Treatment of EGFR mutant advanced NSCLC

Transcription

1 Treatment of EGFR mutant advanced NSCLC Raffaele Califano Department of Medical Oncology The Christie and Manchester University Hospital Manchester, UK

2 Outline Data on first-line Overcoming T790M mutation Conclusion

3 EGFR-TKIs in pre-treated NSCLC patients ISEL BR.21 Thatcher et al, Lancet 2005; Shepherd et al, NEJM 2005,

4 EGFR activating mutations Lynch et al, NEJM 2004

5 EGFR activating mutations Sharma et al, Nat Rev Cancer 2007

6 Gefitinib

7 IPASS Trial Never or light ex-smoker with adenocarcinoma PS 0 2 Stage IIIB or IV chemo-naive NSCLC N=1217 R A N D O M I Z E Gefitinib (250 mg/day) Carboplatin/Paclitaxel up to 6 cycles Mok et al, NEJM 2009

8 PFS in ITT population Probability of PFS Gefitinib Carboplatin / paclitaxel 5.7 vs 5.8 months Months At risk : Gefitinib Carboplatin / paclitaxel

9 IPASS - Biomarker analysis N=1217 (100%) N=1038 biomarker consent (85%) N=683 provided samples (56%) N=437 evaluable for EGFR mutation (36%)

10 Probability of progression-free survival Probability of progression-free survival PFS in EGFR M+ and M- EGFR mutation positive EGFR mutation negative 1.0 Gefitinib (n=132) Carboplatin / paclitaxel (n=129) 1.0 Gefitinib (n=91) Carboplatin / paclitaxel (n=85) 0.8 HR (95% CI) = 0.48 (0.36, 0.64) p< HR (95% CI) = 2.85 (2.05, 3.98) p< vs 6.3 months At risk : Gefitinib C / P Months Months Treatment by subgroup interaction test, p< ITT population Cox analysis with covariates

11 Overall Survival Probability of survival Gefitinib Carboplatin / paclitaxel 18.8 vs 17.4 months HR 0.90; P = Months At risk : 24 Gefitinib Carboplatin / paclitaxel

12 ORR in EGFR M+ and WT

13 % patients with sustained clinically relevant improvement Quality of life p= p< p=0.3037

14 Gefitinib in Asian Studies EGFR M+ Study N Regimen RR (%) PFS HR NEJ G C/P WJTOG G C/D Maemondo et al, NEJM 2010; Mitsudomi et al, Lancet Oncol 2010

15 Erlotinib

16 Erlotinib in EGFR M+ Study N Regimen RR (%) PFS HR OPTIMAL 165 E C/G EURTAC 174 E Platinum doublet Zhou et al, Lancet Oncol 2011; Rosell et al, Lancet Oncol 2012;

17 Afatinib

18 LUX-LUNG 3 Stage IIIB/IV Adeno PS 0 1 Chemotherapy-naïve EGFR mutant (n=345) R 2:1 Afatinib 40mg OD (n=230) Pemetrexed/Cisplatin q21d up to 6 cycles (n=115) Primary endpoint: PFS (IRR) Sequist LV, et al, JCO 2013

19 LUX-LUNG 6 Stage IIIB/IV PS 0 1 Chemotherapy-naïve EGFR mutant (n=364) Primary endpoint: PFS (IRR) Only East Asia R 2:1 Afatinib 40mg OD (n=242) Cisplatin/Gemcitabine up to 6 cycles (n=122) Wu Y-L, et al, Lancet Oncol 2014

20 LUX-Lung 3 and 6 Efficacy LUX-LUNG 3 LUX-LUNG 6 Afatinib n=230 Cis/pem n=115 Afatinib n=242 Cis/gem n=122 ORR (%) Median PFS (mos) HR (95% CIl) 0.58 ( ) p= ( ) P<0.0001

21 Other Endpoints Better tolerated Symptom control Afatinib arm Global health status/qol

22 LUX-Lung 3 and 6: Updated OS LUX-Lung 3 (n=345) LUX-Lung 6 (n=364) Recruitment period Aug 09 Feb 11 Apr 10 Nov 11 Primary PFS analysis Feb 12 (221 events) Oct 12 (221 events) Required maturity of OS At least 209 events At least 237 events OS analysis Dec 13 (213 events; 61.7%) Jan 14 (246 events; 67.6%) Median OS follow-up 41 months 33 months OS result, overall population 28.2 vs 28.2 months HR=0.88, p= vs 23.5 months HR=0.93, p= Yang, et al, Lancet Oncol 2015

23 Trials of EGFR-TKIs vs CT in M+ Study N Median PFS (mos) Median OS (mos) TKI Chemo HR (95 % CI) TKI Chemo IPASS ( ) First Signal ( ) NEJ ( ) WJTOG ( ) OPTIMAL ( ) EURTAC ( ) LUX-LUNG ( ) LUX-LUNG (

24 What s the best EGFR-TKI?

25 Lux-Lung 7 Stage IIIB/IV adenocarcinoma EGFR mutation (Del19 and/or L858R) No prior treatment for advanced/ metastatic disease ECOG PS 0/1 N= 319 1:1 Afatinib 40 mg OD Stratified by Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 250 mg OD Treatment beyond progression allowed Primary endpoints: PFS (IRR), TTF, OS Paz-Ares et al, Ann Oncol 2017

26 Efficacy PFS (months) TTF (months) OS (months) Afatinib (n=160) Gefitinib (n=159) HR (95%CI) ( ) ( ) ( ) p

27 ORR and DOR p= % 56% Median DoR (mos) Afatinib (n=112) Gefitinib (n=89) % CI ( ) ( ) Afatinib n=112/160 Gefitinib n=89/159

28 Adverse Events Events, % Afatinib (n=160) Gefitinib (n=159) Any AE Drug-related AEs AEs leading to dose reduction* * Drug-related AEs leading to discontinuation Serious AEs Drug-related serious AEs Drug-related fatal AE *No dose reductions foreseen for gefitinib according to prescribing information Including four patients with drug-related ILD (no drug-related ILD on afatinib) One patient died of hepatic failure

29 ARCHER 1050 Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 No brain metastases N=440 R A N D O M I Z E Dacomitinib 45mg qd Gefitinib 250mg qd Primary endpoint: PFS Wu et al, lancet oncology 2017

30 ARCHER 1050: PFS (IRR)

31 SAEs and dose modification Outcome Serious AE, n (%) Any Treatment related Causing discontinuation Causing death Median duration of dose reduction, mos (range) Reduced dose given, n (%) 30 mg/day 15 mg/day Dacomitinib (n = 227) 62 (27.3) 21 (9.3) 22 (9.7) 2 (0.9) Gefitinib (n = 224) 50 (22.3) 10 (4.5) 15 (6.7) 1 (0.4) 11.3 ( ) 5.2 ( ) 87 (38.3) 63 (27.8) Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0) NA

32 Mechanism of resistance to 1 st /2 nd generation EGFR-TKIs Camidge DR et al. Nat Rev Clin Oncol. 2014

33 Tackling T790M resistance mutation

34 Osirmetinib wt EGFR EGFRm T790M TAGRISSO Potential to Inhibition of T790M Inhibition of EGFRm Low activity on wt EGFR Overcome resistance Continue targeting sensitizing mutations Lower incidence of rash and diarrhoea Cross DAE, et al. Cancer Discovery 2014

35 Phase I Osirmetinib Clinical development AURA Ph I/II Patients with T790M-positive ansclc whose disease has progressed following either one prior therapy with an EGFR-TKI or following treatment with both EGFR-TKI and other anticancer therapy Rolling six design AURA2 Ph II Patients with confirmed EGFRm locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR-TKI Escalation Cohort 1 20 mg Cohort 2 40 mg Cohort 3 80 mg n=63 Cohort mg Cohort mg Positive Positive Positive Positive Positive Negative Negative Negative Central T790M mutation testing* of biopsy sample collected following confirmed disease progression Expansion First-line Biopsy Tablet Cytology First-line Biopsy T790M positive T790M negative AURA Phase II Extension (n=201) Osimertinib 80 mg QD Pooled Phase II AURA2 (n=210) Osimertinib 80 mg QD Not eligible for enrollment Janne PA et al, NEJM 2015; Goss et al, Lancet Oncol 2016

36 Probability of PFS Probability of PFS Progression-Free Survival AURA Ph I AURA pooled Ph II Number of patients at risk: Osimertinib 80 mg Month Number of patients at risk: Month Osimertinib 80 mg AURA Ph I (80 mg) N=63 AURA pooled Ph II (80 mg) N=411 Median PFS *, months (95% CI) 9.7 (8.3, 13.6) 11.0 (9.6, 12.4) Remaining alive and progression-free, % (95% CI) 12 months 18 months 24 months 41 (29, 53) 29 (18, 41) 17 (8, 30) 48 (42, 53) NC NC Yang JCH, et al. ELCC 2016

37 Adverse Events AE category, all causality, n (%) AURA Ph I (80 mg) N=63* AURA pooled Ph II (80 mg) N=411 Any AE 62 (98) 406 (99) Any AE Grade 3 29 (46) 149 (36) Any AE leading to death 1 (2) 14 (3) Any AE leading to dose interruption 16 (25) 87 (21) Any AE leading to dose reduction 1 (2) 16 (4) Any AE leading to discontinuation 3 (5) 26 (6) Any serious AE 18 (29) 107 (26) AE category, causally-related Any AE 57 (91) 364 (89) Any AE Grade 3 11 (18) 56 (14) Any AE leading to discontinuation 0 16 (4) Any serious AE 3 (5) 23 (6) Yang JCH, et al. ELCC 2016

38 AURA3 study Key eligibility criteria Locally advanced or metastatic NSCLC Evidence of disease progression following first-line EGFR-TKI therapy Documented EGFRm and central confirmation of tumour EGFR T790M mutation after firstline EGFR-TKI treatment PS 0 or 1 No more than one prior line of treatment for advanced NSCLC Stable asymptomatic CNS metastases allowed R 2:1 Osimertinib 80 mg OD (n=279) Platinumpemetrexed +/- maintenance pemetrexed (n=140) Endpoints Primary: PFS by investigator assessment (RECISTv1.1) Secondary and exploratory: OS ORR DoR DCR Tumour shrinkage BICR-assessed PFS PROs Safety and tolerability Optional crossover: Protocol amendment allowed patients on chemotherapy to begin post- BICR confirmed progression open-label osimertinib treatment Mok TS et al, NEJM 2016

39 Probability of Progression-free Survival Progression-free Survival (investigator) Osimertinib (n=279) Platinum-pemetrexed (n=140) Median PFS (95% Cl) 10.1 ( ) 4.4 ( ) HR for disease progression or death, 0.30 (95% Cl, ) P< Months

40 Response Rate Osimertinib (n=279) Platinumpemetrexed (n=140) ORR, % (95% CI) 71% (65, 76) 31% (24, 40) Odds ratio* (95% CI) Complete response, n (%) Partial response, n (%) Stable disease 6 weeks, n (%) Progression, n (%) RECIST progression, n (%) Death Not evaluable, n (%) 5.39 (3.47, 8.48); P< (1) 193 (69) 63 (23) 18 (6) 15 (5) 3 (1) 1 (<1) 2 (1) 42 (30) 60 (43) 26 (19) 22 (16) 4 (3) 10 (7) DCR, % (95% CI) 93 (90, 96) 74 (66, 81) Odds ratio (95% CI) Median time to response, weeks (95% CI) 4.76 (2.64, 8.84); P< (NC, NC) 6.4 (6.3, 7.0) Median DoR, months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6)

41 Safety AE category*, n (%) Osimertinib (n=279) Platinum-pemetrexed (n=136) Any AE 273 (98) 135 (99) Any AE Grade 3 63 (23) 64 (47) Any AE leading to death 4 (1) 1 (1) Any serious AE 50 (18) 35 (26) Any AE leading to discontinuation 19 (7) 14 (10) AE category, possibly causally related, n (%) Any AE 231 (83) 121 (89) Any AE Grade 3 16 (6) 46 (34) Any AE leading to death 1 (<1) 1 (1) Any serious AE 8 (3) 17 (13) Any AE leading to discontinuation 10 (4) 12 (9)

42 Adverse Events N (%) 15% cut-off Osimertinib (n=279) Platinum-pemetrexed (n=136) Any grade Grade 3 Any grade Grade 3 Any AE 273 (98) 63 (23) 135 (99) 64 (47) Diarrhoea 113 (41) 3 (1) 15 (11) 2 (1) Rash 94 (34) 2 (1) 8 (6) 0 Dry skin 65 (23) 0 6 (4) 0 Paronychia 61 (22) 0 2 (1) 0 Decreased appetite 50 (18) 3 (1) 49 (36) 4 (3) Cough 46 (16) 0 19 (14) 0 Nausea 45 (16) 2 (1) 67 (49) 5 (4) Fatigue 44 (16) 3 (1) 38 (28) 1 (1) Stomatitis 41 (15) 0 21 (15) 2 (1) Constipation 39 (14) 0 47 (35) 0 Vomiting 31 (11) 1 (<1) 27 (20) 3 (2) Thrombocytopaenia 28 (10) 1 (<1) 27 (20) 10 (7) Neutropaenia 22 (8) 4 (1) 31 (23) 16 (12) Leukopenia 22 (8) 0 20 (15) 5 (4) Anaemia 21 (8) 2 (1) 41 (30) 16 (12) Asthenia 20 (7) 3 (1) 20 (15) 6 (4) Select adverse events Interstitial lung disease 10 (4) 1 (<1) 1 (1) 1 (1) QT prolongation 10 (4) 1 (<1) 1 (1) 0

43 FLAURA Patients with locally advanced or metastatic NSCLC Key inclusion criteria 18 years* WHO performance status 0 / 1 Exon 19 deletion / L858R (enrolment by local # or central EGFR testing) No prior systemic anti-cancer / EGFR-TKI therapy Stable CNS metastases allowed Stratification by mutation status (Exon 19 deletion / L858R) and race (Asian / non-asian) Osimertinib (80 mg p.o. qd) (n=279) Randomised 1:1 EGFR-TKI SoC ; Gefitinib (250 mg p.o. qd) or Erlotinib (150 mg p.o. qd) (n=277) RECIST 1.1 assessment every 6 weeks until objective progressive disease Crossover was allowed for patients in the SoC arm, who could receive open-label osimertinib upon central confirmation of progression and T790M positivity Primary endpoint: PFS (investigator) Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety Soria JC et al, NEJM 2017

44 Probability of progression-free survival Progression-free Survival Median PFS, months (95% CI) Osimertinib 18.9 (15.2, 21.4) SoC 10.2 (9.6, 11.1) HR 0.46 (95% CI 0.37, 0.57) p< No. at risk Osimertinib SoC Time from randomisation (months)

45 Safety AE, any cause, n (%) Osimertinib (n=279) SoC (n=277) Any AE 273 (98) 271 (98) Any AE Grade 3 94 (34) 124 (45) Any AE leading to death 6 (2) 10 (4) Any serious AE 60 (22) 70 (25) Any AE leading to discontinuation Safety 37 (13) 49 (18) AE, possibly causally related, n (%) Any AE 253 (91) 255 (92) Any AE Grade 3 49 (18) 78 (28) Any AE leading to death 0 1 (<1) Any serious AE 22 (8) 23 (8)

46 Safety AEs n (%) Diarrhoea Any grade 161 (58) Osimertinib (n=279) Grade 1 Grade 2 Grade 3 Grade (43) 35 (13) 6 (2) 0 Any grade 159 (57) SoC (n=277) Grade 1 Grade 2 Grade 3 Grade (42) 35 (13) 6 (2) 0 Dry skin 88 (32) 76 (27) 11 (4) 1 (<1) 0 90 (32) 70 (25) 17 (6) 3 (1) 0 Paronychia 81 (29) 37 (13) 43 (15) 1 (<1) 0 80 (29) 46 (17) 32 (12) 2 (1) 0 Stomatitis 80 (29) 65 (23) 13 (5) 1 (<1) 1 (<1) 56 (20) 47 (17) 8 (3) 1 (<1) 0 Dermatitis acneiform Decreased appetite 71 (25) 61 (22) 10 (4) (48) 71 (26) 50 (18) 13 (5) 0 56 (20) 27 (10) 22 (8) 7 (3) 0 51 (18) 24 (9) 22 (8) 5 (2) 0 Pruritis 48 (17) 40 (14) 7 (3) 1 (<1) 0 43 (16) 30 (11) 13 (5) 0 0 Cough 46 (16) 34 (12) 12 (4) (15) 25 (9) 16 (6) 1 (<1) 0 Constipation 42 (15) 33 (12) 9 (3) (13) 28 (10) 7 (3) 0 0 AST increased 26 (9) 18 (6) 6 (2) 2 (1) 0 68 (25) 38 (14) 18 (6) 12 (4) 0 ALT increased 18 (6) 11 (4) 6 (2) 1 (<1) 0 75 (27) 31 (11) 19 (7) 21 (8) 4 (1)

47 Take Home Message EGFR-TKIs are standard of care in EGFR M+ Look for T790M resistance mutation Osirmetinib: a new option for 1 st line treatment

48 Backup Slides

49 Aura 3 EGFR Plasma ctdna Patients with tissue sample available at screening (n=756) Plasma ctdna test results, n Tissue T790M positive (n=399) Tissue Exon 19 deletion positive (n=427) Tissue L858R positive (n=253) Plasma positive Plasma negative No plasma test / invalid 37 / 3 91 / 3 47 / 0 Percent agreement using tissue test as reference, % (95% CI) * Positive percent agreement (sensitivity) Negative percent agreement (specificity) 51 (46, 57) 82 (77, 86) 68 (61, 74) 77 (71, 83) 98 (96, 100) 99 (98, 100) Overall concordance 61 (57, 65) 89 (86, 91) 88 (85, 90)

50 Probability of progression-free survival Probability of progression-free survival AURA3: Efficacy in pts with plasma and tumour tissue T790M+ status Tumour T790M-positive (ITT) PFS HR (95% CI) Median PFS, months (95% CI) Osimertinib Platinumpemetrexed Platinumpemetrexed 0.30 (0.23, 0.41)*, p< (8.3, 12.3) 4.4 (4.2, 5.6) ORR, % (95% CI) 71 (65, 76) 31 (24, 40) Plasma T790M-positive status Osimertinib PFS HR (95% CI) 0.42 (0.29, 0.61) Median PFS, months (95% CI) 8.2 (6.8, 9.7) 4.2 (4.1, 5.1) ORR, % (95% CI) 77 (68, 84) 39 (27, 53) Osimertinib (n=279) Platinum-pemetrexed (n=140) Osimertinib (n=116) Platinum-pemetrexed (n=56) Months Months

51 AURA3 Subgroup analysis CNS mets cfas Pts with measurable and/or nonmeasurable CNS metastases cefr Pts with 1 measurable CNS metastases Key Eligibility Criteria: Locally advanced or metastatic NSCLC Disease progression following first-line EGFR TKI therapy Documented EGFRm and central confirmation of tumour EGFR T790M mutation after first-line EGFR TKI No more than 1 prior line of treatment for advanced NSCLC Stable* asymptomatic CNS metastases allowed R 2:1 Osimertinib 80 mg orally once daily n = 279 Platinumpemetrexed n = 140 CNS metastases n = 75 (27%) CNS metastases n = 41 (29%) 1 measurable CNS metastases n = 30 (11%) 1 measurable CNS metastases n = 16 (11%) N = 419 n = 116 (28%) CNS tumour assessment by BICR ENDPOINTS CNS PFS by RECIST v1.1 ENDPOINTS CNS ORR CNS duration of response 1. Mok TS, et al. N Engl J Med. 2017; 376: Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:

52 Probability of Progression-free Survival Probability of Progression-free Survival AURA3: PFS in patients with or without CNS metastases at baseline With CNS metastases 1 Without CNS metastases 10.8 ( ) 2 Median PFS, months (95% Cl) Osimertinib (n=93) 8.5 ( ) Platinum-pemetrexed 4.2 ( ) (n=51) Hazard ratio for disease progression or death, 0.32 (95% Cl, ) Osimertinib (n=186) Platinum-pemetrexed (n=89) Hazard ratio for disease progression or death, 0.40 (95% Cl, ) Median PFS, months (95% Cl) 5.6 ( ) No. at risk Osimertinib 0 Platinumpemetrexed Months Months Mok TS, et al. N Engl J Med. 2017; 376: Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:

53 AURA 3: subgroup analysis CNS metastases Osimertinib 80 mg n = 30 Chemotherapy n = 16 CNS ORR (95% CI) 70% (51-85) 31% (11-59) Odds ratio (95% CI) 5.13 ( ); P =.015 Median time to response, wk Median DoR, mo (95% CI) 8.9 (4.3-NC) 5.7 (NC-NC) DCR (95% CI) 93% (78-99) 63% (35-85) Patients with CNS metastases were stable and asymptomatic 1. Mok TS, et al. N Engl J Med. 2017; 376: Suppl. Info for: Mok TS, et al. N Engl J Med. 2017; 376:

54 AURA3: competing risk analysis The probability of experiencing a CNS progression event was lower for osimertinib than for chemotherapy at both 3 and 6 months a a conditional on the patient not experiencing a competing risk at that time. Mok T. et al. Presented at ASCO Annual Meeting 2-6 June 2017; Chicago, IL USA. J Clin Oncol. 2017;35 suppl:abstr 9005.

55 Estimated OS probability Estimated OS probability LUX-Lung 3 and 6: OS in common mutations Median, months HR (95%CI), p-value LUX-Lung 3 Afatinib n=203 Pem/Cis n= ( ), p= Median, months HR (95%CI), p-value LUX-Lung 6 Afatinib n=216 Gem/Cis n= ( ), p= Time (months) Time (months)

56 Estimated OS probability Estimated OS probability OS in Del19 subgroup 1.0 Median, months HR (95%CI), p-value LUX-Lung 3 Afatinib n=112 Pem/Cis n= ( ), p= Median, months HR (95%CI), p-value LUX-Lung 6 Afatinib n=124 Gem/Cis n= ( ), p= Time (months) Time (months)

57 Estimated OS probability Combined OS analysis: common mutations (n=631) Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value 0.81 ( ), p= Time (months)

58 Estimated OS probability Estimated OS probability Combined OS analysis: mutation categories Median, months HR (95%CI), p-value Del19 Afatinib n=236 Chemo n= ( ), p= Median, months HR (95%CI), p-value L858R Afatinib n=183 Chemo n= ( ), p= Time (months) Time (months)

59 Treatment at progression LUX-Lung 3 LUX-Lung 6 Afatinib (n=203) Pem/Cis (n=104) Afatinib (n=216) Gem/Cis (n=108) Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100) Subsequent systemic therapy, n (%) 144 (78) 88 (85) 123 (63) 70 (65) Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27) EGFR TKI therapy, n (%) 81 (44) 78 (75) 50 (26) 61 (56) Erlotinib Gefitinib Afatinib AZD9291 Dacomitinib Icotinib EGFR TKI combinations 61 (33) 28 (15) 2 (1) 2 (1) 5 (3) 46 (42) 44 (42) 7 (7) 1 (1) 1 (1) 9 (9) 21 (11) 19 (10) 11 (6) 5 (3) 22 (20) 39 (36) 3 (3) 3 (3) Other systemic therapy, n (%) 5 (3) 2 (2) 3 (2) 4 (4) Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0)