1. REVISIÓN ESTADIOS IV SEGUNDA LÍNEA “WILD TYPE” Sergio Vázquez Estévez Servicio Oncoloxía Médica Hospital Universitario Lucus Augusti. Lugo Baiona, 25 Abril 2015

2. MOLECULAR BASIS

3. Wild-type EGFR plays an important role in tumour cell survival and proliferation PI3K-AKT pathwayMAPK pathway EGFR WT EGFR Mut+ PPPP Yarden, et al. Mol Cell Biol 2001 Promotes cell survival Promotes cell proliferation

4. Activation of EGFR/HER1 EGFR Wild Type PPPP EGFR Mut+ Ligand-dependent activationLigand-independent activation ATP Jorissen, et al. Exp Cell Res 2003; Wang, et al. Nat Struct Mol Biol 2011

5. Inhibition of EGFR WT and EGFR Mut+ signalling by Erlotinib Wild-type EGFR EGFR Mut+ Erlotinib prevents ATP binding and blocks intracellular signalling X X X X Jorissen, et al. Exp Cell Res 2003; Wang, et al. Nat Struct Mol Biol 2011; Moyer, et al. Cancer Res 1997; Carey, et al. Cancer Res 2006 ATP ERLOTINIB

6. Inhibition of EGFR WT and EGFR Mut+ signalling by Erlotinib Datos de PK del estudio BR.21 y del estudio de unión a proteínas plasmáticas OSI-774-TILL-01; Valores IC 50 de la inhibición celular de la actividad quinasa. Carey K, et al. Cancer Res 2006;66:8163–71 285684112140168 1,000 100 10 0 Time (days) Free Erlotinib concentration (ng/mL) IC 50 EGFR wild-type IC 50 EGFR mut

7. CLINICAL RESULTS

8. BR.21 Shepherd, et al. N Engl J Med 2005

9. BR.21: Patient characteristics Characteristic Tarceva (n=488) Placebo (n=243) Median age (years)6259 Female (%)3534 PS 0, 1 (%)13, 5214, 54 PS 2, 3 (%)26, 923, 9 Adenocarcinoma (%)5049 Prior regimens 1, 2, 3 (%) Prior platinum (%) 50, 49, 1 93 50, 49, 1 92 Response to prior chemotherapy (%) CR/PR SD PD 40 39 21 40 39 21 Measurable disease (%)8887

10. *HR and p (log-rank test) adjusted for stratification factors at randomisation and HER1/EGFR status BR.21: Overall Survival 42.5% improvement in median survival Survival distribution function Survival time (months) HR=0.73, p<0.001* 1.00 0.75 0.50 0.25 0 051015202530 Tarceva Placebo Shepherd F, et al. N Engl J Med 2005;353:123-32

11. BR.21: Progression-free survival HR=0.61, p<0.001* 25% 10% Survival distribution function Survival time (months) 1.00 0.75 0.50 0.25 0 051015202530 Tarceva Placebo Shepherd F, et al. N Engl J Med 2005;353:123-32 *HR and p (log-rank test) adjusted for stratification factors at randomisation and HER1/EGFR status

12. BR.21: OS benefits with Tarceva vs placebo across patient subgroups in BR.21 Subgroup analyses of OS in the BR.21 study showed that the survival benefit with Tarceva versus placebo was evident in almost all patient subgroups. Active second-line treatment with Tarceva should therefore be considered for patients regardless of their clinical or patient characteristics Shepherd, et al. N Engl J Med 2005

13. Kaplan-Meier Survival Curves BR21 Role KRAS and EFGR in BR21. J Clin Oncol 26:4268-4275.

14. SATURN: Tarceva versus placebo as 1 st line maintenance in NSCLC following chemotherapy Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region 1:1 Chemonaïve advanced NSCLC n=1,949 Non-PD n=889 4 cycles of 1st-line platinum-based doublet* Placebo PD Erlotinib 150mg/day PD Mandatory tumour sampling *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel EGFR = epidermal growth factor receptor; IHC = immunohistochemistry Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: Overall survival (OS) in all patients and those with EGFR IHC+ tumours; OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) Cappuzzo, et al. Lancet Oncol 2010

15. PFS probability 1.0 0.8 0.6 0.4 0.2 0 081624324048566472808896 Time (weeks) Log-rank p<0.0001 HR=0.68 (0.56–0.83) Erlotinib (n=252) Placebo (n=235) 11.1 12.4 Log-rank p=0.0059 HR=0.74 (0.60–0.92) Erlotinib (n=184) Placebo (n=210) 11.3 12.1 1.0 0.8 0.6 0.4 0.2 0 081624324048566472808896 Time (weeks) SATURN: PFS according to response to first-line chemotherapy (ITT population) SDCR/PR Measured from time of randomisation into the maintenance phase Coudert, et al. Ann Oncol 2012

16. SATURN: OS benefits with Tarceva vs placebo across SD patient subgroups The OS benefits seen across clinical and patient characteristics with Tarceva versus placebo in BR.21 were also seen across subgroups in patients who had SD after first-line chemotherapy in the SATURN study OS in SATURN according to clinical subgroups of patients with SD following first-line chemotherapy Coudert, et al. Ann Oncol 2012

17. SATURN: OS in EGFR wild-type group with SD on first-line chemotherapy OS probability 1.0 0.8 0.6 0.4 0.2 0 Time (months) 0369121518212427303336 8.712.4 Erlotinib (n=114) Placebo (n=103) HR=0.65 (0.48–0.87) Log-rank p=0.0041 Measured from time of randomisation into the maintenance phase Coudert, et al. Ann Oncol 2012 +3,7months

18. Meta-analysis Erlotinib vs placebo in EGFR WT NSCLC PFS/TTF* Osarogiagbon, et al. ASCO 2013; Zhang, et al. Lancet Oncol 2012 OS BR.21 SATURN BR.21 + SATURN meta-analysis BR.21 SATURN BR.21 + SATURN meta-analysis 0.20.40.60.81.01.52.0 HR Favours EGFR TKIFavours placebo HR Favours EGFR TKIFavours placebo

19. Efficacy BR.21 and TRUST Real practice confirms efficacy of BR.21: 1. Shepherd, et al. N Engl J Med 2005; 2. Heigener, et al. Lung Cancer 2011; 3. Reck, et al. J Thorac Oncol 2010

20. TITAN was an international, phase III study of second-line Tarceva versus chemotherapy (docetaxel or pemetrexed) in patients with advanced NSCLC. There were no significant differences in PFS or OS between the two treatment arms TITAN: 2L Tarceva vs chemotherapy in patients with advanced NSCLC TITAN: PFS and OS in patients with EGFR WT disease Favours ErlotinibFavours chemotherapy* HR OS PFS 0.10.251.010.00.52.04.0 n HR (95% CI) 149 1.25 (0.88–1.78) 0.85 (0.59–1.22) Patients with EGFR WT disease *Pemetrexed or docetaxel at the investigators’ discretion Ciuleanu, et al. Lancet Oncol 2012

21. TITAN: OS in EGFR WT population OS estimate 03691215182124273033363942454851 Erlotinib (n=75) Chemotherapy (n=74) HR=0.85 (0.59–1.22) 4.46.6 1.0 0.8 0.6 0.4 0.2 0 Time (months) Ciuleanu, et al. Lancet Oncol 2012

22. The phase III HORG study assessed second-/third-line Tarceva versus pemetrexed in patients with advanced NSCLC. There were no significant differences in TTP or OS between the two treatment arms HORG: 2/3L Erlotinib vs Pemetrexed in patients with advanced NSCLC HORG: TTP and OS in patients with EGFR WT disease Favours TarcevaFavours pemetrexed HR OS TTP 0.10.251.010.00.52.04.0 n HR (95% CI) 55 0.92 (0.61–1.38) 1.19 (0.77–1.84) Patients with EGFR WT disease Karampeazis, et al. Cancer 2013

23. PFS Erlotinib vs Chemotherapy in EGFR WT disease 1.9 2.7 2.1 2.3 Zugazagoitia, et al. 1 Chemotherapy: pemetrexed Median PFS (months) 1. Zugazagoitia, et al. Oncology 2013; 2. Fiala, et al. Neoplasma 2013 p=0.683 p=0.879 n=150n=129 Fiala, et al. 2 Chemotherapy: pemetrexed, docetaxel or other n=19n=21 Erlotinib Chemotherapy

24. Meta-analysis of Erlotinib in NSCLC EGFR wild-type OVERALL SURVIVAL Erlotinib EGFRwt HR: 0,78 (0,65-0,93) p= 0,006 Jazieh et al. Annals of Thorac Med, vol 8, issue 4, oct-dec 2013

26. Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3

32. TAILOR: 2L docetaxel vs Tarceva in Italian patients with EGFR WT disease The phase III TAILOR study was conducted by community oncologists in Italy, which compared second- line Tarceva with docetaxel in patients with EGFR WT NSCLC. Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3 PFSOS Tarceva (n=109) Docetaxel (n=110) Tarceva (n=109) Docetaxel (n=110) 0S probability 1.0 0.8 0.6 0.4 0.2 0 Time (months) 5.48.2 02468101214161820 1 2 3 4 5 6 7 8 2.42.9 PFS probability 1.0 0.8 0.6 0.4 0.2 0 Time (months) HR=0.72 (0.55–0.94)* Log-rank p=0.01 HR=0.78 (0.51–1.05) * Log-rank p=0.10 *Unadjusted HR shown; adjusted PFS HR 0.71 (0.53–0.95), p=0.02; OS HR 0.73 (0.53–1.00), p=0.049 HRs shown above are for docetaxel vs Tarceva. For comparison purposes, 1/HR values are; 1.39 (PFS) and 1.28 (OS) 0

33. Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3

36. TOXICITIES

37. Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066

39. CLINICAL RESULTS IN PHASE III CLINICAL TRIALS (OVERALL PATIENT POPULATION) Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066

40. CLINICAL RESULTS IN EGFRwt POPULATION Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066

41. BASELINE CHARACTERISTICS OF PHASE III TRIALS Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066

42. Clinical Lung Cancer, Vol. 7, No. 6, 389-394, 2006

44. ANOTHER TREATMENT SELECTION FACTORS IN EGFRwt POPULATION Erlotinib is taken orally. The ORR and progression-free interval related to first-line treatment. Toxicities related to first-line treatment. Patient’s comorbid conditions. Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066

45. Erlotinib as second-line therapy for patients with advanced non- squamous EGFR-wild type lung cancer

46. Characteristics of patients and tumors at baseline Total (n=47) Sex male, n (%)39 (83.0) Age, median age (range)62.0 (38.0–83.0) Smoking habits, n (%) Smokers16 (37.2) Ex-smokers18 (41.9) Non-smokers9 (20.9) ECOG PS, n (%) 04 (8.5) 136 (76.6) 27 (14.9) Tumor histology, n (%) Adenocarcinoma38 (80.9) Large-cell lung carcinoma2 (4.3) Others7 (14.9) Staging of lung cancer, n (%) Primary tumor T1b2 (4.3) T2 / T2a11 (23.4) / 1 (2.1) T34 (8.5) T421 (44.7) Tx8 (17.0) Regional lymph nodes N09 (19.1) N218 (38.3) N317 (36.2) Nx3 (6.4) Distant metastasis M01 (2.1) M1/ M1a43 (91.5) / 3 (6.4) Main metastasis locations, n (%) Bone18 (38.3) Lungs15 (31.9) Kidney13 (27.7) Pleura13 (27.7)

47. 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival 3 6 9 12 Time (months) 0 Median PFS=3.2 (2.7–4.2) Progression-Free Survival Median PFS=2.33 (95% CI, 1.84–2.83) Patients at risk: Number of events: 47 0 18 29 3 44 1 46 - -

48. 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival 6 Time (months) 0 Median PFS=3.2 (2.7–4.2) Progression-Free Survival Median PFS=2.6 (0.4–10.9) Patients at risk: Number of events: 47 0 21 26 12 18 2430 364248 8 36 4 40 2 42 1 Survival function Censored - - - - Overall Survival Median OS=4.00 (95% CI, 1.18–6.82)

49. Erlotinib as second-line therapy for patients with advanced squamous EGFR-wild type lung cancer (GGCP 55/012)

50. Design

51. CONCLUSIONS SIMILAR EFFICACY OF THE THREE AGENTS (DOCETAXEL, PEMETREXED, ERLOTINIB) IN THE SECOND-LINE TREATMENT OF ADVANCED EGFRwt NSCLC. SELECTION OF TREATMENT WILL HAVE TO BE ACCORDING TO: – HISTOLOGICAL TYPE – PATIENT PREFERENCE – PATIENT’S COMORBID CONDITIONS – PREVIOUS OR RESIDUAL TOXICITIES – RISK OF NEUTROPENIA – RESPONSE AND DURATION OF FIRST-LINE CHEMOTHERAPY – HISTORY OF SMOKING