Treatment of advanced NSCLC: Where are we now?

Patient selection in lung cancer: Evolution over time 2000 Non-small cell lung cancer Small-cell lung cancer 2008 Adenocarcinoma Large-cell carcinoma Squamous cell carcinoma Established targets Mutation negative/unknown Today 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

Treatment goals in advanced NSCLC Quality of life Safety OS PFS Disease control Symptom improvement/control NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

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.

Overall survival in NSCLC: Evolution over time First-line treatment of advanced NSCLC 2000 Non-small cell lung cancer Median overall survival (months) Cisplatin+paclitaxel Cisplatin+gemcitabine Cisplatin+docetaxel Carboplatin+paclitaxel 7.8 8.1 7.4 10 20 30 40 100 80 60 Survival (%) Survival time (months) Schiller JH, et al. N Engl J Med 2002;346:92–8

Overall survival in NSCLC: Evolution over time First-line treatment: Importance of histology for patient selection 2008 Non-squamous cell carcinoma Squamous cell carcinoma Non-squamous* (n=1000) Squamous (n=473) 1.0 1.0 Median overall survival (months) Pemetrexed+cisplatin 11.8 Gemcitabine+cisplatin 10.4 HR 0.81 (95% CI 0.70–0.94) p=0.005 Median overall survival (months) Pemetrexed+cisplatin 9.4 Gemcitabine+cisplatin 10.8 HR 1.23 (95% CI 1.00–1.51) p=0.05 0.8 0.8 0.6 0.6 Probability of survival Probability of survival 0.4 0.4 0.2 0.2 0.0 0.0 6 18 12 24 30 6 18 12 24 30 Survival time (months) Survival time (months) * Non-squamous = adenocarcinoma and large cell carcinoma NSCLC histology. Scagliotti GV, et al. J Clin Oncol 2008;26:3543–51

Overall survival in NSCLC: Evolution over time First-line bevacizumab when added to chemotherapy 2008 Non-squamous cell carcinoma Trial Hazard ratio (95% CI) AVF-0757g 7.5 1.13 (0.52–2.42)* AVF-0757g 15 1.18 (0.54–2.59)* ECOG 4599 0.80 (0.69–0.93) AVAiL 7.5 0.92 (0.75–1.13) AVAiL 15 1.02 (0.83–1.26) JO19907 0.99 (0.65–1.50) Total 0.90 (0.81–0.99) p=0.03 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Favours bevacizumab Favours control Test for heterogeneity p=0.44 *AVF-0757g trial: direction of OS HR unknown, worst scenario chosen. CI, confidence interval; RCTs, randomised controlled trials. Results as reported in meta-analysis. Soria JC, et al. Ann Oncol 2013;24:20‒30

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

Overall survival in NSCLC: Evolution over time Targeted treatment improves PFS but not OS in selected patients Today Established targets EGFR Study (patients randomised who had EGFR mutations) TKI Analysis population PFS HR (95% CI) Overall survival IPASS1 (n=261) Gefitinib EGFRM+ (n=261) 0.48 (0.36–0.64) (INV)* 1.00 (0.76–1.33) First – SIGNAL2 (n=42) EGFRM+ (n=42) 0.54 (0.27–1.10) (INV) 1.04 (0.50–2.18) NEJ0023,4 (n=230) EGFRM+ (n=224) 0.32 (0.24–0.44) (IND)* 0.89 (0.63–1.24) WJTOG34055,6 (n=177) Common mutations (n=172) 0.49 (0.34–0.71) (INV)* 1.25 (0.88–1.78) EURTAC (EU)7 (n=173) Erlotinib Common mutations (n=173) 0.34 (0.23–0.49) (IND)* 0.93 (0.64–1.35) OPTIMAL (China)8,9 (n=165) Common mutations (n=154) 0.16 (0.10–0.26) (INV)* 1.19 (0.83–1.71) ENSURE (China)10 (n=217) Common mutations (n=217) 0.34 (0.22-0.51) (IND)* 0.91 (0.63–1.31) LUX-Lung 311,12 (n=345) Afatinib Common mutations (n=307) 0.47 (0.34–0.65) (IND)* 0.78 (0.58–1.06) LUX-Lung 612,13 (n=364) Common mutations (n=324) 0.25 (0.18–0.35) (IND)* 0.83 (0.62–1.09) *Patients with tumours harbouring common mutations. Note: data are provided as a summary of different trial findings. Data pertaining to different trials cannot be compared due to inherent differences in trial design and methodology. 1. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 2. Han JY, et al. J Clin Oncol 2012;30:1122–8; 3. Maemondo M, et al. N Engl J Med 2010;362:2380–2388; 4. Inoue A, et al. Ann Oncol 2013;24(1):54–9; 5. Mitsudomi T, et al. Lancet Oncol 2010;11:121–8; 6. Yoshioka et al. ASCO 2014. Poster 8117; 7. Khozin S, et al. Oncologist 2014;19:774–9; 8. Zhou C, et al. Lancet Oncol 2011;12:735–42; 9. Zhou et al Ann Oncol, 2015; 10. Wu et al. Ann Oncol 2015; 11. Sequist LV, et al. J Clin Oncol 2013;31:3327–34; 12. Yang JC, et al. Lancet Oncol 2015;16:141–51; 13. Wu SI, et al. Lancet Oncol 2014;15:213–22

ESMO clinical practice guidelines: Testing for EGFR mutations Recommendations Strength Evidence level EGFR mutation testing is recommended in all patients with advanced NSCLC of a non-squamous subtype A I Testing is not recommended in patients with a confident diagnosis of squamous cell carcinoma, except in never/former light smokers (<15 packs per year) IV Conducted using a validated mutation detection platform in a laboratory participating in an external quality assurance scheme – with adequate sensitivity for all clinically relevant mutations V Reck M, et al. Ann Oncol 2014;25(suppl 3):iii27–iii39

EGFR mutation testing rates in advanced NSCLC Results from an international survey* Patients not tested for EGFR mutation status Tested but results not available before treatment decision Tested and results available before treatment decision *Survey designed to assess the prevalence of mutation testing, attitudes and barriers to testing, and how results affect choice of therapy. Spicer J, et al. Annal Oncol 2015;26(suppl 1) LBA2 PR and presentation

EGFR mutation testing in advanced NSCLC: Reasons for low testing frequency Results from Europe* *Germany, France, Italy, Spain and UK. Spicer J. et al. Annal Oncol 2015;26(suppl 1) LBA2 PR and presentation

ESMO clinical practice guidelines: Testing for anaplastic lymphoma kinase (ALK) fusion genes Recommendations Strength Evidence level Testing for ALK rearrangement should be systematically carried out in advanced NSCLC with a non-squamous histology A II Detection of the ALK translocation by FISH remains the standard, but IHC may have a role in screening out negative cases Reck M, et al. Ann Oncol 2014;25(suppl 3):iii27–iii39

Oncogenic drivers for patients with full genotyping 10 genes assayed in 733 patients Kris MG, et al. JAMA 2014;311:1998–2006; Kris MG, et al. J Thorac Oncol 2013;8:S3

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

Therapies with an impact on OS approved by the EMA* Overall survival in NSCLC: Treatment of advanced NSCLC after first-line chemotherapy Therapies with an impact on OS approved by the EMA* Docetaxel: improved OS versus best supportive care1 2000 Erlotinib: improved OS versus best supportive care2 2004 Nintedanib + docetaxel: improved OS versus docetaxel in patients with adenocarcinoma histology NSCLC3 2014 Nivolumab: improved OS versus docetaxel in patients with squamous cell histology NSCLC4 2015 *Available from and http://www.ema.europa.eu. Registration conditions differ internationally. Country-specific information is contained in the locally approved registration documents. 1. Shepherd FA, et al. J Clin Oncol 2000;18:2095–103; 2. Shepherd FA, et al. N Engl J Med 2005;353:123–32; 3. Reck M, et al. Lancet Oncol 2014;15:143–55; 4. Brahmer J, et al. N Engl J Med. 2015;373(2):123–35

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 EGFR TKI or docetaxel or nivolumab Crizotinib Docetaxel + nintedanib or docetaxel 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

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