1. Oncologia Polmonare – AOU S. Luigi Gonzaga, Orbassano (To)
Torino, 3 Febbraio 2018
Paolo Bironzo
Oncologia Polmonare – AOU S. Luigi Gonzaga, Orbassano (To)

2. Where are we now? Locally-advanced unresectable NSCLC
Chemo-radiotherapy
EGFR-mutated advanced NSCLC
1st or 2nd generation EGFR TKI
ALK-rearranged advanced NSCLC
Crizotinib
Monochemotherapy (vinorelbine, gemcitabine, pemetrexed rechallenge)
Pretreated Malignant Mesothelioma

3. Locally-advanced unresectable NSCLC
Where are we now?
Locally-advanced unresectable NSCLC
Chemo-radiotherapy

4. PACIFIC: a randomized, double blind, international phase III trial
Median age: 64 yrs; 70% men; 91% current/former smokers; 53% stage IIIA; 45% squamous; 92% RT dosage ≥54 and ≤66 Gy; 27% induction CT.
Antonia SJ, NEJM 2017

5. PACIFIC: results (interim analysis)
Median Time to Distant Metastasis or Death 23.2 vs 14.6 months
HR 0.52 (95% CI, ; p<0.001 )
mPFS 16.8 vs 5.6 months
HR 0.52 (95% CI, ; p<0.001 )
Antonia SJ, NEJM 2017

6. PACIFIC: safety and QoL
AEs leading to discontinuation:
-pneumonitis /radiation pneumonitis 6.3% vs 4.3%
Pneumonia 1.1% vs 1.3%
Incidence of pneumonitis/radiation pneumonitis: 33.9% vs 24.8%
Global health status/QoL (C30) 15 -5
-10
-15
Change from baseline 4
(n=649)
Week 8
(n=591) 16
(n=506) 24
(n=443) 32
(n=393) 40
(n=356) 48
(n=311) 10 5
(n=647)
(n=593)
(n=507)
(n=444)
(n=355)
(n=310)
Physical functioning (C30)
Durvalumab
Placebo
Antonia SJ, NEJM 2017; Hui R, WCLC 2017

7. EGFR-mutated advanced NSCLC 1st or 2nd generation EGFR TKI
Where are we now?
EGFR-mutated advanced NSCLC
1st or 2nd generation EGFR TKI
Lee CK, J Natl Cancer Inst 2017

8. FLAURA: first-line osimertinib vs 1st gen TKIs in EGFR+ advanced NSCLC
Median age 64 years; 64% women and 62% Asian; 65% never smokers; CNS mts 19% vs 23%; del19 63% and L858R 37%; control arm: 66% gefitinib vs 34% erlotinib.
Ramalingam SS, ESMO 2017; Soria JC, NEJM 2018

9. FLAURA: results Superior PFS in patients with CNS disease
mPFS 18.9 vs 10.2 months (HR 0.46, 95% CI, , p<0.001)
Ramalingam SS, ESMO 2017; Soria JC, NEJM 2018

10. ALK-rearranged advanced NSCLC
Where are we now?
ALK-rearranged advanced NSCLC
Crizotinib
Solomon BJ, NEJM 2014

11. ALEX: first-line alectinib vs crizotinib in ALK+ advanced NSCLC
Median age 58 (A) vs 54 (C) years; women 55% vs 58%; 61% vs 65% never smokers; CNS mts 42% vs 38%; no previous brain RT 83% vs 86%.
Peters S, NEJM 2017

12. ALEX: results Tolerability: - G3-4 AEs 41%(A) vs 50% (C)
12 months events-free survival rate 68.4% vs 48.7%
mPFS NR vs11.1 months
Tolerability:
- G3-4 AEs 41%(A) vs 50% (C)
- GI toxicity higher with crizotinib
Gadgeel SM, ESMO 2017; Peters S, NEJM 2017

13. Where are we now?
Monochemotherapy (vinorelbine, gemcitabine, pemetrexed rechallenge)
Pretreated Malignant Mesothelioma
Ceresoli GL, Cancer Treat Rev 2015

14. MPM: MAPS-2 trial (2nd/3rd line)
Histological diagnosis of Malignant Pleural Mesothelioma
Unresectable cancer with documented progression after maximum 1 or 2 previous lines of chemotherapy including a pemetrexed/platinum doublet
Measurable disease (mRECIST)
ECOG PS 0-1
Weight loss <10%
Age : > 18 years
Life expectancy > 12 weeks
Available tumor tissue (at least 4 slides)
Anti-PD-1 Nivolumab
3 mg/kg IV / 2 weeks
+ Anti-CTLA4 Ipilimumab
1mg/kg IV / 6 weeks
until progression or unacceptable toxicity (or 2 years max)
57 patients
 Primary Endpoint = Disease control rate (DCR) at 12 weeks in the first 2x 54 accrued eligible patients in each arm separately: 57 pts to be included assuming 5% ineligibility
Randomized, non-comparative phase 2 trial - One-step Fleming design (each arm independently)
CT-scan reassessment at Week 12…
R 1:1
until progression or unacceptable toxicity (or 2 years max)
Zalcman G, ESMO 2017

15. MAPS-2 trial early results
G5 AEs: 1 fulminant hepatitis, 1 encephalitis, 1 acute kidney failure
Analysis by PD-L1 expression levels
Zalcman G, ESMO 2017

16. Where are we going? Locally-advanced unresectable NSCLC
Chemo-radiotherapy  IOs?
EGFR-mutated advanced NSCLC
First-line 3rd generation EGFR TKIs?
ALK-rearranged advanced NSCLC
First-line Alectinib (or other new generation agent)?
Pre-treated Malignant Mesothelioma
Any room for Immune Checkpoint Inhibitors?

17. Open issues Locally-advanced unresectable NSCLC
Chemo -radiotherapy  IOs
Waiting for OS results…
EGFR-mutated advanced NSCLC
3rd generation TKIs
Is early always better?
ALK-rearranged advanced NSCLC
Alectinib (or other new generation agent)?
Pretreated Malignant Mesothelioma
Interesting DCR
Checkpoint inhibitors?