Gli Inibitori di I e II generazione sono tutti uguali? Roberta Buosi Camogli, 30 aprile 2016

ERBB Family ErbB1, ErbB2, ErbB3, ErbB4 Ubiquitarriamente espressi su tutti i tessuti epiteliali e anche nel SNC

MECCANISMO D’AZIONE

Formula chimica GefitinibErlotinib Afatinib

AFFINITA’ DI LEGAME the overall characteristics of these kinase inhibitors remain the same: a heterocyclic core scaffold makes many of the same contacts as the purine ring of ATP. Side chains on the scaffold allow for the generation of inhibitors that target a diverse set of kinases. Among the many reported heterocyclic cores, the 4-anilinoquinazoline plays a particularly important role in demonstrating the potential for selectivity. All three clinically approved TKIs for EGFR based on the 4-anilinoquinazoline scaffold. b) Gefitinib c) AEE 788 d) ATP

Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342. Afatinib si lega con legame covalente e blocca in modo irreversibile tutti gli omo ed eterodimeri formati dai 4 recettori ErbB. Meccanismo d’azione di afatinib

Efficacia?

Benefit of 1 st- line EGFR TKIs: 9 randomized phase III studies

Phase III Trials in EGFR Mutation–Positive NSCLC: PFS negli studi clinici controllati Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. NR * Cisplatin/Pemetrexed * *

PFS mediana nei trials di fase III nel NSCLC EGFRmut+ Exon 19 Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. Mok T, et al. N Engl J Med 2009;361:947–957; Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; Estimation from Kaplan–Meier Curves in Fukuoka M. et al. J Clin Oncol 2011; 29: 2866–2874. Sequist et al. J Clin Oncol. 2013;31:3327. Wu et al. Lancet Oncol. 2014;15:213. Rosell R, et al. Lancet Oncol 2012;13:239–246; EU CHMP Variation Assessment Report, Tarceva, July Phase III Trials in EGFR Mutation–Positive NSCLC: Exon 19

Fukuoka et al, J Clin Oncol 2011 Exon 19 L858R

Lux–Lung 3 Del 190,54 (0,36 – 0,79) Lux-Lung 6 Del 190,64 (0,44 – 0,94) IPASS Del 190,79 (0,54 – 1,15) NS NEJ002 Del 190,83 (0,52 – 1,34) NS EURTAC Del 190,94 (0,57 – 1,54) NS ENSURE Del 19NA Studio OS HR (95% CI) 1.Sequist et al. J Clin Oncol 2013;31:3327; 2. Wu et al. Lancet Oncol 2014; ; 3. Mok et al. N Engl J Med. 2009;361:947; 4. Fukuoka et al. J Clin Oncol. 2011;29:2866; 5. Yang et al. Eur J of Cancer (suppl1;S633); 6. Maemondo et al. N Engl J Med. 2010;362:2380; 7. Inoue et al. Ann Oncol. 2013;24:54; 8. Rossel et al. Lancet Onco ;13:239; 9.TARCEVA® (erlotinib) prescribing information, 2013; 10. Wu et al. J Thorac Oncol. 2013;8:suppl 2 (P ). Del19: Quali evidenze? OS nei trials di Fase III nel NSCLC EGFRmut+ Del NS = dato non statisticamente significativo AFATINIB GEFITINIB ERLOTINIB

Yang JC et al, Lancet Oncol 2015

PFS mediana nei trials di Fase III nel NSCLC EGFRmut+ Exon 21 Modified from Sebastian et al. Eur Respir Rev. 2014; 23:92. Mok T, et al. N Engl J Med 2009;361:947–957; Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; Estimation from Kaplan–Meier Curves in Fukuoka M. et al. J Clin Oncol 2011; 29: 2866–2874. Sequist et al. J Clin Oncol. 2013;31:3327. Wu et al. Lancet Oncol. 2014;15:213. Rosell R, et al. Lancet Oncol 2012;13:239–246; EU CHMP Variation Assessment Report, Tarceva, July Phase III Trials in EGFR Mutation–Positive NSCLC: Exon 21

Confronto Indiretto

Progression Free Survival Haspinger E, CROH 2014

DELEZIONE 19 Haspinger E, CROH 2014

I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, WLCC 2013 Gefitinib verso erlotinib

I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, CROH 2014 Gefitinib verso Afatinib

I STITUTO N AZIONALE PER LO S TUDIO E LA C URA DEI T UMORI Haspinger E, CROH 2014 Erlotinib vs Afatinib

…no statistically significant differences between afatinib and erlotinib or gefitinib in terms of PFS, some numerical differences were observed, particularly in patients with common EGFR mutations. All comparisons for PFS versus currently available reversible TKIs (erlotinib and gefitinib) showed a trend favouring afatinib.

The Lancet Oncology, 2014 CONFRONTO DIRETTO 134 centres in 23 countries, 878 patients 439 dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib locally advanced or metastatic non-small-cell lung cancer, ECOG 0–2, dacomitinib (45 mg/day) or erlotinib (150 mg/day) Randomisation was stratified by histology (adenocarcinoma vs non- adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian subcontinent), performance status (0–1 vs 2), and smoking status. Median PFS 2·6 months in dacomitinib group and erlotinib group

Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/21 Ramalingam SS et al. WCLC EGFR Mutant Patients Retrospectively analysed from ARCHER 1028 (Ramalingam S JCO 2012) and ARCHER 1009 (Ramalingam S Lancet Oncol 2014) PFSOS Dacomitinib (N=66)Erlotinib (N=55)Dacomitinib (N=66)Erlotinib (N=55) Events(%)51 (77.3%)44 (80.0%)39 (59.1%)32 (58.2%) Median (95% CI) in Mons10.9 ( )9.6 ( )26.6 ( )24.1 ( ) Un-stratified HR (95% CI)0.815 ( )0.958 ( ) P-value (1-sided) PFS OS

Eventi avversi Daconitinib Gr 3/4 Erlotinib Gr 3/4 rash7%3% diarrea 11 % 2% stomatiti3% < 1% AES 12% 9%

DIRECT COMPARISON: LUX Lung 7 Randomized explorative phase IIb Study Complete accrual on Aug Complete accrual on Aug Sample size Increased to 319 Sample size Increased to 319

LL7: END-POINTS DI EFFICACIA - PFS

LL7: END-POINTS DI EFFICACIA - TTF

RISPOSTA SU POPOLAZIONE GLOBALE

Our analysis reported that exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome S786I and S786I þ L858R mutations were thought to be sensitizing in the afatinib study different effect with different TKIs rare frequencies, it is practically impossible to enroll enough patients to power a clinical trial Barbara Klughammer, J Thor Oncol, 2016

PROFILO DI TOSSICITA’

W Liang et al, PLOS One 2014

* Toxicity is referred to total 607 pts 1 Y Wu et al, P ASCO 2013; 2 Yang et al, P ASCO 2012; 3 Rosell et al, Lancet Oncol 2012; 4 Mok et al, NEJM 2009;

M Takeda et al, Lung Cancer 2015

ALGORITHM: DOSE MODIFICATION DUE TO TREATMENT-RELATED DERMATOLOGIC AEs According to CTCAE Version 3.0 Proactive management Use alcohol-free skin products Minimise exposure to the sun Use protective clothing/hat Use sunscreen with a high protection factor and UVA/UVB protection Avoid any perfume or perfume- based skin products Grade 1 or tolerable grade 2 skin reaction Grade ≥3 or intolerable grade 2 Initiate dermatologic treatment CONTINUE TKI AT CURRENT DOSE Refer to dermatologist or continue dermatologic treatment Lacouture et al. Expert Rev Anticancer Ther INTERRUPT UNTIL GRADE 0/1 1. Resume treatment with dose reduction by 10-mg decrements 2. If patient cannot tolerate 20 mg/day, permanent discontinuation should be considered

J Yang… F de Marinis et al, ASCO 2015

Conclusioni Esistono diverse sfumature … dipende da quale lato le si osserva -1° linea in EGFR + i TKI sono meglio della CT Diversi in : meccanismo d’azione Profilo di tossicità ciò che è statisticamente significativo non sempre ha significato clinico Efficacia sovrapponibile …