Target therapy nel NSCLC con EGFR M+ Cesare Gridelli Division of Medical Oncology S.G. Moscati Hospital Avellino (Italy) cgridelli@libero.it
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)
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)
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
Percentage of EGFR-Positive Mutation Patients Treated With First-Line Chemotherapy and Never Receiving EGFR TKI Study % IPASS 60.5 WJTOG 3405 42.0 NEJ 002 5.4 TORCH 25.0 EURTAC 24.0 LUX LUNG-3 25.0 LUX LUNG-6 44.0
Differences between EGFR-TKIs? Gefitinib Erlotinib Afatinib Dose (daily) 250mg 150mg 40mg Bioavailibility (%) 59 60 90 Food effect No Yes ( ) Yes ( ) Active metabolite No 2 1 or more Elimination Faeces Faeces Faeces Drug interaction CYP3A4 CYP3A4 No MTD (mg/d) 800-1000 150 70
Impact Mutations on safety de l EGFR (IPASS) (EURTAC) (L LUNG 3) Multidisciplinary Oncology & Therapeutic Innovations INSERM U911 CRO2 Marseille - France
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
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
Combined OS analysis: common mutations (n=631) Estimated OS probability 1.0 0.8 0.6 0.4 0.2 Afatinib n=419 Chemo n=212 Median, months 27.3 24.3 HR (95%CI), p-value 0.81 (0.66 0.99), p=0.0374 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No of patients Time (months) Afatinib 419 411 390 371 343 320 284 251 225 201 181 141 77 58 33 9 1 0 Chemo 212 199 185 173 162 141 124 110 101 83 70 52 34 23 10 5 1 0 Yang J et al, ASCO 2014
Combined OS analysis: mutation categories Del19 L858R 1.0 Median, months Afatinib n=236 Chemo n=119 31.7 20.7 1.0 Median, months Afatinib n=183 Chemo n=93 22.1 26.9 Estimated OS probability 0.8 0.6 0.4 HR (95%CI), p-value 0.59 (0.45 0.77), p=0.0001 Estimated OS probability 0.8 0.6 0.4 HR (95%CI), p-value 1.25 (0.92 1.71), p=0.1600 0.2 0.2 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) No of patients Afatinib 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0 Chemo 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0 Time (months) No of patients Afatinib 183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0 Chemo 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0 Yang J et al, ASCO 2014
OS in common mutations: subgroups Patients Total 307 0.78 Gender Male 103 0.73 Female 204 0.79 Age (years) <65 189 0.82 65 118 0.73 EGFR mutation Del19 169 0.54 L858R 138 1.30 Baseline ECOG score 0 115 0.96 1 191 0.71 Smoking history Never smoker 210 0.75 <15 pack yrs, stopped >1 yr ago 29 0.79 Other current/ex-smoker 68 0.91 Race Non-Asian 83 0.68 Asian 224 0.82 LUX-Lung 3 LUX-Lung 6 HR Patients HR 324 0.83 111 0.70 213 0.88 246 0.87 78 0.60 186 0.64 138 1.22 78 0.82 246 0.83 251 0.71 11 1.22 62 1.29 1/16 1/4 1 4 1/16 1/4 1 4 16 Favors Afatinib Favors Pem/Cis Favors Afatinib Favors Gem/Cis
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
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
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
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
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
SUBTYPING PROGRESSIVE DISEASE
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)
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
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
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
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
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
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
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
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
Targeting CTLA-4 and PD-1 pathways
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-936559 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
CA209-012 Study Design: Nivolumab in Combination With Erlotinib in EGFR M+ Gettinger et al, CMSTO 2014
Gettinger et al, CMSTO 2014 Results in NSCLC pts treated with nivolumab plus erlotinib
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)(CA209-057) 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.
Overall Survival 100 90 80 70 Nivolumab (n = 292) Docetaxel (n = 290) mos, mo 12.2 9.4 HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015 OS (%) 60 50 40 30 1-yr OS rate = 39% 1-yr OS rate = 51% Nivolumab 20 Number of Patients at Risk Nivolumab 292 232 194 169 146 123 62 32 9 0 Docetaxel 10 Docetaxel 0 0 3 6 9 12 15 18 21 24 Time (months) 290 244 194 150 111 88 34 10 5 0 27
Treatment Effect on OS in Predefined Subgroups N Unstratified HR (95% CI) Overall 582 0.75 (0.62, 0.91) Age Categorization (years) <65 339 0.81 (0.62, 1.04) 65 and <75 200 0.63 (0.45, 0.89) 75 43 0.90 (0.43, 1.87) Gender Male 319 0.73 (0.56, 0.96) Female 263 0.78 (0.58, 1.04) Baseline ECOG PS 0 179 0.64 (0.44, 0.93) 1 402 0.80 (0.63, 1.00) Smoking Status Current/Former Smoker 458 0.70 (0.56, 0.86) Never Smoked 118 1.02 (0.64, 1.61) EGFR Mutation Status Positive 82 1.18 (0.69, 2.00) Not Detected 340 0.66 (0.51, 0.86) Not Reported 160 0.74 (0.51, 1.06) 0.25 Nivolumab 0.5 1.0 2.0 4.0 Docetaxel All randomized patients (nivolumab, n = 292; docetaxel, n = 290).