EGFR M+ and personalized therapy in NSCLC

Transcription

1 EGFR M+ and personalized therapy in NSCLC 2015/02 嘉義長庚胸腔科系胸腔腫瘤科方昱宏

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3 主要癌症死亡人數 ( 全國 ) 肺癌 肝癌 大腸癌 乳癌 口腔癌 胃癌 前列腺癌 食道癌 胰臟癌 子宮頸癌

4 Lung cancer 兩年存活率 ( 全國 ) Stage I Stage II Stage III Stage IV

5 One size fits all Paclitaxel 135mg/m 2 Cisplatin 75mg/m 2 Performance status: 0 or 1 vs. 2 Weight loss in previous 6 months Disease stage: IIIB vs. IV or recurrent disease NSCLC Presence or absence of brain metastases Randomize Gemcitabine 10 3 mg/m 2 Cisplatin 100mg/m 2 Docetaxel 75mg/m 2 Cisplatin 75mg/m 2 Paclitaxel 225mg/m 2 Carboplantin 6 mg/ml/min Joan H. Schiller et. al. N Engl J Med 2002

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7 EGFR signaling pathway Stanley Cohen,

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9 Squamous cell carcinoma with high EGFR expression (3+) (original magnification 400x); Cut-off value of 10% positive cell (2+, 3+).

10 Lancet Oncol 2003; 4:

11 EGFR detected by IHC is not an effective predictor of response to tyrosine kinase inhibitor Lancet Oncol 2003; 4:

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13 Addiction Proliferation Survival

14 Frequency of mutations in exons of the EGFR gene and the association with responsiveness to EGFR TKIs

15 Primary endpoint - PFS IPASS Carboplatin AUC 5 6 d1 + paclitaxel 200mg/m 2 d1, q3w x6 Chemo-naïve, stage IIIB or IV NSCLC, never or light ex-smokers* with adenocarcinoma histology and ECOG PS 0 2 (n=1,217) R Gefitinib 250 mg/day PFS Gefitinib Chemo months HR=0.48 ( ) p<0.0001

16 EGFR mutant EGFR wild

17 Chemo-naїve, stage IIIB or IV NSCLC and ECOG PS 0 2 EGFR Act Mut+ (exon 19 deletion or exon 21 L858R mutation) (n=165) OPTIMA R Gemcitabine 1,000 mg/m 2 d1,8 + Carboplatin AUC5 d1, q3w, up to 4 cycles Erlotinib 150 mg/day PFS Erlotinib Chemo months (n=82) (n=72) HR=0.164 ( ) p<0.0001

18 First line EGFR TKI in M(+) results summary Study Response rate, % Median PFS, months Median OS, months (HR [95%CI]) IPASS 1,2 * N= vs 47.3 (p<0.001) 9.5 vs 6.3 p< vs 21.9 p=0.990 WJTOG3405 3,4 N= vs 32.2 (p<0.0001) 9.6 vs 6.6 p< vs 38.8 p=0.443 NEJ002 5,6 N= vs 30.7 (p<0.001) 10.8 vs 5.4 p<0.001) 27.7 vs 26.6; p=0.483 OPTIMAL 8 10 N= vs 36 (p<0.0001) 13.7 vs 4.6 p<0.0001) 22.7 vs 28.9 p=0.692 EURTAC 11,12 N= vs 18 (p<0.0001) 10.4 vs 5.1 p<0.0001) 22.9 vs 20.8 p= Mok et al, N Engl J Med 2009; 2. Fukuoka et al, J Clin Oncol 2011; 3. Mitsudomi et al, Lancet Oncol 2010; 4. Mitsudomi et al, ASCO 2012; 5. Maemondo et al, N Engl J Med 2010; 6. Inoue et al, Ann Oncol 2013; 7. Douillard, EMCTO 2013; 8. Chen et al, Ann Oncol 2013; 9. Zhou et al, Lancet Oncol 2011; 10. Zhou et al, ASCO 2012; 11. Rosell et al, Lancet Oncol 2012; 12. Rosell et al, ESMO 2012; *These data relate to the subset of EGFR mutation positive patients in IPASS. 13. Sequist et al, J Clin Oncol 2013; 14. Wu et al, ASCO 2013

19 Gefitinib Erlotinib Afatinib

20 LUX-Lung 3 1 (n=345) LUX-Lung 6 2 (n=364; Asian pts) Cisplatin + Pemetrexed 75 mg/m mg/m 2 IV q21d, up to 6 cycles Afatinib 40 mg/d b Cisplatin + Gemcitabine 75 mg/m mg/m 2 D1, D8 IV q21d, up to 6 cycles

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22 Lux-lung 3 and 6 : combined OS analysis Exon 19 deletion L858R 31.7 v.s v.s 26.9 Lancet Oncology, January 12,

23 Pharmacokinetic profiles overview Gefitinib Erlotinib Afatinib Gefitinib 250 mg/day 1 3 Erlotinib 150 mg/day 1,4 Afatinib 40 mg/day 5 Binding to EGFR Reversible Reversible Irreversible Bioavailability 59% 60% Absolute bioavailability in humans is unknown Major routes of metabolism Liver primarily by CYP3A4 Liver primarily by CYP3A4 and less by CYP1A2 Minimal metabolism detected in healthy volunteers b, not metabolised by liver 6 C max ng/ml a T ½ terminal hours 41 (mean) 36 (median) 37 (mean) AUC ss µg.h/ml a 15.2 ( ) 968 ng.h/ml Vd ss (L), mean c 23 a At doses of 225 and 300 mg/day; b At dose of 15 mg/day; c Data refers to apparent volume of distribution during the terminal Phase after an extravascular dose 1. Adapted from Rukazenkov et al, Anticancer Drugs 2009; 2. Ranson et al, J Clin Oncol 2002; 3. Baselga et al, J Clin Oncol 2002; 4. Yamamoto et al, Cancer Chemother Pharmacol 2008; 5. Yap et al, J Clin Oncol 2010; 6. Stopfer et al, Cancer Chemother Pharmacol 2012

24 Studies in 1st-line NSCLC treatment overall survival > 2 years Median OS (months) L EGFR Mut+ Maintenance trials 1L trials Recruitment All-comers Scagliotti 2 Gatzemeier 5 Giaccone 6 Schiller 1 Alberola3 Non-PD after AVAPERL 17 4cycles ATLAS 9 PARAMOUNT 11 E EGFR Mut+ Scagliotti 7 NEJSG First-SIGNAL 15 EURTAC 14 IPASS 12 OPTIMAL 13 AVAiL 8 POINTBREAK Schiller, et al. NEJM 2002; 2. Scagliotti, et al. JCO 2002; 3. Alberola, et al. JCO2003; 4. Sandler, et al. NEJM 2006; 5. Gatzemeier, et al. JCO 2007; 6. Giaccone, et al. JCO 2004; 7. Scagliotti, et al. Clin Cancer Res 2005; 8. Reck, et al. Ann Oncol 2010; 9. Kabbinavar, et al. ASCO 2010; 10. Barlesi, et al. EMCC 2011; 11. Paz-Ares, et al. ASCO 2012; 12. Fukuoka, et al. JCO 2011; 13. Zhou, et al. ASCO 2012; 14. de Marinis, et al. EMCC 2011; 15. Han, et al. JCO 2012; 16. Maemondo NEJM 2010; 17. Patel, et al. IASLC 2012 (Chicago) Adapted from the presentation by Martin Reck at 2012 ESMO

25 LUX Lung 7 Afatinib Gefitinib V.S WJOG5108L Erlonib Gefitinib

26 WJOG5108L

27 Data from National Cancer Institute Lung Cancer Mutation Consortium (n=1000) Data in Korean patients (n=200)

28 N Engl J Med Jun 20;368(25): doi: /NEJMoa Epub 2013 Jun

29 Lancet 2013; 382:

30 A long long journey 3 rd generation TKIs

31 The rising stars Agents Phase N Study Arms AZD9291 (irreversible inhibitor for EGFR+/T790 M) I/II 233 Daily oral dose of AZD9291 [NCT ] AZD9291 First Time In Patients Ascending Dose Study CO1686 (3 rd - generation EGFR TKI) I/II 170 Oral CO-1686 monotherapy Estimated completion date July 2015 September 2015 [NCT ] Study to Evaluate Safety, Pharmacokinetics, and Preliminary Efficacy of CO-1686 in Previously Treated Mutant EGFR NSCLC

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36 Thanks for your attention

37 Adverse effects of EGFR TKIs

38 Summary of AEs from EGFR-TKI trials Randomized, phase III, first-line use Incidence of AEs (%) IPASS (All comers) N=607 Gefitinib WJTOG3405 N=87 NEJ002 N=114 EURTAC N=84 Erlotinib OPTIMAL N=83 Accrual period All grades AE NR NR Grade 3 AE 28.7 NR Discontinuation due to drug-related AE 6.9 NR NR 6 0 ILD All grades / grade 3 (%) Skin rash/acne Diarrhea Stomatitis/ mucositis NR NR 13 1 Paronychia NR NR NR NR 4 0 Livertransaminases increased NR

39 In a randomised Phase II study of 96 Korean patients a treated with either gefitinib or erlotinib, a greater number of patients treated with erlotinib reported grade 2/3 skin rash (43.7% vs 10.4%) and fatigue (16.7% vs 0%) 1 In a retrospective analysis of Japanese patients, erlotinib was associated with a higher incidence of AEs than gefitinib (see table below) 2 Skin disorders b All (%) Grade 2 (%) All (%) Diarrhoea Grade 2 (%) Anorexia, nausea and vomiting All (%) Grade 2 (%) Gefitinib (n=85) Erlotinib (n=69) P value 0.033* * 0.016* 0.015* <0.0001* <0.0001* a With locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least 2 of 3 clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker); b Skin disorders include skin rash, eruption, exanthema, acne and dry skin; 1. Kim et al, Lung Cancer 2012; *Statistically significant with the Χ 2 test or Fisher s exact test; p< Togashi et al, Lung Cancer 2011

40 WJOG5108L

41 All Grades LUX-Lung 3 1 LUX-Lung 6 2 Afatinib Cis/Pemetrexed Afatinib Cis/Gemcitabine Grade 3/4 All Grades Grade 3/4 All Grades Rash/acne a / / Grade 3/ / 0.4 All Grades Grade 3/ / 0 Diarrhoea / / / / 0 Paronychia/nail effect a / / / / 0 Stomatitis/mucositis a / / / / 0 Decreased appetite / / / / 0 Vomiting / / / / 3.5 Fatigue a / / / / 0 Nausea / / / / 0.9 Dry skin/pruritus b / / / / 0 Neutropenia / / / / 8.8 Anaemia / / / / 1.8 Leukopenia / / / / 1.8 ALT increase / / / / 0.9 AST increase / / / / 0

42 % of Patients LUX-Lung 3 1,2 LUX-Lung 6 2,3 Afatinib (n=229) Cis/Pem (n=111) Afatinib (n=239) Cis/Gem (n=113) Drug-related AEs Drug-related AE grade Drug-related AEs leading to discontinuation Discontinuation due to rash Discontinuation due to diarrhoea 8 a,b 12 6 c (5 pts) (3 pts) Drug-related SAE a Includes 3 patients (1%) who discontinued due to diarrhoea, no discontinuations for rash. b Includes 3 patients (1%) with ILD-like events (1 grade 1, 1 grade 3; 1 grade 5). c Including 1 patient with ILD. SAE = serious adverse event; ILD = interstitial lung disease

43 Trial IPASS (607) WJTOG3405 (87) NEJ002 (114) IFUM (107) OPTIMAL (83) EURTAC (84) LUX-Lung 3 (229) LUX-Lung 6 8 (239) Rash (%) Diarrhoea (%) Nausea/vomit ing (%) Stomatitis (%) Paronychia (%) Liver dysfunction (%) All 3 All 3 All 3 All 3 All 3 All <1 17 a <1 a 14 <1 NR c 28 c b 3 b NR NR NR NR 5.6 d 0 d c 4 c NR NR NR NR NR NR a 16 a a 9 a c 2 c a 1 e 52 a 5 a c 2 c a Grouped term of closely related AEs; b Listed as nail changes c Increased ALT; d Increased AST e Reduction to less than 40 mg per day NR, not reported 1. Mok et al, N Engl J Med 2009; 2. Mitsudomi et al, Lancet Oncol 2010; 3. Maemondo et al, N Engl J Med 2010; 4. Douillard, EMCTO 2013; 5. Zhou et al, Lancet Oncol 2011; 6. Rosell et al, Lancet Oncol 2012; 7. Sequist et al, J Clin Oncol 2013; 8. Wu et al, ASCO 2013 Adapted from the presentation at 2012 ESMO

44 First line First-line EGFR-TKI in M(+): safety data Trial Dose Dose reductions (%) Discontinuations (%) IPASS 1 (gefitinib, 607) IFUM 2 (gefitinib, 107) OPTIMAL 3 (erlotinib, 83) EURTAC 4 (erlotinib, 84) LUX-Lung 3 5 (afatinib, 230) LUX-Lung 6 6 (afatinib, 239) a 7 a 250 NR 8 a b 52 c 8 40 b 32 d 6 a Not specific to drug-related AE b Afatinib dose could be reduced by 10 mg decrements in case of related grade 3 or prolonged grade 2 AEs; c Reduction to less than 40 mg per day, with 19% having more than one dose reduction; d With 6% having two dose reductions NR, not reported 1. Mok et al, N Engl J Med 2009; 2. Douillard, EMCTO 2013; 3. Zhou et al, Lancet Oncol 2011; 4. Rosell et al, Lancet Oncol 2012; 5. Sequist et al, J Clin Oncol 2013; 6. Wu et al, ASCO 2013

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46 Managements of AEs of TKIs Skin Rash

47 Grade Description Specific intervention Grade 1 Grade 2 Macular or papular eruption or erythema without associated symptoms Macular or papular eruption or erythema with pruritus or other associated symptoms Localised desquamation or other lesions covering <50% of BSA Continue afatinib at current dose: Topical steroids* or tacrolimus ointment bd alternative Topical antibiotic bd (clindamycin 1-2%, erythromycin 1-2%) Continue afatinib at current dose: Topical steroids* or tacrolimus ointment bd alternative Oral antibiotic for 6 weeks (doxycycline 100 mg bid, minocycline 100 mg bid) Grade 3 Severe, generalised erythroderma or macular, papular, or vesicular eruption Desquamation covering 50% of BSA Generalised exfoliative, ulcerative, or bullous dermatitis Interrupt TKI. Refer to a dermatologist and resume afatinib at reduced dose (10 mg) if patient recovers to Grade 1: Oral antibiotic for 6 weeks (doxycycline 100 mg bid, minocycline 100 mg bid) If infection is suspected (yellow crusts, purulent discharge, or painful skin/nares): Switch oral antibiotic to broad spectrum/gramnegative cover Consider skin swab for bacterial culture Topical steroids* or tacrolimus ointment bd alternative

48 Paronychia 甲溝炎之治療可投予局部 20% 硝酸銀 (Silver nitrate) 溶液一周一次或亞硫酸鐵 (ferric subsulfate) 溶液每日浸泡緩衝以緩解症狀 疑似感染者該部位做微生物培養再投予合適之口服抗生素

49 Diarrhea CTCAE v3.0 grade-specific recommendations for the treatment of afatinib-associated diarrhoea Grade Description Specific intervention 1 Increase of <4 stools per day over baseline; mild increase in ostomy output compared with baseline 2 Increase of 4 6 stools per day over baseline; IV fluids indicated for <24 hours; moderate increase in ostomy output compared with baseline; not interfering with ADL 1. Stop laxatives 2. Drink 8 10 glasses of clear fluid QD 3. Immediately start loperamide; 4 mg (two tablets) followed by 2 mg (one tablet) after each loose stool (up to 16 mg/day) until bowel movements cease for 12 hours 1. See Grade 1 2. Continue loperamide; 3. Assess for dehydration and electrolyte imbalance; 4. Consider IV fluids and electrolyte replacement

50 CTCAE v3.0 grade-specific recommendations for the treatment of afatinib-associated diarrhoea Grade Description Specific intervention 3 Increase of 7 stools per day over baseline; incontinence; IV fluids >24 hours; hospitalization; severe increase in ostomy output compared with baseline; interfering with ADL 4 Life-threatening consequences (e.g. haemodynamic collapse) 1. See Grade 2 2. Plus: An infectious process should be ruled out with stool cultures; 3. Aggressive IV fluid replacement for 24 hours; 4. Hospitalization to monitor progress; 5. Consider prophylactic antibiotics if the patient is also neutropenic See Grade 3

51 Tolerance Starting dose 50mg daily 51 patients from LUX-Lung 1, 5 and compassionate use Starting dose of LUX-Lung 1, 5 and compassionate use: 50mg daily Afatinib-associated diarrhea generally occurred early during the treatment between the first 7 and 14 days.

52 Interstitial lung disease IPASS EURTAC Lux-Lung 3 Lux-Lung 6 2.6% 1.0% 1.6% 0.4%

53 Liver toxicity

54 Thanks for your attention