Overall survival in NSCLC Advantages and challenges as an endpoint Continuous (compared to PFS) Gold standard endpoint Clinically relevant Easily and accurately assessed Role of crossover Large patient populations required Impact of subsequent therapy Longer follow-up times than other endpoints Advantages Challenges PFS, progression-free survival. Soria J, et al. Ann Oncol 2010;21:2324–32

Treatment of advanced NSCLC Based on EMA approved indications Squamous cell carcinoma Non-squamous cell carcinoma Histological subtype ALK-rearranged NSCLC Mutation negative/unknown EGFR mutation-positive Platinum-based doublets Pemetrexed/ platinum Pemetrexed-based doublets ± bevacizumab* Cisplatin + third-generation regimen± bevacizumab* EGFR TKI* (afatinib, erlotinib or gefitinib) First-line Switch maintenance: erlotinib or docetaxel Continuation maintenance: gemcitabine Continuation maintenance: pemetrexed Continuation maintenance: pemetrexed Switch maintenance: Pemetrexed or erlotinib EGFR TKI Maintenance I think this should be on EMA approved indications, and assume best practice: For ALK+: exculde criz as first line as not EMA approved. Only pem-platinum these patients get pem maintenance. Second line they get criz and 3rd line line ceritinib FOR EGFR M+ on 2nd line delete “prior chemo box” as asuming best practice within license EGFR TKI or docetaxel or nivolumab Crizotinib Docetaxel (±nintedanib) or pemetrexed or erlotinib Platinum doublet Prior EGFR TKI After first-line Ceritinib *PS 3 or 4, best supportive care only. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Adapted from Reck M, et al. Ann Oncol 2014;25(suppl. 3):iii27–iii39 based on EMA approved indications

Nivolumab vs docetaxel: Overall survival Squamous NSCLC (CheckMate-017) Non-squamous NSCLC (CheckMate-057) 100 100 Nivolumab (n=135) Docetaxel (n=137) Median OS (months) 9.2 6.0 HR 0.59 (95% CI: 0.44–0.79): p=0.00025 Nivolumab (n=292) Docetaxel (n=290) Median OS (months) 12.2 9.4 HR 0.73 (95% CI: 0.59–0.89): p=0.0015 80 80 60 60 Overall survival (%) Overall survival (%) 40 40 20 20 3 6 12 9 18 21 15 24 3 6 12 9 18 21 15 27 24 Time (months) Time (months) Patients at risk Nivolumab 135 113 86 69 52 31 15 7 Docetaxel 137 103 68 45 30 14 2 Patients at risk Nivolumab 292 232 194 169 146 123 62 32 9 Docetaxel 290 244 150 111 88 34 10 5 CI, confidence interval; HR, hazard ratio; OS, overall survival. Brahmer J, et al. N Engl J Med. 2015;373(2):123–35; Paz-Ares, L. et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109) and presentation.

Nivolumab vs docetaxel (CheckMate-057): OS and PFS Impact of PD-L1 expression on survival in non-squamous NSCLC PD-L1 expression level Nivolumab/docetaxel (n) Interaction p value* Overall survival ≥1% 123/123 0.0646 <1% 108/101 ≥5% 95/86 0.0004 <5% 136/138 ≥10% 86/79 0.0002 <10% 145/145 Not quantifiable baseline 61/66 PFS 0.0227 <0.0001 0.25 0.5 1.0 2.0 Nivolumab Docetaxel PD-L1 not quantifiable PD-L1 non-expressors PD-L1 expressors *Interaction p value from Cox proportional hazard model with treatment, PD-LI expression and treatment by PD-L1 expression interaction. CI, confidence interval; HR, hazard ratio; OS, overall survival. Paz-Ares, L. et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109) and presentation.

Question: In your opinion, what is the most important consideration to guide treatment choice in NSCLC? Overall survival Progression-free survival Disease control Symptom improvement/control Quality-of-life Safety and tolerability A combination of the above Other

Patient selection in lung cancer: Evolution over time ~1990s Lung cancer ~2000 Non-small cell lung cancer Small-cell lung cancer 2008 Adenocarcinoma Large-cell carcinoma Squamous cell carcinoma Today Established targets Mutation negative/unknown EGFR ALK ROS1 Adenocarcinoma Large cell carcinoma Squamous cell carcinoma Adenocarcinoma and treatable oncogenic alterations Small-cell lung cancer Adapted from Reck M, et al. Lancet 2013;382:709–19

EGFR mutation testing in selected patients Question: What validated biomarkers do you routinely use for patient selection in advanced NSCLC? EGFR mutation testing in selected patients ALK testing in selected patients Both EGFR mutation testing and ALK testing in selected patients Multiplex/next generation sequencing Other

Patient selection in lung cancer in 2015: Integration of molecular profiling Tumour tissue Traditional pathology Biomarker testing (PCR-based tests, IHC, FISH, etc.) Multiplex/next generation sequencing Tumour morphology Tumour biomarkers Tumour genotype Treatment selection FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; PCR, polymerase chain reaction. Adapted from Pao W, et al. Clin Cancer Res 2009;15:5317–22

Use of multiplexed testing in lung cancer: Improved OS in patients receiving matched targeted agents Kris M, et al. JAMA 2014;311(19):1998–2006

Personalised medicine studies Molecular Analysis for Therapy Choice Study (NCI-MATCH) Adults with solid tumours/lymphomas and disease progression ≥1 systemic therapy Tumour accessible to biopsy Performance status ECOG 0-1 Adequate organ function Actionable mutation detected by genetic sequencing Patient assigned study agent (patients with PD checked for additional actionable mutations) ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study Advanced solid tumour, multiple myeloma, or B cell non-Hodgkin lymphoma Targetable genomic variation No longer responding to standard treatment Molecular Tumour Board agrees treatment Patient assigned study drug based on profile EORTC Screening Patients for Efficient Clinical Trial Access (SPECTA)-Lung Any lung cancer, malignancy, malignant pleural mesothelioma or thymic malignancy Availability of tumour tissue Any line of therapy Molecular tumour profile established from next-generation sequencing Patient assigned targeted treatment based on molecular profile http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match (Accessed: Sept 2015); http://www.asco.org/practice- research/targeted-agent-and-profiling-utilization-registry-study (Accessed: Sept 2015); https://clinicaltrials.gov/ct2/show/NCT02214134 (Accessed: Sept 2015)

Frequency of actionable mutations in NCI-MATCH Bold text indicates mutations frequently found in NSCLC. http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match; Lovly CL, Horn W, Pao. Molecular Profiling of Lung Cancer (2015). http://www.mycancergenome.org/content/disease/lung-cancer/(Accessed: Sept 2015)

Question: In your opinion, what is the biggest barrier to widespread use of next generation sequencing? Availability of tumour tissue Timeliness of results (takes too long) Access to technology/testing Cost Ethical concerns Other

Questions and discussion