Is advanced lung cancer becoming a chronic disease?

Transcription

1 Is advanced lung cancer becoming a chronic disease? James Chung-Man HO ( 何重文 ) M.D. FRCP Associate Professor, The University of Hong Kong Honorary Consultant, Department of Medicine Specialist in Respiratory Medicine Queen Mary Hospital, Hong Kong 1

2 Disclosures Received honoraria for lectures or served as advisory board consultant for AstraZeneca, BMS, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, and MSD Received research funding from Roche and AstraZeneca

3 Outline of Lecture Lung cancer statistics Advances in anticancer options Current management algorithm of advanced non-small cell lung cancer Conclusions 3

4 4

5 Incidence rate: 2014 HK Cancer Registry 5

6 Mortality rate: 2014 HK Cancer Registry 6

7 Incidence of lung cancer in HK: Male (ASR) 18% HK Cancer Registry 7

8 Mortality of lung cancer in HK: Male (ASR) 27% HK Cancer Registry 8

9 Incidence of lung cancer in HK: Female (ASR) 9% HK Cancer Registry 9

10 Incidence of lung cancer in HK: Female (ASR) 15% HK Cancer Registry 10

11 Survival rates for lung cancer (stage III/IV): QMH Resp N=44 N=54 N=66 N=79 N= % adenocarcinoma Mean age yrs Unpublished data 11

12 12

13 PKC: clinical presentation M/62 Chronic cough Chest Xray: L lung shadow in Aug 2013 Workup confirmed lung adenocarcinoma (EGFR L858R + T790M) 13

14 Driver mutations in NSCLC are heavily influenced by ethnicity Japan 2 France 1 China 3 EML4- ALK 7% KRAS 7% MET 5% BRAF 2% PTEN 6% Unknown 29% EGFR 40% 1. Barlesi F et al. Lancet 2016;387: ; 2. Mitsudomi T. Jpn J Clin Oncol 2010;40:101 6; 3. Wu YL, Ann Oncol 2011;22 (suppl 9):Abstract

15 Spectrum of EGFR Mutations EGFR Gene Tyrosine Kinase Domain Exons Sensitivity Exon 18 Exon 19 Exon 20 Exon 21 G719C G719S G719A 5% Del E746-A750 Del E746_S752>V Del E746_T751>A Del E746_T751 Del L747_A750>P Del L747_E749 Del L747_P753>Q Del L747_P753>S Del L747_S752 Del L747_T751>P Del L747_T751 Del S752_I759 & additional deletions ~45% T790M D770_N771 (ins NPG) D770_N771 (ins SVQ) D770_N771 (insg) S768I ~5% Lynch et al., 2004 Paez et al., 2004 Sharma et al., 2007 Hirsch and Bunn, 2009 L858R L861Q ~45% Resistance 15

16 EGFR TKIs vs Chemotherapy in EGFR M+ NSCLC (1L) EGFR TKI Trial N EGFR mutaiton IPASS ORR* (%) 71 vs 47 P<0.001 PFS* (months) 9.5 vs 6.3 HR 0.48 ( ) OS* (months) 21.6 vs 21.9 HR 1.00 ( ) Gefitinib NEJ vs 31 P< vs 5.4 HR 0.32 ( ) 27.7 vs 26.6 HR 0.89 ( ) First Generation TKI WJTOG EURTAC vs 32 P< vs 15 P-value NR 9.2 vs 6.3 HR ( ) 9.7 vs 5.2 HR 0.37 ( ) 36 vs 39 HR 1.19 ( ) 22.9 vs 19.6 HR 0.92 ( ) Erlotinib OPTIMAL vs 36 P< vs 4.6 HR 0.16 ( ) 22.8 vs 27.2 HR 1.19 ( ) ENSURE vs 34 P= vs 5.6 HR 0.42 ( ) 26.3 vs 25.5 HR 0.91 ( ) Second Generation TKI Afatinib LUX-Lung LUX-Lung vs 44 P= vs 31 P< vs 6.9 HR 0.41 ( ) 13.7 vs 5.6 HR 0.26 ( ) 31.6 vs 28.2 HR 0.78 ( ) 23.6 vs 23.5 HR 0.83 ( ) PFS = progression-free survival; OS = overall survival. *Results described refer to common mutations only. Mok TS et al. N Engl J Med. 2009;361:947-57; Fukuoka M et al. J Clin Oncol. 2011;29: ; Maemondo M et al. N Engl J Med. 2010;362: ; Mitsudomi T et al. Lancet Oncol. 2010;11:121-8; Yoshioka H et al. J Clin Oncol. 2014;32(suppl):abstract 8117; Rosell R et al. Lancet Oncol. 2012;13:239-46; Leon L et al. ESMO Abstract 1273P; Zhou CC et al. Lancet Oncol. 2011;12:735-42; Zhou CC et al. J Clin Oncol. 2012;30(suppl):abstract 7520; Wu YL et al. Ann Oncol. 2015;26:1883-9; Sequist LV et al. J Clin Oncol. 2013;31: ; Wu YL et al. Lancet Oncol. 2014;15:213-22; Yang JC et al. Lancet Oncol 2015;16:

17 PFS in EGFR mutation positive and negative lung adenoca: IPASS EGFR mutation positive EGFR mutation negative Probability of progression-free survival Gefitinib (n=132) Carboplatin/paclitaxel (n=129) HR (95% CI) = 0.48 (0.36, 0.64) p< No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Median PFS G, 9.5 months Median PFS C/P, 6.3 months Patients at risk : Months Gefitinib C/P Probability of progression-free survival Gefitinib (n=91) Carboplatin/paclitaxel (n=85) HR (95% CI) = 2.85 (2.05, 3.98) p< No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Median PFS G, 1.5 months Median PFS C/P, 5.5 months Months Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population Mok TS et al. NEJM 2009;361:947-57

18 PKC: clinical presentation LU lobectomy in private in Aug 2013 Adjuvant chemotherapy x 4 cycles in Aug-Nov 2013 PET-CT in July 2014: disease recurrence with L pleural nodules/effusion Started Tarceva in Oct-Dec 2014 no response 18

19 PKC: clinical presentation Referred to QMH for clinical trial option VATS pleural biopsy in Jan 2015: confirmed adenocarcinoma (EGFR L858R + T790M) Considered for AURA 3 trial 19

20 Mechanisms of Acquired Drug Resistance to EGFR TKIs T790M mutation is the most common mechanism Managing acquired resistance is a challenge in the treatment of patients with EGFR M+ NSCLC 1.Stewart EL et al. Transl Lung Cancer Res 2015;4:67 81; 2.Wu SG et al. Oncotarget 2016;7: Sacher AG et al. Cancer 2014;120:

21 Three Generations of EGFR TKIs: Potency and Specificity T790M T790M Relative IC x 10x 1x Wt EGFRm Wt EGFRm T790M Wt EGFRm Wt EGFRm T790M Gefitinib Erlotinib Afatinib Osimertinib Li D, et al. Oncogene. 2008;27: Ranson M, et al. WCLC Abstract MO Moyer JD, et al. Cancer Res. 1997;57: Kancha RK, et al. Clin Cancer Res. 2009;15:

22 AURA (Ph I/II) & AURA 2 (Ph II): Osimertinib (80 mg QD) for EGFR T790M Resistance Efficacy Parameter Objective Response Rate * (95% CI) AURA (Ph II extension, T790M+) (N=201) 57% (50, 64) AURA 2 (Ph II, T790M+) (N=210) 61% (54, 68) Overall (N=411) 59% (54, 64) Complete Response 0 1% 0.5% Partial Response 57% 60% 59% Duration of Response US approval of Osimertinib for EGFR T790M+ NSCLC on 13 Nov % of patients in both trials had ongoing responses at the time of primary analysis mdor had not been reached with duration of ongoing responses ranging from 1.1 to 5.6 months * Objective response rate determined by RECIST v1.1 as assessed by Independent review Janne et al. N EnglJ Med. 2015;372:1689.

23 PKC: clinical presentation Eligible for AURA 3 trial Received AZD9291 (osimertinib) since Feb 2015 Very well tolerated CT reassessment: partial response Last follow-up on 13 Apr

24 PKC: CT thorax Jan 2015 Feb

25 PKC: CT thorax Jan 2015 Feb

26 AURA 3: PFS Mok TS et al. NEJM 2017;376:

27 Mok TS et al. NEJM 2017;376:

28 WYC: clinical presentation Male, 36 years-old Ex-light smoker Performance score: 0 Incidental finding of left lung shadow on chest X-ray in 2008 during routine body check PET-CT: primary tumour in left hilar node, two satellite nodules in LUL, mediastinal lymph nodes Mediastinoscopy in private hospital: adenocarcinoma EGFR WT, T4N2 Referred to hospital authority oncology unit 28

29 WYC: clinical presentation July 2008 April 2010 April 2010 October 2010 Advised chemoradiotherapy treatment Patient refused treatment Patient returned: cough, mild shortness of breath CT of thorax Multiple tumors: ~8 cm mass in LUL; bilateral multiple lung nodules, multiple mediastinal and supraclavicular nodes 6 cycles of chemotherapy with carboplatin/paclitaxel + bevacizumab (SOC) Stable disease Progressive disease: stable extracranial disease but new metastases in the brain 29

30 WYC: clinical presentation Nov 2010 Dec 2010 March 2011 June cycles of pemetrexed (every three weeks) WBRT (concurrent with pemetrexed) PET-CT Progressive disease PD + new bone metastases (L4 vertebra and right ilium) Erlotinib Assessed for eligibility to PROFILE 1005: ALK positive tumour 30

31 EML4-ALK fusion oncogene Anaplastic lymphoma kinase (ALK): normally not expressed in lung Echinoderm microtubule associated protein-like 4 (EML4) EML4-ALK fusion first discovered in 2007: inversion of chromosome 2 [Inv(2) (p21p23)] N terminus: EML4 C terminus: entire intracellular tyrosine kinase domain of ALK Variants: different truncations of EML4 (at least 9) Other fusion partners with ALK: TRK-fused gene KIF5B EML4-ALK fusions ligandindependent activation of kinase ~ 3-7% in NSCLC Soda M et al. Nature 2007;448: Koivunen JP et al. CCR 2008;14:

32 Predictive biomarkers for ALK FISH IHC

33 Typical population with ALK fusion Neversmokers or ex-light smokers Adenocarcinoma Young age of onset Solid pattern with abundant signet ring cells EGFR WT IPASS population IPASS population in Asians ~ 60% EGFR activating mutations IPASS population with EGFR WT, around 33% will have EML4-ALK Mok TS et al. NEJM 2009;361:947-57

34 PROFILE 1005: study design Phase II, single-arm, multicenter study; ~1,100 patients 1,2 Key eligibility criteria: ALK-positive NSCLC by central laboratory Local test allowed on case-bycase basis per protocol amendment (January 2011) ECOG PS: prior line of chemotherapy Stable/controlled brain metastases allowed Treatment Crizotinib 250 mg BID PO; continuous daily dosing Primary endpoints: ORR Safety/tolerability Secondary endpoints include: OS PFS Duration of response Time to response PRO/HRQoL 1. Riely G, et al. Abstract 166. Presented at IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology 2012, Chicago, Illinois, 6 8 September, 2012; 2. Kim D, et al. Ann Oncol 2012;23(Suppl 9):ix402:Abstract 1230PD. 34

35 PROFILE 1014: study design Accrual period: January 2011 July 2013 Key entry criteria ALK-positive by central FISH testing Locally advanced, recurrent, or metastatic nonsquamous NSCLC No prior systemic treatment for advanced disease ECOG PS 0 2 R A N D O M I Z E a Measurable disease Stable treated brain N=343 metastases allowed Crizotinib 250 mg BID PO, continuous dosing (N=172) Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC 5 6 q3w for 6 cycles (N=171) Crossover to crizotinib permitted after progression Endpoints Primary PFS (RECIST v1.1, by IRR) Secondary ORR OS Safety PROs (EORTC QLQ-C30, QLQ-LC13, EQ-5D) a Stratification factors: ECOG PS (0/1 vs 2), Asian vs non-asian race, and brain metastases (present vs absent); c Assessed by IRR Solomon BJ, et al. N Engl J Med 2014;371:

36 PROFILE 1014: primary endpoint PFS by IRR (ITT population) PFS probability (%) Crizotinib Chemotherapy No. at risk: Time (months) Crizotinib Chemotherapy a 2-sided stratified log-rank test Crizotinib (n=172) Chemotherapy (n=171) Events, n (%) 100 (58) 137 (80) Median, mo HR (95% CI) 0.45 ( ) p a < Solomon BJ, et al. N Engl J Med 2014;371:

37 WYC: clinical course July 2011 September 2011 Enrolled in PROFILE 1005 Crizotinib Partial response, stable in the brain Scan at baseline Scan after 2 months 37

38 WYC: clinical course September 2011 October 2012 Crizotinib Partial response, stable in the brain Small new right high parietal brain lesion (2.3 x 3.2 x 2.5 mm) detected Scan after 2 months 38

39 WYC: clinical course September 2011 October 2012 April 2013 Crizotinib Partial response New brain metastasis Continue crizotinib Progressive thoracic disease Stable brain disease 39

40 Acquired Resistance in ALK+ NSCLC ALK-rearranged (ALK+) NSCLC is sensitive to crizotinib 1 3 Most patients develop resistance to crizotinib 4,5 Usually within 1 2 years CNS relapses are common 6 Mechanisms of resistance are diverse 4,5 ALK resistance mutations Alternative signalling pathways amp, amplification; mut, mutation. 1. Camidge DR, et al. Lancet Oncol. 2012;13: ; 2. Kim D-W, et al. ESMO; Abstract 1230PD; 3. Shaw AT, et al. ESMO; Abstract LBA1_PR; 4. Katayama R, et al. Sci Transl Med. 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res. 2012;18: ; 6. Takeda M, et al. J Thorac Oncol. 2013;8:

41 2 nd generation TKI ceritinib: ASCEND-5 Phase III, randomized (1:1), controlled, multicenter study; 231 patients Key eligibility criteria: ALK-positive NSCLC by central laboratory 1 prior line of chemotherapy Previous treatment with an ALK inhibitor ECOG PS: 0 3 Stable/controlled brain metastases allowed Ceritinib (750 mg/d) Chemotherapy (pemetrexed [500 mg/m 2 ] or docetaxel [75 mg/m 2 ]) Primary endpoint (PFS) results: Median 5.4 vs 1.6 months, HR=0.49, (P<0.001) Previous exploratory data from the Phase 1 ASCEND-1 trial also reported improved intracranial responses to ceritinib in patients with brain metastases Scagliotti, G. Abstract LBA42. Presented at ESMO 2016 Congress in Copenhagen, Denmark, 9 October, Kim, DW. Lancet Oncol. 2016;17:

42 ASCEND 5: PFS Probability of PFS (%) Ceritinib 750 mg (N=115) Censoring times Chemotherapy (N=116) Events, n (%) 83 (72.2) 89 (76.7) Median (95% CI), months 5.4 (4.1, 6.9) 1.6 (1.4, 2.8) Hazard ratio (95% CI) 0.49 (0.36, 0.67) Log-rank p-value < No. of patients at risk Ceritinib 115 Chemo Time (Months) Scagliotti G et al. ESMO

43 WYC: clinical course April 2013 May 2013 Progressive thoracic disease by CT scan Ceritinib through the CLDK378A2201 trial Stable disease; transient interruption due to hepatitis 43

44 Stable response to ceritinib May 2013 July

45 WYC: February 2014 Suspected progressive disease (left upper lung collapse and consolidation) Referred to MRI for neck and shoulder pain which showed new brain metastasis (15 mm lesion in medulla) 45

46 WYC: clinical course February 2014 April 2014 Progressive thoracic disease and new brain metastasis Stereotactic radiotherapy for brainstem lesion Continue treatment with ceritinib post-progression Stable disease in thorax and CNS 46

47 Medullary lesion poststereotactic radiotherapy July 2014 March months 11 months 47

48 WYC: clinical course February 2014 April 2014 March 2015 Progressive thoracic disease and new brain metastasis Stereotactic radiotherapy for brainstem lesion Ceritinib withheld due to increased ALT for 2 weeks Continue treatment with ceritinib post-progression Stable disease in thorax and CNS PD in CNS 48

49 Alectinib Alectinib has demonstrated high potency and selectivity, and promising antitumor effects in NSCLC Preclinical studies: active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M Phase III ALUR results suggest longer PFS with alectinib compared with chemotherapy in pretreated patients Ongoing Phase III study (ALEX) Wong KM et al. Drugs Today (Barc) 2015;51: Wolf, J. Ann Oncol 2016;27(suppl_6): 1290TiP 49

50 J-ALEX: Phase III study design Randomized controlled multi-center open-label Phase III study comparing the efficacy and safety of alectinib versus crizotinib (44 sites) Key Entry Criteria Stage IIIB/IV or recurrent ALK-positive NSCLC ALK centralized testing (IHC and FISH or RT-PCR) ECOG PS measurable lesion assessed by investigator Treated/asymptomatic brain metastases allowed 1 prior chemotherapy R 1:1 Alectinib 300 mg BID PO, 28-day cycle (N=100) Crizotinib 250 mg BID PO, 28-day cycle (N=100) Endpoints Primary - PFS assessed by IRF* Secondary - OS - ORR - PK - HRQoL - Time to CNS progression - Safety Stratification factors: Clinical stage (IIIB/IV vs recurrent) Prior chemotherapy (0 vs 1) ECOG PS (0/1 vs 2) Objective: To demonstrate superiority in PFS with alectinib compared with crizotinib in previously untreated patients or patients received one line of chemotherapy, based on independent review Kim YH, et al. Presented at the IASLC 17 th World Conference on Lung Cancer. December 4 7, Vienna, Austria, Presentation No Nokihara T, et al. Presented at ASCO Annual Meeting. June 3 7, Chicago, IL,

51 J-ALEX: PFS by CNS disease PFS rate (%) Without CNS disease at baseline Alectinib (N=89) Crizotinib (N=75) Event 24 (27.0%) 42 (56.0%) Median [95% CI] 20.3 [17.5 ; -] 10.0 [8.2 ; 13.9] P-Value HR [95% CI] a 0.37 [0.22 ; 0.62] PFS rate (%) With CNS disease at baseline Alectinib (N=14) Crizotinib (N=29) Event 1 (7.1%) 16 (55.2%) Median [95% CI] - [- ; -] 10.2 [6.5 ; 14.2] P-Value HR [95% CI] a 0.09 [0.01 ; 0.74] Alectinib Crizotinib 0 Alectinib Crizotinib Time (months) No. of patients at risk Alectinib Crizotinib Time (months) No. of patients at risk Alectinib Crizotinib Alectinib demonstrated greater efficacy in patients with CNS disease versus crizotinib However, it should be noted that there was an imbalance in patients with brain metastases at baseline (crizotinib = 29 vs alectinib = 14) as this was not a stratification factor for randomization Kim YH, et al. Presented at the IASLC 17 th World Conference on Lung Cancer. December 4 7, Vienna, Austria, Presentation No

52 WYC: clinical course March 2015 May 2015 December 2015 Applied for compassionate use of alectinib Decrease in multiple brain lesions including brainstem PD in medullary lesion Continued on ceritinib Continued on ceritinib Initiated alectinib 52

53 Response to alectinib in CNS December 2015 June 2016 WYC experienced occasional, transient myosistis on alectinib 53

54 WYC: Summary of therapy progress WBRT ALK mutation identified Stereotactic radiotherapy Progressive CNS disease Patient passed away: 19 Apr 2017 Chemotherapy Erlotinib Crizotinib Ceritinib Alectinib Aug 2010 Mar June 2011 July 2011 May 2013 Dec 2015 Partial response Stable disease Progression Progression Progression Progression ~ 6 years 54

55 NCCN guideline version NSCLC: 1L Adenoca Large cell NSCLC NOS Molecular testing (EGFR, ALK, ROS1); EGFR + ALK + Metastatic disease Squamous cell ca Consider molecular testing (EGFR, ALK, ROS1) esp. in nonsmokers, small bx, mixed histologies; 55 ROS1 + PD-L1 + EGFR/ALK/ROS1 ve or unknown PD-L1/ EGFR/ALK/ROS1 ve or unknown

56 Emerging 1L treatment algorithm EGFR/ALK/ROS1 WT Advanced lung adenoca/selected squamous cell ca PD-L1 1-49% EGFR/ALK/ROS1 driven Specific TKIs PD-L1 50% Pembro Chemotherapy options 1.pem/platinum (nonsquamous) 2.Bev + chemo (nonsquamous) 3.Gem or taxane /platinum (squamous) EGFR/ALK/ROS1 / PD-L1 ve or unknown Based on KEYNOTE 024 data and NCCN guideline

57 Conclusions Non-small cell lung cancer is a heterogeneous disease with diverse molecular profile Early detection of actionable targets (e.g. EGFR mutations, ALK or ROS1 rearrangement) allows specific targeted therapies Emerging anticancer therapies (esp. targeted therapy and immunotherapy) significantly improve the general outlook for advanced lung cancer Advanced lung cancer is now becoming a chronic disease

58 Acknowledgements Respiratory team (medical and nursing): QMH Co-investigators of clinical trials Research nurse (Christina Yan) Research coordinators (Vivian Li, Joy Zhang) All patients and their families taking part in clinical trials