful
- requires adequate overage of the many possible fusion genes
- challenged by the availability of adequate quality nuclei can acid from typical samples and by the method itself
3
Q
What does Crizotinib block?
A
Dual ALK and MET TKI
MET = Mesenchymal Epithelial Transition Factor
4
Q
What do you understand from the term, “Continuation maintenance”?
A
Maintained use of an agent included in 1st-line treatment
5
Q
What do you understand from the term “switch maintenance”?
A
Introduction of a new agent after 4# of platinum-based chemotherapy
6
Q
What is the definition of oligometastases?
A
Maximum of 5 metastatic lesions in the body
Can be synchronous or metachronous.
Synchronous:
- diagnosed within 1 month before or after primary tumor was identified.
Metachronous:
- if they appear after treatment of the primary
7
Q
What do you do when there is a solitary lesion in the contra lateral lung?
A
In most cases, this should be considered as a synchronous secondary primary tumor, and treated, if possible, with surgery and adjuvant chemo if indicated, definitive radiotherapy or ChemoRT.
8
Q
Tell me about the AJCC staging system (7th edition)
A
T1:
- Tumor 3cm or less. No evidence of invasion into the main bronchus.
T2: - Tumor >3cm, but 7cm or less. - Or with any of the following features: >> involves main bronchus >> 2cm or more distal to the carina >> Invades visceral pleura (PL1 or PL2) >> A/w atelectasis >> A/w obstructive pneumonia is that extends to the hilar region, but does not involve the entire lung
T3: - >7cm - or one that directly invades any of the following: >> parietal pleura >> Chest wall (including superior sulcus tumors) >> diaphragm >> phrenic nerve >> Mediastinal pleura >> Parietal pericardium - Tumor in the the main bronchus >> > or associated atelectasis or obstructive pneumonia is of the entire lung >> separate nodule In the same lobe
T4: - Tumor of any size that invades any of the following: >> Mediastinum >> Heart >> Great vessels >> trachea >> Recurrent laryngeal nerve >> Esophagus >> vertebral body >> carina >> Separate tumor nodule in a different ipsilateral lobe
9
Q
Tell me about the AJCC 7th edition staging for NSCLC - N
A
N0 : No regional LN
N1:
- Ipsilateral peri bronchial and/or
- ipsilateral hilar LN and intrapulmonary LN
- Including involvement by direct extension
N2:
- Ipsilateral mediastinal and/or
- Ipsilateral sub Cardinal LN
N3:
- Contralateral mediastinal,
- Contralateral hilar
- Ipsilateral or Contralateral scalene
- Ipsilateral or Contralateral supraclavicular LN
10
Q
Tell me about the T1 staging of the AJCC 7th edition for NSCLC
A
T1:
- Tumor 3cm or less, without bronchoscopic evidence of invasion more proximal than the lobar bronchus
T1a Tumor 2cm or less
T1b Tumor >2cm, but 3cm or less
11
Q
Tell me about the T2 staging from the AJCC 7th edition for NSCLC?
A
T2: - Tumor >3cm, but 7cm or less; or - Tumor with any of the following: >> Involves main bronchus >> 2cm or more distal to the carina >> Invades visceral pleura - a/w atelectasis or obstructive pneumonitis that extends to the hilar region but does NOT involve the entire lung
T2a: Tumor >3cm, but 5cm or less
T2b: Tumor > 5cm, but 7cm or less
12
Q
Tell me about the T3 of the AJCC 7th edition
A
T3: - >7cm; or - one that directly invades any of the following: >> Parietal pleura >> Chest wall, including superior sulcus tumors >> Diaphragm >> Phrenic nerve >> mediastinal pleura >> Parietal pericardium - tumor in the main bronchus,
13
Q
Tell me about the T4 of the 7th edition AJCC staging
A
T4: Tumor of any size that invades any of the following:
- mediastinum
- heart
- great vessels
- trachea
- recurrent laryngeal nerve
- esophagus
- vertebral body
- carina
- separate tumor nodule in a different Ipsilateral lobe
14
Q
Some conclusions about the Stage for NSCLC
A
N1 is at least a stage IIA disease
N2 is at least a stage IIIA disease
N3 is at least a stage IIIB disease
T4 is at least a stage IIIA disease
15
Q
What are 3rd generation cytotoxics in NSCLC?
A
Gemcitabine
Vinorelbine
Paclitaxel
Docetaxel
16
Q
What is the Schiller paper about?
A
NEJM 2002
Aim:
Pac/Cis was standard of care.
To compare if any of the 3 regimens was superior to Pac/Cis
N=1200
Advanced NSCLC
4arms: A) Pac/Cis - Pac 135mg/m2 CI; Cis 75 Day2 q21d B) Gem/Cis - Gem 1000mg/m2 D1,8,15, Cis 100mg/m2 D1 q28d C) Docetaxel/Cis - Docetaxel (75); Cis (75) D1 q21d D) Pac/Carbo - Pac (225) over 3 hours D1; Carbo AUC6 q21d
Results: NO DIFFERENCE
- RR 20%, median survival 8m
- 1y survival rate 30%, 2y survival rate 10%
- Gem/Cis gave better PFS, but a/w 3x ore G3/4/5 renal toxicity (9% vs 3%)
» 3.4m in Pac/CDDP vs 4.2m Gem/CDDP
Conclusion: All 4 regimens similar
17
Q
What is the evidence for using Pemetrexed/CDDP in non-squamous histology for lung CA?
A
Scagliotti JCO 2008
Aim: To assess that Pem/Cis is non-inferior to SOC
N=1700
Chemo-naive, Stage IIIB/IV
Non-inferiority study
2arms: A) Gem/CDDP - Gem (1250) D1,8, CDDP (75) D1 q21days x6 B) Pem/CDDP - Pem (500) D1, CDDP (75) D1 q21days x6
Results:
1) OS Pem/CDDP = Gem/CDDP
2) AdenoCA & Large cell: OS superior for Pem/CDDP
- 12.6m vs 10.9m
3) Sqaumous: Gem/CDDP > Pem/CDDP
- 10.8m vs 9.4m
4) G3/4 neutropenia/anemia/thrombocytopenia lower than Gem/CDDP
5) G3/4 nausea more common with Pem/CDDP
18
Q
What is the pre-clinical data that explains why squamous histology is not as responsive to Pemetrexed?
A
Preclinical data indicated that:
1) overexp of thymidylate synthase correlated with reduced sensitivity to Pemetrexed.
Study in chemo-naive patients showed that baseline expression of thymidylate synthase Gene and protein were significantly higher in Sqaumous cell CA cf adenoCA.
19
Q
What is Pemetrexed?
A
Pemetrexed is a potent inhibitor of thymidylate synthase and other folate-dependent enzymes.
This includes:
- dihydrofolate reductase
- glycinamide ribonucleotide formyl transferase
20
Q
What about the evidence between Vinorelbine/CDDP vs Gem/CDDP or Pac/Carbo?
A
Scaglotti JCO 2002
Aim: To compare: - Vinorelbine/CDDP (Control) >> Vino(25mg/m2/week) x 12 weeks --> alternate week + CDDP (100) D1 q28d - Gem/CDDP >> Gem (1250) D1,8 ,CDDP (750) D2 q21d - Pac/Carbo >> Pac (225) over 3 hours, Carbo AUC 6 D1 q21d
N=600
Advanced NSCLC
Results: No difference in OS/Time to disease progr/TTF
- median suvival ~9-10m
- Neutropenia higher on VC arm
» 40% vs PCb 35% vs GC 17%
21
Q
Between Gem/Carbo and Pemetrexed/Carbo, which would you choose and why?
A
Non-squamous histology, Pem/Carbo.
Besides Scagliotti study, there is also a Norwegian study by Gronberg JCO 2009.
Aim of the study:
- compare Pem/Carbo vs Gem/Garbo
2arms up to 4#: A) Pem/Carbo - Pemetrexed (500) + Carbo (AUC5) D1 Q3w B) Gem/Carbo - Gem (1000) D1,8 + Carbo (AUC5) D1 Q3w
N=450
Results: NO Significant differences in:
- primary HRQoL end points
- OS
Gem/Carbo had higher G3/4 hematologic toxicities, and required more supportive treatment
22
Q
Any benefit with Bevacizumab?
A
Alan Sandler NEJM 2006
Phase 3 study comparing Pac/Carbo vs Pac/Carbo/Bev
N=900
Recurrent or advanced NSCLC (Stage IIIB/IV)
Exclusion criteria:
- Sqaumous Cell CA
- brain mets
- clinically significant hemoptysis
- inadequate organ function
- PS >1
2 arms:
A) Pac/Carbo q3w
B) Pac/Carbo/Bev q3w + Bev q3w until PD/Toxic
Results:
- med OS 12m vs 10m (Chemo alone)
- med PFS 6.2 and 4.5m
- RR 35% vs 15%
- Rates of clinically significant bleeding 4.5% vs 0.7%
- 15 treatment-related deaths in the Bev group, including 5 from pul hemorrhage.
23
Q
Any other evidence for Bev besides ECOG study?
A
AVAiL study by Martin Reck JCO 2009
Aim: to investigate efficacy + Safety of Gem/CDDP/Bev
N=1000
2 arms:
A) Gem 1250 mg/m2 + CDDP 80mg/m2 + low dose Bev 7.5mg/kg
B) Gem 1250 mg/m2 + CDDP 80mg/m2 + High dose Bev 15mg/kg
C) Gem 1250 mg/m2 + CDDP 80mg/m2 + Placebo
* up to 6 cycles with Bev/placebo continuing until PD
Results:
- PFS: 6.7m (LD) vs 6.1 (placebo) vs 6.5m (HD)
- ORR 20% (Pl) 34% (LD) 30% (HD)
- median OS>13m in all treatment groups, but not significantly increased with Bev.
24
Q
What is the PRONOUNCE study about?
A
Zinner JTO 2015
Aim: to prove that Pem/Carbo > Pac/Carbo/Bev in terms of PFS without G4 toxicity.
2 arms (4cycles followed by maintenance): A) Pemetrexed (500) + Carbo (AUC6) --> Pemetrexed maintenance B) Pac (200) + Carbo (AUC6) + Bev (15mg/kg) --> Bev maintenance
Results:
G4PFS 3.9m for Pem/Carbo vs 2.9 (not significant)
25
What is the PointBreak study about?
Patel et al JCO 2013
Comparing 2 groups:
A) Pem/Carbo/Bev --> Maintenance Pem/Bev
B) Pac/Carbo/Bev --> Maintenance Bev
Advanced Stage IIIB/IV NSCLC
ECOG 0/1
N=900
Results:
- NO survival advantage
- PFS HR 0.8 6m vs 5.6m (PacCBev)
- ORR similar about 33%
- DCR 65-70% similar
26
What do you know about Oral S-1 usage in NSCLC?
JCO 2010, W.Japan Oncology Group. Okamoto
Aim: to prove that S-1/Carbo was non-inferior to Pac/Carbo in terms of OS
N=560
Chemo-naive advanced NSCLC
2arms:
A) Carbo (AUC6) + Pac (200mg/m2) D1 q21 days
B) Carbo (AUC6) D1 + S-1 (40mg/m2) D1-14 q21days
Results:
- median OS 15m (S-1) vs 13m (Pac)
- 1yr OS 57%vs 56%
- Diff toxicities
- Carbo/S-1 more delays than Carbo/Pac
Conclusions = S-1+Carbo no inferior in terms of OS
27
What is the evidence for maintenance Pemetrexed?
1) Ciuleanu Lancet 2009
- n=663, Stage IIIB/IV who had not PD on 4# of platinum-based chemo randomized to Pemetrexed+BSC vs Placebo+BSC
- PFS improved 4.3m from 2.6m HR 0.5
- OS improved 13.4m vs 10.6m HR 0.8
2) PARAMOUNT study
- Paz-Ares study. Updated results JCO 2013
- no previous systemic chemo
- induction phase of Pem (500)/CDDP (75) q21days x4.
- 540 did not progress, and went on to be randomized into 2 arms:
A) Maintenance Pem
B) Placebo
- Results (updated):
>> median no. Of cycles 8 vs 5
>> 22% reduction in risk of death HR 0.8; 14m vs 11m
>> med PFS (2012) 4m vs 2.8m
28
What is the Paramount study?
Paz-Ares study, Lancet Onco 2012, updated JCO 2013.
900 patients had induction Pem/CDDP x4 cycle.
540 did not PD, and Randomized into:
A) Maintenance Pem
B) Placebo
Results:
- median number of cycles received 8 vs 5
- 22% reduction in risk of death. 14m vs 11m
- (2012) mPFS 4.1 vs 2.8m
29
What do you know about Bev/Pem maintenance? Any evidence?
AVAPERL study by Barlesi et al. JCO 2013
Induction chemo:
Bev 7.5mg/kg/CDDP (75)/Pem (500) x4 cycles
250 patients had SD/PR.. Randomized to:
A) Bevacizumab maintenance
B) Bev + Pem maintenance
F/u 8 months:
PFS 7.4m (Bev+Pem) vs 3.7m HR 0.5
30
How about maintenance Docetaxel. Any evidence?
Yes.
Fidias JCO 2008
Chemo-naive, Stage IIIB + Pleural effusion / Stage IV
Induction chemo:
Gem (1000) D1,8+ Carbo (AUC5) D1 q21days x 4#
300 pts had SD/PR. Then randomized to:
A) Immediate Docetaxel (75) D1 q21days
B) Delayed Docetaxel
Results:
- toxicity profiles similar
- med PFS 6m vs 3m (delayed)
- Med OS 12m vs 10m (Delayed) but not significant.
31
How about Erlotinib maintenance? Or Gemcitabine maintenance?
1) Perol et al JCO 2012
Aim - to compare continuation maintenance with Gem VS switch maintenance with Erlotinib
Induction chemo:
- Gem/CDDP
Pre-defined 2nd line: Pemetrexed q21days
464 patients with SD/PR with induction chemo, randomized to:
A) Observation
B) Gemcitabine (1250) D1,8 q21 days
C) Erlotinib 150mg OM
Results:
- PFS Gem 4m, Erlotinib 3m, 2m (observation)
- non-significant improvement in OS
```
2) Erlotinib maintenance (SATURN)
Cappuzzo Lancet Oncol 2010
- Induction phase: 4# of platinum doublet chemotherapy
- n=900, 2 arms:
A) Erlotinib 150mg OM
B) Placebo
```
Results:
- median PFS longer with Erlotinib, both in whole group and in subset of EGFR+
>> values same, 11.1weeks vs 12.3 weeks.
32
How about Gefitinib maintenance?
SWOG S0023 study Karen Kelly et al, JCO 2008
Stage III NSCLC
Induction chemo: CDDP (50) D1,8, Etoposide (50) D1-5, q28d x 2# with concurrent thoracic RT --> 3#docetaxel (75)
If no progression, then randomized to:
A) Gefitinib 250 mgOM
B) Placebo
Results:
Study closed early
No improvement in survival
33
What can you use as 2nd line for treatment of met NSCLC?
Docetaxel
Shepherd et al, JCO 2000
Aim of study: evaluate if Docetaxel > BSC in previously tx NSCLC pts
Incl criteria:
- prev treated with platinum-based chemotherapy
- Stage IIIB/IV
Excluded :
- symptomatic brain mets
- prep treatment with paclitaxel
3 arms:
A) Docetaxel 100mg/m2
B) Docetaxel 75mg/m2
C) BSC
N=100
```
Results:
TTP:
- Docetaxel > BSC
- 10.6w vs 6.7w
Med OS
- Docetaxel >BSC
- 7m vs 4.6m
- difference more significant for Docetaxel at 75 mg/m2
1y OS:
- 37% vs 11% (Docetaxel at 75)
```
34
What is the evidence for Pemetrexed > Docetaxel as 2nd line?
Hanna et al JCO 2004
Aim: Compare efficacy and toxicity Btwn Pemetrexed vs Docetaxel in previously treated NSCLC
N=751
```
Results:
- ORR 9% ~
- Med PFS 3m ~
- med survival time 8.3m vs 7.9m ~
- Docetaxel:
>> more G3/4 neutropenia 40% vs 5%
>> more FN 13% vs 2%
>> more neutropenia with infections 3% vs 0%
>> More hospitalization a for neutropenia fever 13% vs 1.5%
```
35
What is Nivolumab?
Fully human IgG4 programmed Death 1 (PD-1) immune checkpoint inhibitor antibody.
It disrupts PD-1 mediated signaling and may restore anti tumor immunity
36
What is the evidence for Nivolumab?
Borghaei et al NEJM 2015 Checkmate 057
Aim: to evaluate if Nivolumab > Docetaxel in previously treated NSCLC
Inclusion criteria:
S/p prior platinum-based doublet therapy
Exclusion criteria:
- Autoimmune disease
- symptomatic ILD
- systemic immunosuppressive
- prior treatment with immune-stimulators anti-tumor agents including Checkpoint-targeted agents
- prior use of Docetaxel
N=582
2 arms:
A) Nivolumab 3mg/kg Q2weeks
B) Docetaxel 75mg/m2 Q3w
```
Results:
- OS longer with Nivolumab
>> 12m vs 9m
- 1y OS 50% vs 40%
- 18m OS: 40% vs 20%
- RR 20% vs 10%
- * PFS 2.3m (Nivolumab) vs 4.2m (Docetaxel), but rate of PFS survival at 1 year was higher with Nivolumab (20% vs 10%)
```
Tumor PD-L1 expression was confirmed when staining of he tumor-cell membrane was observed at 1% or higher, 5% or higher and 10% or higher
37
What is tumor immune escape?
The mechanism by which tumor cells escape recognition and elimination by the immune system.
Eg.
PD-1 receptor Is expressed on activated T-cells
PD-L1 and PD-L2 are tumor-expressed Ligands.
PD-1 is engaged by PD-L1 and PD-L2
- this down-regulates T-cell activation and promotes tumor immune escape
38
Which is better for 1st line to of NSCLC? CDDP or Carboplatin. Why?
Ardizzoni et al JNCI 2007 from CISCA Meta-analysis Group
Aim: to compare Carboplatin and CDDP
Meta-analysis of 9 trials, 3000 patients
Median f/u ~3 years
Results:
- ORR 30% vs 24% (Carbo)
- Increased Hazard of mortality HR 1.07 by using Carboplatin.
>> in Nonsquamous tumors, Carboplain a/w significant increase in mortality HR 1.12
39
What is the evidence that showed Docetaxel/CDDP > Vinorelbine/CDDP ?
TAX 326 by Fosella JCO 2003
Aim: Evaluate if Docetaxel/Platinum > Vinorelbine/CDDP as 1st line therapy
N-1200
Stage IIIB/IV
Treatment-naive
3arms:
A) Docetaxel/CDDP (DC)
- Docetaxel (75)+ CDDP (75) q3w
B) Docetaxel/Carboplatin (DCb)
- Docetaxel (75) + Carboplatin (AUC 6) q3w
C) Vinorelbine/CDDP (VC)
- Vinorelbine 25mg/m2/week + CDDP (100)q4w
Results:
- mOS: 11m (DC) 10m (VC)
- 2y survival rate: 20% (DC) 10% (VC)
- ORR 30% (DC) vs 25% (VC)
- Median survival and response similar for DCb and VC (9-10m and 24%)
- Neutropenia/Thrombocytopenia/FN similar in all
- G3/4 nausea/anemia/vomiting more common with VC
- Improved QoL with Docetaxel
40
Is Pac/Carbo = Vinorelbine/CDDP?
Yes
SWOG study by Karen Kelly JCO 2001
Aim: To determine if Pac/Carbo > Vinorebine/CDDP
N= 400
Incl criteria:
- Stage IIIB/IV, all histo of NSCLC including Squamous
- treatment naiive from chemo and biologics
Excl criteria:
- Brain mets
- G2 or higher peripheral neuropathy
2 arms:
A) CDDP (100) q4w + Vino (25)/week
B) IV Pac (225 over 3 hours) + Carbo (AUC 6) q3w
Results:
- ORR 28% (VC) 25% (PC)
- Med Survival 8m~
- 1y survival rates 36% vs 38%
- G3/4 neutropenia/leukopenia/nausea/vomiting more common on VC
- G3 peripheral neuropathy higher on PC
- more treatment discontinuation on VC arm
- QoL ~
Conclusion = PC = VC
41
Describe the ATLAS Trial for NSCLC
Miller et al JCO 2009
Aim: to evaluate if Bev+ Erlotinib > Bev
- after B+platinum-containing doublet chemotherapy
Based on BETA trial
- bev+Erlotinib >Erlotinib for treatment of advanced NSCLC after failure of standard 1st-line chemotherapy.
- superior in terms of PFS
Inclusion:
- Bev-eligible
- Stage IIIB/IV NSCLC
- included squamous as well
Induction chemo:
- Bev (15mg/kg q3w) + Chemo
N=1200
If no PD, then randomized to:
A) Bev + Erlotinib
B) Bev + Placebo
Results:
-median PFS 4.8m (B+#) vs 3.7m HR 0.7
Conclusion:
- Chemo + B --> B+E improves PFS
42
What is the evidence behind Cetuximab in NSCLC?
For:
1) FLEX trial by Robert Pirker Lancet 2009
Incl criteria:
- chemo naive, advanced IIIB (Wet) / Stage IV NSCLC
- EGFR+
N=1100
```
2 arms:
A) Chemo + Cetuximab
- 6 cycles, Q3w
- CDDP (80) D1
- Vinorelbine 25 mg/m2 D1, D8
- Cetuximab 400 mg/m2 over 2 hours D1, 250mg/m2 D8 onwards over 1 hour
B) Chemo alone
```
```
Results:
- med OS: 11.3m (Chemo+Cetuximab)vs 10.1m HR 0.87
=======================
Against:
1) BMS099 study
Lynch et al JCO 2010
```
Aim: To evaluate efficacy of Cetuximab + Taxane/Carboplatin as 1st line treatment for advanced NSCLC
N=700
Incl Criteria:
Stage IIIB (wet)/IV
Chemo-naive
No restrictions by histology or EGFR expression
2 arms:
A) Cetuximab/TC
- Taxane either Paclitaxel (225) or Docetaxel (75)
- Carboplatin AUC6
- Cetuximab 400mg/m2 D1, 250mg/m2 weekly
B) TC
Results:
PFS 4.4m (Cetuximab) vs 4.24m HR 0.9
OS 10m vs 8m (TC) - trend
ORR 26% vs 17%
Conclusion:
- Addition of Cetuximab to TC did NOT significantly improve PFS
- but did improve ORR
- and trend towards improved OS
43
How does Bevacizumab work?
Inhibits VEGF (key mediator of angiogenesis)
1) Regression of existing tumor microvasculature
2) Normalization of remaining tumor vasculature
3) Inhibition of new tumor vasculature
44
How about safety of Bevacizumab in patients with Brain mets?
PASSPORT trial, Socinski JCO 2009
Incl criteria:
Nonsquamous advanced NSCLC
Previously treated Brain mets, with systemic treatment initiated only at least 4 weeks post-treatment for brain mets
N=115
2 arms:
A) Bev 15mg/kg + Platinum doublet chemo or Erlotinib Q21d until PD
B) BEv 15 mg/kg + Erlotinib or single agent chemo, Q21d until PD
Results:
- no evidence of CNS hemorrhage
- 3% risk of pul haemorrhage of any grade
45
Any evidence for combining Chemo + EGFR TKI?
PLoS ONE study by OuYang et al
8 trials, n=4500
Controversial
At best, combined regimen delayed disease progression HR 0.8
Sequential combination of TKIs and chemo gave higher PFS advantage (subgroup)
46
What is the rate of EGFR + in the iPASS study?
60%
In the iPASS study, all were:
Never/light smokers
Asian
AdenoCA
47
What are the most common EGFR mutations?
Exon 18 = 5%
Exon 19 45%
Exon 20
48
Tell me about the I-PASS study
Tony Mok NEJM 2009
Non-inferior study
```
N=1200
Chemo naive patients
Adenocarcinomas
Never/light ex-smokers
Stage IIIB/IV
```
Never smokers =
49
How about Gefitinib vs Gem/CDDP as first line?
Han et al JCO 2012
First-SIGNAL
N=300
Korean
Neve smokers
Stage IIIB/IV
Aim: demonstrate better OS for Gefitinib
```
2 arms:
A) Gefitinib 250mg OD
B) Gemcitbine/CDDP
- Gem 1250mg/m2 D1,8
- CDDP 80mg/2 D1
- q3w
- up to 9 courses
```
Results:
- OS similar 22m
- 1y PFS 17% vs 3%(GP)
- RR 55% and 46% (GP)
Results: failed to demonstrate superior OS
50
What is the evidence for Gefitinib > Docetaxel/CDDP
Mitsudomi Lancet Onco 2010
Aim: To evaluate if EGFR+ patients has a better PFS cf standard platinum doublet chemotherapy.
N=170
Stage IIIB/IV
Exon 19 or L858R point mutation
2 arms:
A) Gefitinib 250mg OD
B) CDDP (80) + Docetaxel (60) q3w x 3-6 cycles
Results:
- longer PFS 9m vs 6m (chemo)
- 2% risk of ILD
- ORR 60% vs 30% (Chemo)
- Disease control rate 90% (G) vs 80% (chemo)
- Data for OS immature
51
Besides iPASS, what other evidence do you know about from Japan re: Gefitinib or chemo?
Maemondo NEJM 2010 N.E. Japan Study Group (NEJ 002 study)
Aim: To evaluate efficacy and safety profile cf to standard chemo
N=200
Met, chemo-naive
2arms:
A) Gefitinib
B) Pac/Carbo
RESULTS:
- PFS 11m vs 5m HR 0.3
- RR 70% vs 30%
- med OS 31m vs 24m (Chemo)
Updated results 2012 in Annals of Oncology:
- no diff in OS 28m (Gefitinib) vs 27m (Chemo)
>?secondary to high-cross over from chemo to Gefitinib upon PD
52
What is the OPTIMAL trial about?
Zhou et al. Lancet Oncol 2011
Aim: Compared efficacy and tolerability of Erlotinib vs chemo in 1st line in EGFR M+
China
Exon 19 deal or Exon 21 L858R point mutation
Treatment-naive
N=160
2 arms:
A) Erlotinib 150mg/day
B) Gem/Carbo
RESULTS:
- med PFS 13m vs 5m (HR 0.2)
- CR Rate 2% with Erlotinib
- PR rate 80% vs 36%
- ORR: 83% vs 36%
53
What is the LUX-Lung 1 study about?
Miller et al, Lancet Oncol 2012
Aim: to evaluate the efficacy of Afatinib in pts with previous treatment failures on TKI
Incl criteria:
S/p 1 or 2 previous chemo
PD after at least 12 weeks of tx with Erlotinib or Gefitinib
2 arms:
A) Afatinib 50 mg OD
B) Placebo
N=600
RESULTS:
- No significant difference in Med OS 11m (Afatinib) vs 12m (Placebo)
- Med PFS 3.3m (Afa) vs 1m (Placebo)
- Subsequent cancer treatments were given to 70% in Afainib and 80% in placebo.
54
Tell me about LUX-Lung 4
Katakami et al JCO 2013
Phase II
Stage IIIB/IV
PD after 12 week or more of prior Erlotinib and/or Gefitinib
Received Afatinib 50 mg OD
N=60
Results:
80% had acquired resistance to Erlotinib and/or Gefitinib
Med PFS 4m, med OS 19m
55
Tell me about the LUX-Lung 3
Leica Sequist JCO 2013.
Aim: investigate the efficacy of chemo vs Afatinib In 1st-line setting EGFR +
N=350
2 arms:
A) Afatinib 40mg OD
B) CDDP/Pem up to 6# q21d
Results:
- n=350
- median PFS 11m vs 7m (chemo)
- med PFS (Ex 19 and L858R): 14m vs 7m
- Higher RR 60% vs 20%
- Prelim OS 17m vs 15m
56
Tell me about LUX-Lung 6
Wu et al Lancet Oncol 2014
Aim: Compare Afatinib with Gem/CDDP as 1st line for Asian EGFR M+ patients
N=360
2 arms:
A) Afatinib 40 mg OM
B) IV Gemcitabine (1000) D1, D8 + CDDP (75) D1 q3w x6#
Results:
- Med PFS 11m vs 6m (Gem)
- ORR 70% vs 20% (Gem)
- OS data immature, but OS 22m (Afa) vs 22m (Gem)
57
What did the combined OS analysis of LUX-Lung 3 and LUX-Lung 6 show?
Published Lancet Oncol 2015
LUX-LUNG-3:
- n=350
- Afatinib vs Pem/CDDP
LUX-LUNG-6:
- n=360
- Afatinib vs Gem/CDDP
RESULTS:
- LUX-LUNG3: med OS 28m vs 28m
- LUX-LUNG6: Med OS 23m vs 23m
- LUX-LUNG3 (Del19+): 33m vs 21m (Chemo)
- LUX-LUNG6 (Del19+): 31m vs 18m (Chemo)
- LUX-LUNG3 (L858R+): Trend 28m vs 40m (chemo)
- LUX-LUNG6 (L858R+): Trend 20m vs 24m (chemo)
58
Tell me about Afatinib
2nd generation irreversible TKI
| Inhibits signaling from all homodimers and heterodox ears formed by ERBB receptor family members
59
If a patient on Gefitnib PD, and chemo is initiated, any role to continue Gefitinib?
NO. IMPRESS study by Soria Lancet Oncol 2015
Aim: To assess the efficacy and safety of continuing Gefitnib + Chemo v chemo alone in EGFR+ advanced lung CA with acquired resistance to 1st line Gefitinib
N=250
Stage 3B/IV EGFR+
Previous disease control with 1st line Gefitinib and recent PD
2arms (6cycles)
1) Cisplatin (75)+Pemetrexed(500) D1 Q21days + Gefitinib 250m OM
- -> Gefitinib
2) Cisplatin (75)+ Pemetrexed (500) D1Q21days + Placebo --> Placebo
RESULTS:
PD: 70% (Gefitinib) vs 80% (Placebo) not sig.
Med PFS 5.4m~
Conclusion: Continuing Gefitinib beyond radiological PD did not prolong PFS in those who received platinum-based doublet chemo as subsequent line of treatment
60
Any evidence of combining immunotherapy with chemo in 2nd line?
Yes
REVEL study
Garson et al Lancet 2014
N=1200
Squamous and non-Sqaumous
PD during or after 1st line platinum-based chemo
2 arms:
A) Docetaxel (75) + Ramucirumab (10mg/kg)
B) Docetaxel (75) + placebo
Q21days
Aim: to asses efficacy and safety of treatment with Docetaxel+Ramucirumab vs Docetaxel+Placebo
RESULTS:
Med OS: 10.5m vs 9m
Med PFS 4.5m vs 3m
61
Any preference between TKIs?
Yes. LUX-Lung 7
Park et al, an et Oncol 2016
Aim: To compare the efficacy and safety between Afatinib and Gefitinib
Phase 2B
N=300
Stage IIIB/IV, treatment naive
Exon 19 del or L858R
2arms:
1) Afatinib 40 mg BD
2) Gefitinib 250 mg OM
```
RESULTS:
PFS 11m s 11m
TTF 14m (Afatinib) vs 11.5m
OS data not mature
6% in each group discontinued
9% fatal adverse events with Afatinib, vs 6% in Gefitinib
```
62
What is the IHC expected from squamous lung cancer?
P63
Cytokeratins 5/6
P40
63
What is the expected IHC of NSCLC?
TTF1
Napsin A
CK 7
Mucin stains
64
What are the characteristics of ALK-rearranged tumors?
3-5% of adenoCA
Young age of onset
Never or light smoking Hx
AdenoCA, esp with signet ring or acinar histology
Infrequent in squamous cell
Largely mutually exclusive with EGFR or KRAS mutations
65
What LN stations can EBUS access?
2R/2L, 4R/4L, 7, 10R/10L and other hilar LN stations
66
What LN stations can EUS access?
5, 7, 8 and 9
67
What LN stations can anterior mediastionotomy or TTNA access?
Anterior LN stations, 5 and 6
