Target therapy nel NSCLC con EGFR M+ Cesare Gridelli Division of Medical Oncology S.G. Moscati Hospital Avellino (Italy)

Transcription

1 Target therapy nel NSCLC con EGFR M+ Cesare Gridelli Division of Medical Oncology S.G. Moscati Hospital Avellino (Italy)

2 First-Line Treatment of Advanced NSCLC EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Platinum plus Pemetrexed or taxanes OR Platinum combination plus Bevacizumab* (PS 0,1) or Gemcitabine Vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane OR Platinum combination plus Cetuximab Radiotherapy CNS Central airways Bone Soft tissue Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

3 First-Line Treatment of Advanced NSCLC EGFR-mutation analysis Non-squamous cell carcinoma Metastatic NSCLC, PS 0-2 Squamous cell carcinoma EGFR mutation (del 19 or L858R in exon 21) EGFR wild type (or not done) EGFR-TKI Platinum plus Pemetrexed or taxanes OR Platinum combination plus Bevacizumab* (PS 0,1) or Vinorelbine Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly) Platinum plus Gemcitabine or taxane OR Platinum combination plus Cetuximab Radiotherapy CNS Central airways Bone Soft tissue Elderly/PS 2 Platinum combination (preferred in fit elderly) or Monotherapy (preferred in unfit elderly)

4 Phase III Studies Comparing EGFR-TKI With Platinum Doublet in Patients With EGFR Mutations Group Study EGFR Mutation N Result (PFS) TKI Control WJOG 3405 Over X19, L858R 177 HR=0.49 for G (9.2 mos) G CDDP+ DOC NEJ 002 Over X19, L858R, G719A, G719C, G719S, L861Q 194 HR=0.36 for G (10.4 mos) G CBDCA+ PAC SLCG EURTAC X19, L858R 173 HR=0.37 For E (9.7 mos) E Platinum doublet China ML20981 EGFR mutation 154 HR=0.16 for E (13.1 mos) E CBDCA+ GEM Global LUX-Lung 3 EGFR mutation 308 HR=0.58 for A (11.1 mos) A CDDP+ PEM China Lux-Lung 6 EGFR mutation 364 HR= 0.28 for A (11.0 mos) A CDDP+ GEM 4

5 Percentage of EGFR-Positive Mutation Patients Treated With First-Line Chemotherapy and Never Receiving EGFR TKI Study % IPASS 60.5 WJTOG NEJ TORCH 25.0 EURTAC 24.0 LUX LUNG LUX LUNG

6 Differences between EGFR-TKIs? Gefitinib Erlotinib Afatinib Dose (daily) 250mg 150mg 40mg Bioavailibility (%) Food effect No Yes ( ) Yes ( ) Active metabolite No 2 1 or more Elimination Faeces Faeces Faeces Drug interaction CYP3A4 CYP3A4 No MTD (mg/d)

7 Impact Mutations on safety de l EGFR (IPASS) (EURTAC) (L LUNG 3) Multidisciplinary Oncology & Therapeutic Innovations INSERM U911 CRO2 Marseille - France

8 Chairmen F. de Marinis C. Gridelli Panelists F. Cappuzzo F. Ciardiello F. de Marinis C. Gridelli F. Hirsch T. Mok R. Rosell D. Spigel J. Yang

9 Phase III Studies Comparing EGFR-TKI With Platinum Doublet in Patients With EGFR Mutations Group Study EGFR Mutation N OS ( %crossover) TKI Control WJOG 3405 Over X19, L858R 177 HR=1.25 (58) G CDDP+ DOC NEJ 002 Over X19, L858R, G719A, G719C, G719S, L861Q 194 HR=0.89 (99) G CBDCA+ PAC SLCG EURTAC X19, L858R 173 HR=0.93 (76) E Platinum doublet China OPTIMAL EGFR mutation 154 HR=1.04 (NR) E CBDCA+ GEM Global LUX-Lung 3 EGFR mutation 308 HR=0.78 (75) A CDDP+ PEM China Lux-Lung 6 EGFR mutation 364 HR= 0.83 (56) A CDDP+ GEM 9

10 Combined OS analysis: common mutations (n=631) Estimated OS probability Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value 0.81 ( ), p= No of patients Time (months) Afatinib Chemo Yang J et al, ASCO 2014

11 Combined OS analysis: mutation categories Del19 L858R 1.0 Median, months Afatinib n=236 Chemo n= Median, months Afatinib n=183 Chemo n= Estimated OS probability HR (95%CI), p-value 0.59 ( ), p= Estimated OS probability HR (95%CI), p-value 1.25 ( ), p= Time (months) No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Yang J et al, ASCO 2014

12 OS in common mutations: subgroups Patients Total Gender Male Female Age (years) < EGFR mutation Del L858R Baseline ECOG score Smoking history Never smoker <15 pack yrs, stopped >1 yr ago Other current/ex-smoker Race Non-Asian Asian LUX-Lung 3 LUX-Lung 6 HR Patients HR /16 1/ /16 1/ Favors Afatinib Favors Pem/Cis Favors Afatinib Favors Gem/Cis

13 PROVOCATIVE EXPLANATIONS FOR SURVIVAL BENEFIT IN LUX-Lung TRIALS HIGHER NUMBER OF PATIENTS ABLE TO DETECT SURVIVAL DIFFERENCE LOWER CROSSOVER IN THE LARGEST TRIAL (56% in LUX-Lung 6 and 75% in LUX- Lung 3, respectively) LONGER EXPOSURE TO TKI (44% and 26% TKI retreatment in Afatinib arm for LUX-Lung 3 and LUX-Lung 6, respectively) Results by chance It s true

14 CTONG 0901: Erlotinib vs Gefitinib in patients with EGFR exon 21 mutation Advanced NSCLC Adenocarcinoma EGFR exon21 mut+ First-line treatment PS 0-1 R A N D O M I Z E 1 1 Erlotinib 150mg qd Gefitinib 250mg qd PFS 14.3 vs 9.8 months HR 0.67 N= 200 patients

15 LUX-Lung 7 Phase IIb trial in first line NSCLC with EGFR mutation Patients (n=264) with: Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumour tissue Chemonaive ECOG 0 or 1 Randomization Afatinib 40 mg once-daily Gefitinib 250 mg once-daily Co-Primary endpoint: PFS / DCR at 12 mos

16 ARCHER 1050: Randomized Phase III Study Dacomitinib vs Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 R A N D O M I Z E 1 1 Dacomitinib 45mg qd Gefitinib 250mg qd Primary endpoint in PFS 14.8 vs 9.5 months N= 440 patients Stratification -Race -Exon 19 v 21

17 Acquired resistance in EGFR Mut+ NSCLC Mechanisms of acquired resistance to EGFR TKIs Activation of other receptor tyrosine kinases? (eg. ERBB2 amplification) FAS/NFκB activation? Epithelial-mesenchymal transition? (AXL, Slug activation?) Loss or spliced variant of BIM? Other? (eg. CRKL or ERK amplification) ~30 40% Acquired resistance to EGFR TKIs in metastatic setting is inevitable The average PFS is 8 13 months ~1% BRAF mutations ~5% small-cell cancer transformations ~60% second-site EGFR mutations (mostly T790M) ~5% PIK3CA mutations -5 10% MET amplification Ohashi et al, J Clin Oncol 2013

18 SUBTYPING PROGRESSIVE DISEASE

19 Strategies to rechallenge with EGFR-TKI Treatment of sensitive clones with activating EGFR mutation Treatment of resistant clones (T790M, c-met amplification, other) Treatment of re-emerging sensitive clones with activating EGFR mutation A EGFR-TKI chemotherapy Same EGFR-TK B EGFR-TKI chemotherapy Different EGFR-TKI C EGFR-TKI 3 generation TKI (i.e. ZD9291) chemotherapy (i.e. AZD9291)

20 Strategies to rechallenge with reversible EGFR-TKI: ICARUS study Treatment of sensitive clones with activating EGFR mutation Treatment of resistant clones (T790M, c-met amplification, other) Treatment of re-emerging sensitive clones with activating EGFR mutation A GEFITINIB chemotherapy GEFITINIB SEQUENTIAL B Reversible EGFR- TKI chemotherapy Different Reversible EGFR- TKI C Reversible EGFR- TKI chemotherapy Irreversible EGFR-TKI D Reversible EGFR- TKI 3 rd generation EGFR-TKI

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22 IMPRESS: Chemotherapy + gefitinib at progression Gefitinib Gefitinib + Alimta/Platinum Advance stage NSCLC with EGFR Mutation PD By RECIST Primary endpoint: PFS Alimta/Platinum Co-PI: Soria J; Mok T

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24 Materiale di training ad esclusivo utilizzo interno. Non distribuire a Terzi. AstraZeneca raccomanda l'uso dei propri prodotti secondo il Riassunto delle Caratteristiche di prodotto

25 3 rd generation EGFR TKIs under development: AZD9291 AZD9291 Selectively targets mutated EGFR, including T790M Phase I dose escalation study in patients with EGFR Mut+ disease and PD on EGFR TKI encouraging activity : 59% response rate months in 157 pts T790M+ (54% OR in 61 pts treated at recommended dose 80 mg and PFS 13.5 mos) 23% response rate in 69 pts T790M- no DLTs 80 Ongoing clinical development programme Janne P et al, NEJM 2015

26 AURA 3 TRIAL: AZD9291 vs Chemotherapy in II line in patients with EGFR activating mutation and T790M+ Advanced NSCLC Adenocarcinoma EGFR mut+ EGFR T790M+ Second-line treatment PS 0-1 R A N D O M I Z E 1 1 AZD9291 Chemotherapy

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28 FLAURA Phase III trial: AZD9291 vs Gefitnib or Erlotinib in I line in patients with EGFR activating mutation Advanced NSCLC Adenocarcinoma EGFR mut+ First-line treatment PS 0-1 R A N D O M I Z E 1 1 AZD9291 (80 mg) Gefitinib or Erlotinib Background: Phase II study in 1-line EGFR M+ 60 pts OR%= 73% Ramalingam S et al. ASCO 2015

29 3 rd generation EGFR TKIs under development: CO-1686 (rociletinib) CO-1686 Selectively targets mutated EGFR, including T790M spares EGFR WT Phase I dose escalation study in EGFR Mut+ T790M+(n=243/458) encouraging activity: 53% response rate Median PFS 8 months AE profile consistent with lack of EGFR WT inhibition T790M negative 37% OR Positive agreement T790M liquid (81%) vs tissue (87%) biopsy Ongoing clinical development programme Sequist L et al, ASCO 2015

30 TIGER 3 TRIAL: CO 1686 vs chemotherapy in patients with EGFR activating mutation and T790M+ Advanced NSCLC Adenocarcinoma EGFR mut+ EGFR T790M+ 2/3-line treatment PS 0-1 R A N D O M I Z E 1 1 CO 1686 Chemotherapy

31 Targeting CTLA-4 and PD-1 pathways

32 Overview of PD-L1 and PD-1 inhibitors: current development Therapeutic Lead company Antibody type Affinity/K 2 Anti-PDL1 MPDL3280A MEDI-4736 Roche AstraZeneca Engineered IgG1 (no ADCC) Modified IgG1 (no ADCC) 0.4nM Not available BMS Bristol-Myers Squibb IgG4 (humanised) Not available Anti-PD1 Nivolumab Bristol-Myers Squibb IgG4 2.6nM Pembrolizumab Merck & Co IgG4 (humanised) 29pM AMP-224 GlaxoSmithKline PD-L2 IgG1 Fc fusion Not available Pidilizumab (CT-011) CureTech IgG1 (humanised) Not available

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34 CA Study Design: Nivolumab in Combination With Erlotinib in EGFR M+ Gettinger et al, CMSTO 2014

35 Gettinger et al, CMSTO 2014 Results in NSCLC pts treated with nivolumab plus erlotinib

36 Phase 3, Open-Label Randomized Trial of Nivolumab vs. Docetaxel in Previously Treated Advanced or Metastatic Non-Squamous Cell Non-small Cell Lung Cancer (NSCLC)(CA ) ChekMate- 057 Stage IIIB/IV non-sq NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0 1 Failed 1 prior platinum doublet Prior maintenance therapy allowed a Prior TKI therapy allowed for known ALK translocation or EGFR mutation N = 582 Randomize 1:1 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 292 Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity n = 290 Primary Endpoint OS Additional Endpoints ORR b PFS b Safety Efficacy by tumor PD-L1 expression Quality of life (LCSS) Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line) PD-L1 expression measured using the Dako/BMS automated IHC assay 14,15 Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.

37 Overall Survival Nivolumab (n = 292) Docetaxel (n = 290) mos, mo HR = 0.73 (96% CI: 0.59, 0.89); P = OS (%) yr OS rate = 39% 1-yr OS rate = 51% Nivolumab 20 Number of Patients at Risk Nivolumab Docetaxel 10 Docetaxel Time (months)

38 Treatment Effect on OS in Predefined Subgroups N Unstratified HR (95% CI) Overall (0.62, 0.91) Age Categorization (years) < (0.62, 1.04) 65 and < (0.45, 0.89) (0.43, 1.87) Gender Male (0.56, 0.96) Female (0.58, 1.04) Baseline ECOG PS (0.44, 0.93) (0.63, 1.00) Smoking Status Current/Former Smoker (0.56, 0.86) Never Smoked (0.64, 1.61) EGFR Mutation Status Positive (0.69, 2.00) Not Detected (0.51, 0.86) Not Reported (0.51, 1.06) 0.25 Nivolumab Docetaxel All randomized patients (nivolumab, n = 292; docetaxel, n = 290).