Oncologia Polmonare – AOU S. Luigi Gonzaga, Orbassano (To) Torino, 3 Febbraio 2018 Paolo Bironzo Oncologia Polmonare – AOU S. Luigi Gonzaga, Orbassano (To) pbironzo@gmail.com

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

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

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

PACIFIC: results (interim analysis) Median Time to Distant Metastasis or Death 23.2 vs 14.6 months HR 0.52 (95% CI, 0.39-0.69; p<0.001 ) mPFS 16.8 vs 5.6 months HR 0.52 (95% CI, 0.42-0.65; p<0.001 ) Antonia SJ, NEJM 2017

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

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

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

FLAURA: results Superior PFS in patients with CNS disease mPFS 18.9 vs 10.2 months (HR 0.46, 95% CI, 0.37-0.57, p<0.001) Ramalingam SS, ESMO 2017; Soria JC, NEJM 2018

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

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

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

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

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

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

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?

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?