1. Il Paziente senza target
Grande Lung Slam
Roma, 9 Ottobre 2015
Il Paziente senza target
Francesco Grossi
U.O.S. Tumori Polmonari
IRCCS Azienda Ospedaliera Universitaria San Martino IST
Istituto Nazionale per la Ricerca sul Cancro
Genova

2. Interlinking factors to guide personalized therapy in caucasian NSCLC patients
80% of patients
Clinical Factors
Histologic Factors
Molecular Factors
20% of patients

3. ASCO practice guideline update (1/2)
Masters GA, JCO 2015

4. ASCO practice guideline update (2/2)
Masters GA, JCO 2015

5. Old algorithm for the therapy of advanced NSCLC
Proposed treatment algorithm
EGFR mutation positive or ALK fusion positive
Molecular
Good PS
Clinical (PS)
Poor PS
EGFR TKIs or Crizotinib
Nonsquamous
Histologic
Squamous
Single-agent chemotherapy
Bevacizumab eligible
First line
Clinical
Bevacizumab ineligible
Platinum/pemetrexed (or other*) ± bevacizumab
Platinum/pemetrexed (or other*)
Platinum/gemcitabine (or other*)
End of first-line chemotherapy
Maintenance
Bevacizumab or erlotinib or pemetrexed
Pemetrexed or erlotinib
Erlotinib
Based on prior therapy
Progression
Second line
Chemotherapy by algorithm
Based on prior therapy
Based on prior therapy
Based on prior therapy
*Docetaxel, paclitaxel, or vinorelbine.
Adapted from Gandara DR, Clin Lung Cancer 2009

6. Biomarker-unselected non-squamous NSCLC in the real life
Present/Future algorithms:
Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)
Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

7. Biomarker-unselected squamous NSCLC in the real life
Present/Future algorithm:
Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

8. Biomarker-unselected non-squamous NSCLC in the real life
Present/Future algorithms:
Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)
Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

9. JMDB: OS in non-squamous & squamous patients
Scagliotti G, JCO 2008

10. Continuation maintenance:
Continuation (PARAMOUNT) or switch (JMEN) maintenance with pemetrexed: OS
Continuation maintenance:
PARAMOUNT
Switch maintenance:
JMEN
13.9 mos vs 11.0 mos (+2.9mos)
16.9 mos vs 14 mos (+2.9mos)
13.4 mos vs 10.6 mos (+2.8mos)
16.5 mos vs 13.9 mos (+2.6mos)

11. Association between TS and efficacy of pemetrexed: PFS & OS
Wang T, PLOS ONE 2013

12. A better clinical outcome with pemetrexed/cisplatin in low TS only
Sun JM, J Clin Oncol 2015

13. E4599: Bevacizumab-based therapy until progression increases OS
Sandler A, JTO 2010 &
NEJM 2006

14. Efficacy of first-line regimens: pre-planned OS & PFS analyses in adenocarcinoma patients
1. Scagliotti G, Oncologist Sandler A, JTO 2010

15. PRONOUNCE: Study Design
Randomized, open-label, phase III superiority study conducted in US
Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb)
Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev)
Induction Phase q21d, 4 cycles
Maintenance Phase
q21d until PD
Bev-Eligible Population
Inclusion:
- Chemo-naïve patients
- PS 0/1
- Stage IV, nonsquam
- Stable treated CNS mets
Exclusion:
- Uncontrolled effusions
Pemetrexed
(folic acid & vitamin B12)
+ Carboplatin
Pemetrexed
(folic acid & vitamin B12)
R 1:1
180 patients each
Paclitaxel
+ Carboplatin
+ Bevacizumab
Bevacizumab
Stratified for:
PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b)
Zinner RG, JTO 2015 15

16. PRONOUNCE
Zinner RG, JTO 2015

17. PointBreak: study design
Randomized, open-label, phase III superiority study conducted in US
Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
Induction Phase q21d, 4 cycles
Maintenance Phase
q21d until PD
Inclusion:
- No prior systemic therapy for lung cancer
- PS 0/1
- Stage IIIB-IV NS-NSCLC
- Stable tx’t brain mets
Exclusion:
Peripheral neuropathy
> Gr 1
- Uncontrolled pleural effusions
Pemetrexed
(folic acid & vitamin B12 )
+ Carboplatin
+ Bevacizumab
Pemetrexed
(folic acid & vitamin B12 ) + Bevacizumab
R 1:1
450 patients each
Paclitaxel
+ Carboplatin
+ Bevacizumab
Bevacizumab
Stratified for:
PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease
Patel JD, JCO 2013 17

18. PointBreak: PFS and OS from randomization (ITT)
Patel JD, JCO 2013

19. Primary endpoint Overall Survival
ECOG 5508: Schema
Bevacizumab
IIIB/IV NSCLC
PS0/1
No Prior Tx
N=1495 R A N D M I Z E
Carboplatin
Paclitaxel
Bevacizumab
X 4 cycles CR PR SD
N=897
Pemetrexed
Bevacizumab
Pemetrexed
Stratification Factors:
Smoking status, Gender
Histology, Best response, Stage
Primary endpoint Overall Survival
Status: Accrual completed April 2015

20. AvaALL: bevacizumab continued beyond progression in NSCLC
Primary endpoint: OS
Stage IIIB/IV
non-squamous NSCLC
treated with platinum-
doublet (4–6 cycles)
+ bevacizumab PLUS
> 2 cycles of
bevacizumab
maintenance
SOC2* + bevacizumab
SOC3‡ + bevacizumab
SOC4 ± bevacizumab
Randomise 1:1
PD1
PD2
PD3
SOC2*
SOC3‡
SOC4
Enroll
n=600
Graphical elaboration from text data
Primary endpoint: OS
Secondary endpoints include PFS, safety, QoL and biomarker analysis
*SOC2: labelled agents for second-line treatment of NSCLC
‡SOC3 and beyond: choice of labelled agents is the investigator’s choice
Gridelli C, Clin Lung Cancer 2011

21. Trials with PD-1 Inhibitors Added to E4599 Backbone
Arm 1 - Control
Carbo/Paclitaxel + Bevacizumab
Untreated Non-squamous
Stage IV NSCLC
Arm 2
Carbo/Paclitaxel + Bevacizumab
+ PD-1 Inhibitor
Atezolizumab: carbo/paclitaxel +/- bevacizumab +/- atezolizumab N=1200, PFS primary endpoint
Identifier: NCT
Pembrolizumab: Keynote-021- phase I-II, PFS, N=308, One arm is Pembro/carbo/paclitaxel/ bevacizumab
Identifier: NCT
Additional trial looks at bevacizumab maintenance with nivolumab (Identifier:NCT )

22. Second-line strategies in EGFR w/t or ALK- patients
Old second-line
Docetaxel
Pemetrexed
Erlotinib
New second-line
Nivolumab
Docetaxel+nintedanib

23. Biomarker-unselected non-squamous NSCLC in the real life
Present/Future algorithms:
Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)
Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

24. Docetaxel vs Docetaxel+Nintedanib (LUME Lung 1): PFS and OS
Adenocarcinoma & time since start of first-line therapy of less than 9 months
Total population
Adenocarcinoma
Adenocarcinoma
Total population
Squamous-cell
Reck M,
Lancet Oncol 2014

25. Docetaxel vs Docetaxel+Nintedanib (LUME Lung 1): toxicities
Reck M,
Lancet Oncol 2014

26. BeTa: Erlotinib ± Bevacizumab in the second-line setting
Erlotinib 150mg/day + Bevacizumab 15mg/kg every 3 weeks PD
Previously treated advanced non-squamous NSCLC
Erlotinib 150mg/day orally + placebo PD
Arm N
RR (%)
Median PFS (mos)
Median OS (mos)
Erlotinib
6.2
1.7
9.2
Beva+Erlot
12.6
3.4
9.3 HR
0.62
0.97
P-value
0.006
<0.0001
0.75
Herbst RS, Lancet 2011

27. Adenocarcinoma: second-line treatment options

28. CheckMate 057 (NCT01673867) Study Design
Randomize 1:1
Stage IIIB/IV non-SQ NSCLC
Pre-treatment (archival or recent) tumor samples required for PD-L1
ECOG PS 0–1
Failed 1 prior platinum doublet
Prior maintenance therapy alloweda
Prior TKI therapy allowed for known ALK translocation or EGFR mutation
N = 582
Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity
n = 292
Docetaxel
75 mg/m2 IV Q3W until PD or unacceptable toxicity
n = 290
Primary Endpoint OS
Additional Endpoints
ORRb
PFSb
Safety
Efficacy by tumor PD-L1 expression
Quality of life (LCSS)
Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line)
PD-L1 expression measured using the Dako/BMS automated IHC assay14,15
Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness
a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.
Paz-Ares L , ASCO 2015

29. CheckMate 057: OS update
Horn L , ECCO/ESMO 2015

30. Biomarker-unselected squamous NSCLC in the real life
Present/Future algorithm: Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

31. Squire: study design
Thatcher N, ASCO 2014

32. Squire: primary outcome OS
Thatcher N, Lancet Oncol2015

33. Nab-Paclitaxel vs paclitaxel: study design and objectives
Stage IIIb/IV NSCLC
No prior therapy for metastatic disease
ECOG PS 0-1
N = 1052
sb-Paclitaxel 200 mg/m2 d1
(3-h infusion)
Carboplatin AUC 6 d1
21-day cycles
with premedication of
dexamethasone + antihistamines
nab®-Paclitaxel 100 mg/m2 d1, 8, 15
(30-min infusion)
No premedication
Stratification factors: Stage (IIIb vs IV); age; (< 70 vs ≥ 70); sex; histology (adenocarcinoma vs squamous cell vs other); geographic region
Objective: To compare the efficacy and safety of nab-paclitaxel plus carboplatin vs sb-paclitaxel plus carboplatin in advanced NSCLC
Primary endpoint: ORR by independent radiological review (CR + PR)
Secondary endpoints: PFS, OS, DCR (CR + PR + SD), and safety
Socinski MA, JCO 2012

34. Nab-Paclitaxel vs paclitaxel: PFS and OS
Socinski MA, JCO 2012
Socinski MA et al. J Clin Oncol April 30. [Epub ahead of print].

35. Biomarker-unselected squamous NSCLC in the real life
Present/Future algorithm: Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

36. CheckMate 017 (NCT01642004) - Study Design
Nivolumab 3 mg/kg IV Q2W
until PD or unacceptable toxicity
n = 135
Docetaxel
75 mg/m2 IV Q3W until PD or unacceptable toxicity
n = 137
Randomize 1:1
Primary Endpoint: OS
Additional Endpoints:
Investigator-assessed ORR
Investigator-assessed PFS
Correlation between PD-L1 expression and efficacy
Safety
Quality of life (LCSS)
Stage IIIb/IV SQ NSCLC
1 prior platinum doublet- based chemotherapy
ECOG PS 0–1
Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis
N = 272
Patients stratified by region
and prior paclitaxel use
One pre-planned interim analysis for OS
At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis)
The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
Spigel DR , ASCO 2015

37. CheckMate 017: OS update
Reck M , ECCO/ESMO 2015

38. Docetaxel vs Docetaxel + Ramucirumab (Revel trial): OS and PFS
Garon EB, Lancet Oncology 2014

39. Docetaxel vs Docetaxel + Ramucirumab (Revel trial): toxicities
Garon E, Lancet 2014

40. NSCLC: “old” schedules and OS
Pemetrexed/Bevacizumab/Histology 8
Reck M, Lancet 2013

41. Grazie per l’attenzione!