Lung Cancer. Karen Reckamp, MD Medical Director, Clinical Research. Click to edit Master Presentation Date

Transcription

1 Advances in Targeted Therapy for Lung Cancer Karen Reckamp, MD Medical Director, Clinical Research City of Hope Comprehensive Cancer Center Click to edit Master Presentation Date

2 Disclosures Consultant Amgen Ariad Astellas Euclises Nektar Research support (to institution) Ariad, Bristol Myers Squibb, Boehringer Ingelheim, Clovis, Eisai, Novartis, Pfizer, Xcovery, Adaptimmune, Medimmune, Stemcentrx

3 BACKGROUND

4 Evolution of NSCLC subtyping from histologic to molecular based Li T et al. JCO 2013;31:

5 Driver Mutation Incidence In Lung Cancers

6 Oncogene mutations and therapeutic options Oncogene Mutation prevalence Therapy Predicted response rate EGFR Asians 30-40%/ Caucasian 10-20% EGFR TKIs (most Erlotinib 60-80% mutations)/pan-her )p Gefitinib 70% inhibitors Afatinib 60% Osimertinib 50-60% (T790M) ALK 1-7% ALK inhibitors/hsp90 Crizotinib 50-60% inhibitors Ceritinib 60% Alectinib 60% KRAS Asians 10%/ Caucasian 30% possible MEK inhibition; CDK4/6 inhibition ROS1 1.7%, higher in Asians ALK inhibitors Crizotinib 60-70% HER2 2% Trastuzumab; pan-her inhibitors NA Dacomitinib 12% RET 1.7% (15% in RET inhibitors Cabozantinib 40% EGFR/ALK/KRAS-) BRAF 2% BRAF/MEK inhibitors Dabrafeninb 30% Dabraf/tremetinib 60% MET 10% Crizotinib/MET inhibitors 25% NTRK,1% Crizotinib/NTRK inhibitors NA

7 Why Does Testing Matter? Survival by Use of Targeted Therapy Genotype/Therapy Median OS, y 95% CI Oncologic driver + targeted therapy Oncologic di driver + no targeted t dtherapy No targeted therapy Kris et al, 2014.

8 TARGETING EGFR FIRST FIRST LINE

9 IPASS: PFS by EGFR Mutation Status Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217) PFS: gefitinib superior to carboplatin/paclitaxel in ITT population EGFR mutations strongly predicted PFS (and tumor response) to first- line gefitinib ib vs carboplatin/paclitaxel lit l EGFR Mutation Positive EGFR Mutation Negative ty of PFS Probabili Gefitinib Pac/carbo HR: 0.48 (95% CI: ; 0.64; P <.001) ity of PFS Probabili Gefitinib Pac/carbo HR: 2.85 (95% CI: ; P <.001) Mos Since Randomization Mos Since Randomization Mok TS, et al. N Engl J Med. 2009;361:

10 Randomized Studies of First-Line EGFR TKIs in Patients With EGFR Mutations Author Study Agent N (EGFR RR Median PFS OS (mo) mut +) (mo) Mok et al IPASS Gefitinib % vs 47.3% 9.8 vs vs 21.9 Han et al First-SIGNAL Gefitinib % vs 37.5% 8.0 vs vs 25.6 Mitsudomi et al WJTOG Gefitinib % vs 32.2% 9.2 vs vs NR 3405 Maemondo et al NEJGSG002 Gefitinib % vs 30.7% 10.8 vs vs 23.6 Zhou et al OPTIMAL Erlotinib % vs 36% 13.7 vs vs 28.9 Rosell et al EURTAC Erlotinib % vs 15% 9.7 vs vs 19.5 Sequist et al LUX-Lung 3 Afatinib % vs 23% 13.6 vs vs 26.2 Wu et al LUX-Lung 6 Afatinib % vs 23% 11.0 vs vs 22.2 Crossover to an EGFR TKI in the control group reduces any chance of an OS benefit EGFR, epidermal growth factor receptor; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; RR, response rate; TKI, tyrosine kinase inhibitor. Mok et al, 2009; Han et al, 2012; Mitsudomi et al, 2010; Maemondo et al, 2010; Zhou et al, 2011, 2012; Rosell et al, 2012; Sequist et al, 2013; Wu et al, 2013, 2014.

11 EGFR TKIs approved or in development Drug EGFR EGFR Exon EGFR L858R 19 del T790M gefitinib st gen erlotinib icotinib afatinib nd gen dacomitinib neratinib osimertinib (AZD9291) rd gen rociletinib (CO1686) EGF ASP BI AP ALK

12 Overall Survival (OS) in LUX-Lung 3 & 6 Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumor tissue* No prior treatment with chemotherapy for advanced/metastatic disease or EGFR inhibitors ECOG PS 0 or 1 Randomization 2:1 Stratification by EGFR mutation type: Del19/L858R/other & by race (LUX-Lung 3 only): Asian/non-Asian *EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A & G719C (or G719X), S768I. Afatinib 40 mg orally once daily LUX-Lung 3: Cisplatin + pemetrexed up to 6 cycles LUX-Lung Lung 6: Cisplatin + gemcitabine up to 6 cycles Primary endpoint: PFS (independent review) Secondary end points: ORR, DCR, OS, PRO, safety 1. Yang JCH et al. Lancet 2015;16:141; 2. Sequist et al. J Clin Oncol. 2013;31:3327; 3. Wu et al. Lancet Oncol. 2014;15:213.

13 Combined OS analysis: Mutation Categories Estim mated OS prob bability Del19 Afatinib Chemo n=236 n= Median, months HR (95%CI), p-value 0.59 ( ), p= Estim mated OS prob bability Median, months HR (95%CI), p-value L858R Afatinib n=183 Chemo n= ( ), p= Afatinib Chemo 0 No of patients Time (months) Time (months) No of patients Afatinib Chemo Yang JCH et al. Lancet 2015;16:141

14 Multi-study Comparison of PFS & OS in Del19 & L858R cancers in randomized trials 1. Sequist et al. J Clin Oncol. 2013; 2. Wu et al. Lancet Oncol. 2014; 3. Mok et al. N Engl J Med. 2009; 4. Fukuoka et al. J Clin Oncol. 2011; 5. Yang et al. Eur J of Cancer. 2011; 6. Maemondo et al. N Engl J Med. 2010; 7. Inoue et al. Ann Oncol Mitsudomi et al. Lancet Oncol. 2010;; 9. Rosell et al. Lancet Oncol. 2012; 10. TARCEVA (erlotinib) prescribing information, 2013; 11. Zhou et al. Lancet Oncol. 2011; 12. Wu et al. J Thorac Oncol

15 Comparative Toxicity LUX-Lung 3 Afatinib n=229 % EURTAC 1 Erlotinib n=84 % IPASS 2 Gefitinib n=607 % Grade 3 Grade 3 Grade 3 Diarrhea Rash/acne* Stomatitis/mucositis* 8.7 NR 0.2 Paronychia 11.4 NR 0.3 Decreased appetite Fatigue* Vomiting 4.4 NR 0.2 *Group term at least in one of the trials included in the table NR: not reported 1. Rosell R, et al. Lancet Oncol 2012;13: ; 2. Mok T, et al. N Engl J Med 2009;361:

16 Direct Comparisons of EGFR TKIs Ongoing Phase III Trials EGFR-mutated untreated EGFR-mutated untreated EGFR-mutated untreated ARCHER 1050 LUX Lung 7 FLAURA Dacomitinib vs Gefitinib N=440 Afatinib vs Gefitinib N=316 AZD9291 vs Erlotinib/Gefitinib N=650 OS PFS/OS PFS

17 LUX-Lung 7 Afatinib vs. Gefitinib Park K et al. Lancet Oncol 2016

18 LUX-Lung 7 Afatinib vs. Gefitinib Park K et al. Lancet Oncol 2016

19 LUX-Lung 7 Afatinib vs. Gefitinib Park K et al. Lancet Oncol 2016

20 Erlotinib vs Erlotinib + Bevacizumab in EGFR Mutant NSCLC (Phase II) NSCLC with sensitive EGFR El Erlotinib ib n = 75 mutations Stage IIIb/IV No prior chemo. PS 0-1 Erlotinib + Bev Primary endpoint PFS 2ndary endpoints OS Response n = 75 Side-effects Symptoms The sample size was calculated to be 150 in total (alpha = 0.2, power =.80) to confirm the superiority of Arm A (hazard ratio = 0.79). Seto M et al; Lancet Oncol 2014: 15:1236

21 Erlotinib vs Erlotinib + Bevacizumab in EGFR Mutant NSCLC (PFS/OS) PFS OS Seto M et al; Lancet Oncol 2014: 15:1236

22 TARGETING ALK

23 Timeline: ALK-Fusion in NSCLC EML4-ALK chromosomal rearrangements reported in NSCLC [1] Crizotinib antitumor activity in advanced cancers with EML4-ALK rearrangement [4] FDA approves crizotinib for treatment of ALK+ NSCLC [6] Preclinical studies document Crizotinib produces a antitumor activity it of ALK response in 47/82 ALK+ inhibitors in lung cancer cell patients and a 6-mo PFS lines and xenografts [2,3] of 72% [5] 1. Soda M, et al. Nature. 2007;448: McDermott U, et al. Cancer Res. 2008;68: Koivunen JP, et al. Clin Cancer Res. 2008;14: Kwak EL, et al. ASCO Abstract Kwak EL, et al. N Engl J Med. 2010;363: US Food and Drug Administration.

24 EML4/ALK Translocations Typical phenotype Young, male or female, never/scant smokers Adenocarcinoma ± signet ring morphology Poor response to EGFR TKI; conventional response to standard chemotherapy No overlap with EGFR mutation genotype Baseline (%) C hange From 100 ) Crizotinib in ALK-Positive NSCLC (N = 143) PD SD PR CR Camidge DR, et al. Lancet Oncol. 2012;13:

25 MORE TARGETS

26 ROS1 Rearrangements in NSCLC TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 LRIG3-ROS1 FIG-ROS1 First discovered in NSCLC in 2007 Also found in some GBMs, cholangiocarcinomas, and other tumor types Activated by chromosomal rearrangement, leading to constitute kinase activation and oncogene addiction No overlap with ALK ROS1 Bergethon et al., JCO 30(8): , 2012; Takeuchi et al., Nat Med 18(3): , 2012; Rimkunas et al., CCR 18(16): , 2012

27 Summary of ROS1 Anti-Tumor Efficacy in PROFILE 1001 Study Median PFS 19.2 months (95% CI, to NR) Shaw et al. NEJM 371(21): , 2014

28 Dabrafenib/Trametinib in BRAF mutated NSCLC Maximum Percent Redu uction at Time of Best Disease Assessment a 1 patient discontinued at day 23 and did not have any post-baseline scans for efficacy. Best Confirmed Response PR SD PD ORR = 63% and DCR = 88% for dabrafenib plus trametinib 1 ORR = 32% and DCR = 56% for dabrafenib as monotherapy 2 Baseline, October ) Johnson B WCLC 2015; 2) Planchard Lancet Oncol months (May 2015) Images courtesy of B. Johnson et al, Dana-Farber - Boston

29 All patients develop resistance Pre-TKI Response Progression Camidge et al., Lancet Onc 2012

30 EGFR RESISTANCE

31 Mechanisms of therapeutic resistance to kinase inhibitors Christine M. Lovly, and Alice T. Shaw Clin Cancer Res 2014;20:

32 Relative frequencies of mechanisms of EGFR TKI acquired resistance Yu H A et al. Clin Cancer Res 2013;19:

33 Mechanisms of Acquired Resistance to EGFR TKI therapy Secondary Alternative Other mutations pathways EGFR T790M HER2 amplification PD L1 EGFR L844V METamplification EMT EGFR L718Q mtorc1 Small cell transformation EGFR C797S AXL 1 (14.3) EGFR D761Y IGF1R EGFR T854A FGFR BRAF V600E STAT3 NRAS mutation PI3K Riely RIe; and abstract Yu Clin Cancer 8087Res 2015

34 Response to Osimertinib (AZD9291) Jänne PA et al. N Engl J Med 2015;372:

35 Therapy for EGFR + resistant NSCLC Study RR T790M + RR T790M - PFS Afatinib/Cetux 35% 28% 4.7 mo CO % ND increased AZD % 22% increased Grade 3 toxicity it Rash Diarrhea Hyperglycemia Afatinib/Cetux 97% 71% ND CO % 23% 22% AZD % 20% 1% Janjigian YY et al. Cancer Discov 2014; Sequist NEJM 2015; Janne NEJM 2015

36 Best timing for T790M inhibition? No T790M Low level of T790M Inhibition of sensitive mutations T790M Dominance (50%) Baseline (De Novo) Clonal Selection Clinical Resistance Is it best to address T790M at time of clinical resistance or early on (at baseline or through serial plasma monitoring)? adapted from T MOK

37 Detectable T790M at Baseline is Associated with a Worse PFS Maheswaran and Sequist et al NEJM 2009

38 AURA Phase I dose escalation/expansion: study design First-line cohort objective Escala ation Safety and tolerability of osimertinib (80 mg or 160 mg qd orally) as first-line therapy for patients t with ithegfrm advanced d NSCLC Cohort 1 20 mg Cohort 2 40 mg Negative Rolling six design Cohort 3 80 mg Negative Cohort mg Cohort mg Positive Positive Positive Positive Positive T790M Negative cohorts Key inclusion criteria: Aged 18 ( 20 in Japan) Locally advanced or metastatic NSCLC No prior therapy for advanced disease Measurable disease at baseline Patients must have EGFR mutation positive NSCLC (local test) Expansion First-line EGFRm 80 mg Biopsy Tablet First-line EGFRm 160 mg Biopsy Key exclusion criteria: Prior history of ILD Symptomatic brain metastases Cytology Data cut-off: 4 January 2016 Data from cohorts in grayed out boxes are not included in the analyses reported here ILD, interstitial lung disease; qd, once-daily dosing Ramalingam et al ELCC 2016 EUROPEAN LUNG CANCER CONFERENCE 2016

39 Summary of adverse events in osimertinib first-line cohorts AE category, all causality, n (%) Safety analysis set* 80 mg 160 mg Total n=30 n=30 N=60 Any AE 30 (100) 30 (100) 60 (100) Any AE Grade 3 13 (43) 15 (50) 28 (47) Any AE leading to death Any AE leading to dose interruption 8 (27) 9 (30) 17 (28) Any AE leading to dose reduction 3 (10) 14 (47) 17 (28) Any AE leading to discontinuation 4 (13) 2 (7) 6 (10) Any serious AE 11 (37) 7 (23) 18 (30) AE category, drug-related Any AE 29 (97) 30 (100) 59 (98) Any AE Grade 3 4 (13) 6 (20) 10 (17) Any AE leading to discontinuation 2 (7) 1 (3) 3 (5) Ramalingam Any serious et al AE ELCC (13) 1 (3) 5 (8) EUROPEAN LUNG CANCER CONFERENCE 2016

40 Tumor response to osimertinib in first-line cohorts (investigator assessed) ange arget ) est percentage ch om baseline in ta lesion size (%) Be fr D D D DD D D D D D D D D D DD 1 st line 80 mg 1 st line 160 mg D D D D D Confirmed ORR 67% (95% CI 47, 83) Disease control rate* Best objective response Complete response Partial response Stable disease 6 weeks Progressive disease 80 mg 160 mg Total n=30 n=30 N=60 87% (95% CI 69, 96) 77% (95% CI 64, 87) 93% 100% 98% (95% CI 78, 99) (95% CI 88, 100) (95% CI 89, 100) Population: evaluable for response; data cut-off: 4 January 2016 RECIST 1.1, programmatically calculated from investigator-recorded Ramalingam et al ELCC 2016 tumour measurement EUROPEAN LUNG CANCER CONFERENCE 2016 *Complete response, partial response, stable disease CI, confidence interval; D, discontinuation; ORR, objective response rate

41 PFS in osimertinib first-line cohorts S survival Probability of PF Number of patients at risk: 1 st line 80 mg 1 st line 160 mg Month mg n= mg n=30 Total N=60 Median PFS,* months (95% CI) NC (12.3, NC) (11.1, 19.3) (13.7, NC) Remaining alive and progressionfree, % (95% CI) 12 months 18 months Ramalingam et al ELCC (55, 88) 69 (49, 83) 72 (59, 82) 57 (36, 73) 53 (32, 70) 55 (41, 67)

42 Clinical outcome in patients with de novo T790M positive NSCLC A total of 5 (8%) patients had de novo T790M positive NSCLC at study entry (central testing)* Dose Gender, M/F Race Age, Best objective DoR, years response months 80 mg F Asian 50 Partial response mg F Ai Asian 60 Partial response mg F Caucasian 61 Partial response mg F Caucasian 49 Partial response mg M Asian 59 Partial response 18.0 Ramalingam et al ELCC 2016 *1 patient with single de novo T790M mutation without coexisting sensitising mutation, 4 patients EUROPEAN with T790M/L858R LUNG CANCER CONFERENCE 2016 co-existing sensitising mutation

43 FLAURA Study Design Enrollment by local* or central # EGFR mutation testing of biopsy sample Stratified by: Asian / non-asian Ex19del / L858R AZD9291 (80 mg p.o. qd) Randomize patients 1:1 EGFR-TKI standard of care ## : gefitinib (250 mg p.o. qd) or erlotinib (150 mg p.o. qd) RECIST 1.1 assessment every 6 weeks until objective progressive disease Patients randomized to standard of care may receive AZD9291 after progression Primary objective: efficacy by PFS *With central laboratory assessment performed for sensitivity # cobas EGFR Mutation Test (Roche Molecular Systems) ## Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation Patients randomized to the standard of care treatment arm may receive open-label treatment with AZD9291 on central confirmation of both objective disease progression and T790M p Patients randomized to the standard of care treatment arm may receive open-label treatment with AZD9291 on central confirmation of both objective disease progression and T790M p tumor OS, overall survival; PFS2, second progression-free survival (time from randomization to second progression); p.o., orally

44 Phase II/III trial of Afatinib +/- Cetuximab in 1 st line therapy of EGFR-mutated NSCLC (S1403) Stage IIIB IV NSCLC with EGFR mutation 1 st Line EGFR TKI naive R A N D O M I Z A T I O N Afatinib* Afatinib + Cetuximab* *at PD: Biopsy for genomic study & PDX development t( (selected patients) t PD: Progressive Disease PDX: patient derived xenograft PI: Sarah Goldberg Co-PI: Rogerio Lilenbaum Translational PI: Katerina Politi

45 ALK RESISTANCE

46 Mechanisms of acquired resistance to ALK inhibitor therapy Ryohei Katayama et al. Clin Cancer Res 2015;21:

47 Next-generation ALK TKIs ALK TKI Status Ongoing Studies Ceritinib FDA Approved Phase 3 v. chemo Alectinib Approved in Japan & US Phase 3 v. crizotinib Brigatinib Investigational FDA Breakthrough Phase 2 X-396 Investigational Phase 1/2a TSR-011 Investigational Phase 1/2a RXDX-101 Investigational Phase 1/2a PF Investigational Phase ½ CEP Investigational Phase 1

48 Response to Ceritinib, most post crizotinib Shaw AT et al. N Engl J Med 2014;370:

49 PFS with alectinib in crizotinib-resistant ALK+ NSCLC patients 100 Progre ession free survival Overall population (N=138) Censored Median PFS 8.9 months (95% CI ) 58% of patients with event No. at Time (months) Overall risk: ik 17 1 population Updated analysis cut off 8 Jan 2015 Gadgeel SM Lancet Oncol 2014; Ou SH J Clin Oncol 2015 (abstract 8008)

50 S1400: MASTER LUNG-1 Squamous Lung Cancer Matched Sub-studies Non-match Sub-studies PI3K CDK4/ 6 FGFR 1 HRD Checkpoint Naive Checkpoint Refractory Stage 1 GDC 0032 Palbociclib AZD4547 BMN 673* Nivo/Ipi MEDI4736/ Nivolumab Treme* Stage 2 GDC 0032 Vs SoC Palbociclib Vs Soc AZD4547 Vs SoC BMN 673 Vs SoC* Lung-MAP amended to 2 nd line therapy and beyond to accommodate Nivolumab approval Pre-screening added back Eligibility criteria broadened; *Sub-studies in development 50

51 LIQUID BIOPSY

52 TISSUE will always be the ISSUE

53 CTDNA TECHNOLOGIES HIGHLY SENSITIVE; LESS CUMBERSOME THAN CTC DETECTION

54 Slide 6

55 POTENTIAL ADVANTAGES OF PLASMA-BASED TESTING

56 TECHNOLOGIES FOR DETECTION OF CT-DNA

57 PLASMA-BASED TESTING READY FOR PRIME TIME?

58 COMPARISON OF METHODS OF CTDNA DETECTION Presented By Melissa Johnson at 2016 ASCO Annual Meeting

59 Slide 11

60 Slide 12

61 Plasma ddpcr assay characteristics

62 Slide 15

63 MONITORING TREATMENT RESPONSES

64 Analysis of EGFR T790M in tumor, urine and plasma A Urine vs Tissue D ml urine T790M FFPE Tumor, n Positive Negative Inadequate Total Urine, n Positive Negative Total B Plasma vs Tissue T790M FFPE Tumor, n Positive Negative Inadequate Total Positive Plasma, n Negative Failed Total C T790M-positive cases Tissue Plasma Urine Positive by any one specimen type: 56 of 60 (93%) Positive by tissue: 44 of 60 (73%) Positive by plasma: 49 of 60 (82%) Positive by urine: 45 of 60 (75%) Positive by urine and plasma combined: 56 of 60 (93%) Urine vs Plasma Negative by any one specimen type: 4 of 60 (7%) ml urine T790M Plasma, n Positive Negative Failed Total Urine, n Positive Negative Total Reckamp et al. J Thorac Oncol 2016

65 Dynamic monitoring of EGFR T790M during therapy with rociletinib A Ur rine T790M (% Baseline) Baseline Day 21 Day 42 Day 63 Day 84 Day 105 Pt 2 B % Change in % Tumor Best Overall Pt 6 Urine T790M at Shrinkage at Confirmed Patient Day 21 Day 42 Response Pt * 38 PR Pt SD Pt PD Pt SD Pt SD Pt SD Pt PD SD PR Treatment Days Reckamp et al. J Thorac Oncol 2016

66 READY FOR PRIME TIME?--NOT YET

67 Slide 18

68 SUMMARY

69 Patients respond to multiple therapies and sequencing can improve outcomes 1 st gen 3 rd gen Chemo mo 8-10 mo 4 Immunotherapy 3+? 3rd gen 19 mo 1 st gen Chemo Immunotherapy unknown 4+ 3+? 1 st gen/bev or combination 16 mo 3 rd gen Immunotherapy Chemo 7-13 mo 3++? 4+

70 Summary / Future Directions With tumor heterogeneity in NSCLC, options for targeted therapy and overcoming resistance may become more personalized Patterns of resistance will help to guide subsequent therapy, and choice of first-line therapy Liquid biopsies will allow for sequencing after progression Improved survival with maintained quality of life is the ultimate goal and sequencing will be important New targets and agents are under investigation and New targets and agents are under investigation and show promise: NTRK, MET, RET

71 Questions? THANK YOU