Giorgio V. Scagliotti University of Torino Dipartment of Oncology [email protected]
EGFR, ALK, ROS1, (NGS)
NS-NSCLC SQ-NSCLC*
Molecular tests positive
Appropriate targeted agent until
progression
NS & SQ NSCLC PDL-1 + > 50%
NS-NSCLC PDL-1 + < 50%
SQ NSCLC PDL- 1 + < 50%
Cis/carbo/pem for 4-6 cycles (± Bevacizumab)
Pemetrexed maintenance until progression
Pembrolizumab until
progression**
*Consider molecular tests if SQ-NSCLC is diagnosed in a never smoker or < 40 years
** according to the eligibility criteria of KEYNOTE 024
Cis/carbo doublets for 4-6
cycles or
Necitumumab plus Cis/gem
Progression of the disease TTF-1, p63 (p40), PDL-1
Diagnostic box
Advanced NSCLC , PS 0-1, cytology or histology
≈ 20%
≈ 15-20%
≈ 25%
≈ 40%
EGFR, ALK, ROS1, (NGS) NS-NSCLC
Molecular tests positive
Appropriate targeted agent until
progression
*Consider molecular tests if SQ-NSCLC is diagnosed in a never smoker or < 40 years
** according to the eligibility criteria of KEYNOTE 024
Progression of the disease TTF-1, p63 (p40), PDL-1
Diagnostic box
Advanced NSCLC , PS 0-1, cytology or histology
≈ 20%
EGFR Inhibitors :
First & second generation Third generation?
ALK inhibitors : Crizotinib
Alectinib? Ceritinib?
ROS1 inhibitors : Crizotinib
Clinical trials
B-raf inhibitors (clinical trials) Ex14 MET (clinical trials)
HER-2 (clinical trials)
RET inhibitors (clinical trials)
EGFR, ALK, ROS1, (NGS)
NS-NSCLC SQ-NSCLC*
NS-NSCLC SQ NSCLC
Cis/carbo/pem for 4-6 cycles (± Bevacizumab)
Pemetrexed maintenance until progression
*Consider molecular tests if SQ-NSCLC is diagnosed in a never smoker or < 40 years
** according to the eligibility criteria of KEYNOTE 024
Cis/carbo doublets for 4-6
cycles or
Necitumumab plus Cis/gem
Progression of the disease TTF-1, p63 (p40)
Diagnostic box
Advanced NSCLC , PS 0-1, cytology or histology
≈ 30%
≈ 50%
EGFR, ALK, ROS1, (NGS)
NS-NSCLC SQ-NSCLC*
NS-NSCLC PDL-1 + < 50%
SQ NSCLC PDL- 1 + < 50%
Cis/carbo/pem for 4-6 cycles (± Bevacizumab)
Pemetrexed maintenance until progression
*Consider molecular tests if SQ-NSCLC is diagnosed in a never smoker or < 40 years
** according to the eligibility criteria of KEYNOTE 024
Cis/carbo doublets for 4-6
cycles or
Necitumumab plus Cis/gem
Progression of the disease TTF-1, p63 (p40), PDL-1
Diagnostic box
Advanced NSCLC , PS 0-1, cytology or histology
≈ 25%
≈ 40%
Front line strategies according to histology
Maintenance approaches
Second line treatments
Future treatment opportunities
Finta didascalia
Rossi G. et al. Int.J. Surg. Pathol. 2013; 21:326
Patients who get benefit from molecular diagnosis
Scagliotti GV et al. J. Clin. Oncol 2008; 26:3543
p<0.0001
Adenocarcinoma Squamous
P<0.001
Relative expre. levels
Relative expre. levels
P<0.001
Ceppi P. et al. Cancer 2006
Sandler A. et al. J. Thor.Oncol.2010; 5:1416
Invasive
Tissue biopsy
Interstitial fluid pressure measurement
Measurement of tissue oxygenation
Skin wound healing
Minimally Invasive
Circulating endothelial cells
Circulating progenitor cells
Protein levels in plasma
VEGF polymorphisms
Non-Invasive
Imaging
CT imaging
PET imaging 15O FDG
MRI
Clinical
HTN
Gender
Urine protein (MMP, VEGF)
Jain RK. Nat Clin Practice 2006;3:24–40; Davis DW. Br J Cancer 2003;89:8–14
D ecreasing incidence, mirrors transition (in demographic and geographic populations) from unfiltered to filtered cigarettes, with 2-3 decade lag time
Arises from proximal airways, gives rise to more central cancers, more co- morbidities
Higher mutational burden
Therapy
Cis/carbo doublets x 4-6 courses
No role for maintenance
Ipilimumab plus carbo/paclitaxel some activity
Nab-paclitaxel superior ORR compared to carbo/paclitaxel
Necitumumab in combination with cis/gem improved survival over cis/gem
Garon, ESMO 2014; Reviewed in Hirsch, JTO 2008 Socinski MA et al. J Clin Oncol. 2012
;30:2055-62; Thatcher N. et al. Lancet Oncol. 2015; 16:763-774
41%
37%
26%
37%
24%
29%
25%
30%
0%
10%
20%
30%
40%
50%
Independent Radiologic
Review
Investigator Assessment
Independent Radiologic
Review
Investigator Assessment
nab-P/C P/C
% R esponses
Squamous Non-squamous
P < 0.001 P = 0.060 P = 0.808 P = 0.069
n = 228 n = 221 n = 292 n = 310
* Not a pre-specified endpoint
Socinski MA et al. J Clin Oncol. 2012 ;30:2055-62
Socinski MA et al. J Clin Oncol. 2012 ;30:2055-62
Thatcher N. et al. Lancet Oncol. 2015; 16:763-774
FLEX:
Platinum Doublet +/- Cetuximab
SQUIRE:
Platinum Doublet +/- Necitumumab
Pirker, Lancet 2009; Thatcher, Lancet Oncol 2015
• Extremely similar agent; extremely similar results
• Should there be a distinction between statistical and clinical significance?
• Front line strategies according to histology
• Maintenance approaches
• Second line treatments
• Future treatment opportunities
Goal
– To extend progression-free and overall survival of patients with advanced NSCLC already treated with induction chemotherapy
– To extend symptom-free survival of advanced NSCLC patients
Therapeutic Action
– Continuous administration of single agents/combos of cytotoxic agents and/or targeted agents
Which target population?
– Those with CR, PR or SD following induction and
minimal cumulative toxicity
Continuation Maintenance Switch Maintenance
Total
HR 0.54 (0.46-0.63) p<.00001
Total
HR 0.61 (0.51-0.74) p<.00001
Total
HR 0.65 (0.59-0.72) p<.00001
Cai H, et al. Clin Lung Cancer 14:333-41, 2013
Cai H, et al. Clin Lung Cancer 14:333-41, 2013 Total
HR 0.82 (0.66-1.01) p=.06
Total
HR 0.80 (0.63-1.01) p=.06
Total
HR 0.81 (0.71-0.92) p=.001
Total
HR 0.80 (0.72-0.92) p=.0002
7 trials report no detrimental effect on QOL
Continuation Maintenance Switch Maintenance
Previously untreated stage IIIB–IV
nsNSCLC
Arm A:
bevacizumab
Arm B:
bevacizumab + pemetrexed Bevacizumab
+ pemetrexed + cisplatinb
CR/PR/SD per RECISTc
First-line induction 4 cycles, q3w
R
PD
Continuation maintenance q3w until PD
Follow-up N=376
N=253 67%
N= 125
N=128
Stratification factors:
Gender
Smoking status
Response at randomization
Primary objective: progression-free survival
Secondary objectives: Overall survival, response rate, disease control rate, duration of response, duration disease control, safety, QOL
Barlesi F, et al. J Clin Oncol 30 July 8, 2013 [epub ahead of print]
Barlesi F, et al. J Clin Oncol 30 July 8, 2013 [epub ahead of print]
Induction Phase 4 cycles, q21d
Maintenance Phase q21d until PD
Pemetrexed +
(folic acid & vitamin B12 )
Carboplatin + Bevacizumab
Paclitaxel + Carboplatin +
Bevacizumab Stratified for:
PS (0 vs. 1) ; sex (M vs. F); disease stage (IIIB vs. IV); measurable vs. non-measurable disease
Pemetrexed +
(folic acid & vitamin B12 )
Bevacizumab
Bevacizumab
450 patients each
R
1:1 Inclusion:
- No prior systemic therapy for lung cancer
- ECOG PS 0/1
- Stage IIIB-IV NS-NSCLC - Stable treated brain mets
allowed
Exclusion:
- Peripheral neuropathy
≥Grade 1
- Uncontrolled pleural effusions
Patel J. et al. J. Clin. Oncol. 2013; 31. 4349-4357
Patel J. et al. J. Clin. Oncol. 2013; 31. 4349-4357
1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.4.2016 2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39
Progression during or after platinum therapy
Chemotherapy Antiangiogenics Immune checkpoint
inhibitors
Nintedanib (+ docetaxel)
Docetaxel Pemetrexed Ramucirumab
(+ docetaxel) Nivolumab
Not suitable for squamous NSCLC
Only approved for adenocarcinoma If not given
previously
If docetaxel not given previously EGFR TKI
Erlotinib
May be inferior to chemotherapy in WT patients
Pembro- lizumab
Only approved for patients whose tumors express PD-L1
aApproved in EU only; bApproved in US only
Afatinib
Only approved for squamous NSCLC
Atezolizumab
Health Prevents cancer
development
DNA repair
Disease/Cancer
Interferes with anti-cancer
therapy
Anti-cancer therapy
DNA repair
Identifying BRCAness through genetic testing, functional assays or array-based procedures can potentially widen the therapeutic span of PARP-targeted strategies
De S., Ganesan S. Ann. Oncol. 2016; ahead of print
