Lung Cancer in Paul Wheatley-Price BSc, MBChB, MRCP (UK), MD

Transcription

1 Lung Cancer in 2015 Paul Wheatley-Price BSc, MBChB, MRCP (UK), MD Assistant Professor, Division of Medical Oncology, Department of Medicine, University of Ottawa 1

2 Disclosures Honorarium for advisory boards, invited speaking: Lilly, Astra Zeneca, Amgen, Pfizer, Boehringer Ingelheim, Merck 2

3 Before we get started... 3

4 Before we get started... I ll fight for the guy who doesn t have a voice 4

5 Who gets lung cancer? More common in low income groups More common in those with less education Overall a 5 year survival of 16-17% >20,000 deaths per year in Canada So who will be the voice? Mao et al, Int J Epidem 2001; 30 (4) ; Canadian Cancer Statistics 5

6 Stage 4 NSCLC in Ottawa N=528, seen as a new out-patient consult Only 55% received any systemic therapy Of those untreated, poor functional status in twothirds N=223, seen initially while hospitalized 24% received chemotherapy Ontario provincial data N=8113 Identified from linked provincial databases 70% saw a medical oncologist Only 24% received any systemic therapy (although that increased over time) Brule et al, ASCO 2015; Gotfrit et al, WCLC 2015 Sacher et al, ASCO

7 Barbera et al JCO

8 Lung Cancer Canada: Canada s only national charity solely dedicated to lung cancer. 8

9 9

10 Outline A journey to the current advanced NSCLC treatment algorithm, including... A brief overview of the last year with respects to: Me Canadian politics Lung Cancer 10

11 From this... 11

12 From this... 12

13 ... to this 13

14 ... to this 14

15 But do I know the Canadian politicians? 15

16 And do you?? 16

17 Milestones in lung cancer therapy First evidence showing longer survival with palliative chemotherapy First evidence to show benefit from second line therapy First evidence for the role of adjuvant chemotherapy 3 rd line therapy The molecular era Immunooncology 17

18 Case 1 62 year old female Seen in February month of painful back mass 50 pack years, quit in 2011 PS-1 18

19 Case 1 Pathology Poorly differentiated adenocarcinoma Received palliative RT to paraspinal mass, then developed left sided weakness 19

20 Case 1 Neurosurgery for debulking Cyberknife RT to the tumour bed Now PS-2 Options? 20

21 Case 1 Neurosurgery for debulking Cyberknife RT to the tumour bed Now PS-2 Options? Palliative chemotherapy Best supportive care 21

22 Who was Canadian PM in 1995? 1. Brian Mulroney 2. Kim Campbell 3. Jean Chrétien 22

23 Who was Canadian PM in 1995? Brian Mulroney Kim Campbell Jean Chrétien Bonus question: Who was the British PM in 1995? 23

24 1995: Chemotherapy prolongs survival First analysis to show longer survival with platinum chemotherapy 1-year survival of 25% versus 15% Median survival with chemotherapy improved by approximately 6 weeks Non-small Cell Lung Cancer Collaborative Group, BMJ 1995;311:

25 A choice of platinum doublets Median survival with chemotherapy 8.0 months Schiller et al, NEJM 2002; 346(2):

26 Histology matters 26

27 Histology matters Pemetrexed is superior in non-squamous NSCLC Scagliotti et al. J Clin Onc; 2008;26(21):

28 Case 1 initial treatment Tested for EGFR and ALK (more later) both negative Commenced platinum doublet chemotherapy cisplatin / pemetrexed Hearing loss / tinnitus developed, so cisplatin switched to carboplatin Pre chemo Post-chemo 28

29 How much / how long? Trial Treatment Number Overall survival P-value Carbo / Taxol (Socinski et al) MVP (Smith et al) Carbo / Vinorelbine (von Plessen et al) Platinum doublet (Park et al) 4 cycles mo 0.63 Until progression mo 3 cycles mo cycles mo 3 cycles wk cycles wk 4 cycles mo cycles mo 29

30 Can the benefits of initial treatment be maintained? 30

31 Or are they destined to end badly? 31

32 Who was Liberal party leader in 2009? 1. Stéphane Dion 2. Michael Ignatieff 3. Bob Rae 32

33 Who was Liberal party leader in 2009? 1. Stéphane Dion 2. Michael Ignatieff 3. Bob Rae 33

34 Maintenance therapy Switch maintenance Induction platinum doublet, then change to new single agent as maintenance Continuation maintenance Induction platinum doublet, then continue with the nonplatinum agent The evidence Phase III studies of maintenance pemetrexed treatment after platinum doublet 1 st line therapy 34

35 Maintenance pemetrexed Switch maintenance Median overall survival Pemetrexed: 13.4 months Placebo: 10.6 months HR 0.79 ( ), p=0.01 Ciuleanu T, et al. Lancet 2009;374: Continuation maintenance Median overall survival Pemetrexed: 13.9 months Placebo: 11.0 months HR 0.78 ( ), p=0.02 PARAMOUNT Trial. Paz Ares et al. JCO 2013;31:

36 Case 1 an update Seen in clinic on 28 th September 2015 Now receiving maintenance pemetrexed (6 cycles so far) Ongoing shrinkage of metastatic disease Ongoing hearing loss Heading to Las Vegas this weekend 36

37 Who was USA VP in 2000? 1. Al Gore 2. Dick Cheney 3. Dan Quayle 37

38 Who was USA VP in 2000? 1. Al Gore 2. Dick Cheney 3. Dan Quayle 38

39 Prolonged survival on progression 2000: efficacy of further CT after platinum failure Docetaxel versus best supportive care Median survival 7.0 months versus 4.6 months Shepherd et al. J Clin Oncol; 18:

40 2004: Pemetrexed in 2 nd -line Median survival with chemotherapy: months Hanna et al. J Clin Oncol; 22:

41 The second line space is becoming crowded more later 41

42 Who was Canadian PM in 2005? 1. Jean Chrétien 2. Paul Martin 3. Stephen Harper 42

43 Who was Canadian PM in 2005? 1. Jean Chrétien 2. Paul Martin 3. Stephen Harper 43

44 Erlotinib as 2 nd /3 rd line treatment BR.21 Study Erlotinib or placebo after failure of chemotherapy in advanced NSCLC 488 patients received erlotinib 243 patients received placebo Shepherd et al. NEJM 353; ,

45 BR.21 - Results Median overall survival 6.7 v 4.7 months (p<0.001) Response best seen in never-smokers, adenocarcinoma and EGFR expressors Shepherd et al. NEJM 353; ,

46 Treatment algorithm Patients with advanced NSCLC and good PS 1 st line Platinum doublet CT Maintenance Maintenance pemetrexed 2 nd line Pemetrexed or Docetaxel 3 rd line Erlotinib 46

47 The targeted era is here 47

48 Case 2: 40 year old male Previously healthy Never smoker Presented with 1 year of visual changes RUL adenocarcinoma with a right sided retinal metastasis EGFR mutation detected (exon 19 deletion) 48

49 EGFR mutation population There are numerous randomized phase 3 studies comparing EGFR TKI to chemotherapy in EGFR m+ NSCLC, all showing significant benefits to the targeted therapy Erlotinib (Erlotinib ) Gefitinib (Iressa ) Afatinib (Giotrif ) 49

50 1 st line gefitinib vs chemotherapy Han et al. NEJ002. NEJM 2010 (362):

51 1 st line erlotinib vs chemotherapy Rossel et al. EURTAC. Lancet Oncology 2012 (13):

52 1st line afatinib vs chemotherapy Sequist et al. LUX-LUNG 3. JCO 31(27): ,

53 Case 2: Progress on treatment Commenced gefitinib 250mg od Jan 2012 Grade 1 rash and diarrhea Vision improved within a few weeks Dec 2011 March

54 What is ALK? Approximately 3-4% NSCLC have a genetic rearrangement called EML4-ALK Chromosome 2 fusion gene created by an inversion that juxtaposes Echinoderm microtubule-associated protein-like 4 (EML4) [2p21) Anaplastic lymphoma kinase (ALK) [2p23] This leads to a novel fusion oncogene EML4- ALK, a 200-kDa transmembrane tyrosine kinase 54

55 Shaw and Solomon. Clin Canc Res 2011;17:

56 The rapid history of ALK EML4-ALK was first identified in a 62 year old Japanese lung adenocarcinoma patient in 2007 Crizotinib had actually entered first-in-man studies in 2006 First study patient for ALK+ NSCLC was August 27 th 2008 FDA granted accelerated approval to crizotinib on August 26 th 2011 Health Canada approval April 2012 CCO funding October

57 Efficacy Response rate (CR/PR) 61% Disease control rate (CR/PR/SD) 83% PFS 9.7 m PFS (1 st line) 18.3 m Camidge. Lancet Oncology 2012; 13 (10):

58 Crizotinib oral agent targeting ALK Camidge et al. Lancet Oncology (epub Sept 2012) 58

59 Crizotinib vs Chemotherapy Crizotinib versus platinum / pemetrexed chemotherapy as 1 st line treatment for stage 4 ALK-positive lung cancer Solomon et al. NEJM 2014; 371(23):

60 Crizotinib vs Chemotherapy Crizotinib versus docetaxel or pemetrexed chemotherapy as 2nd line treatment for stage 4 ALK-positive lung cancer Shaw et al. NEJM 2014; 368(25):

61 Standard of care Early 2014 Patients with advanced NSCLC and good PS EGFR mutation positive EGFR / ALK ve NSCLC ALK translocation positive Gefitinib / Erlotinib / Afatinib Pemetrexed Platinum doublet CT Pemetrexed (m) Non- Squamous Squamous Docetaxel Crizotinib Erlotinib 61

62 The news from 2015 that affects us 1. For those with actionable mutations, there are now more lines of non-cytotoxic therapy 2. We are in the era of immuno-oncology 62

63 Case 2 an update The response to gefitinib lasted 1 year 4 cycles cis / pemetrexed - no response Brief response to afatinib: Mar-Sep 2014 Sept 2014 functional decline Liver, brain and lung metastases Not keen on docetaxel (low response rate) Biopsy repeated T790M mutation 63

64 Targeting T790M T790M is a mutation that commonly emerges The most common resistance mechanism to first line EGFR TKI therapy A number of 3 rd generation TKIs target common mutations and T790M Osimertinib (AZD9291) Rociletinib (CO-1686) 64

65 Case 2: Enrolled on trial of 3 rd gen EGFR TKI Baseline scans September

66 Case 2: Spectacular response Baseline Repeat scans after 4 weeks 66

67 Case 2: Spectacular response Baseline Repeat scans after 4 weeks 67

68 AZD 9291 Janne et al. NEJM 2015; 372(18):

69 Also 2 nd generation ALK inhibitors Multiple 2 nd line ALK inhibitors: Ceritinib (Novartis) Alectinib (Roche) Brigatinib (Ariad) Ceritinib (Zykadia) is commercially available, Health Canada approved, but not publicly reimbursed 69

70 Crizotinib as a ROS1 inhibitor ROS1 oncogene Related to ALK 1% NSCLC Never smokers Adenocarcinoma Phase 1 study of crizotinib in ALK, then included a ROS1 expansion cohort N=50 Shaw et al. NEJM Sept

71 Immunotherapy Immune checkpoint inhibitors Cancer cells express ligands that supress T-cell response Inhibition of these inhibitory effects allows T-cell response 2013 Drug of the year: PD-1 and PD-L1 monoclonal antibodies. Breakthrough of the Year

72 Different mechanisms Antibodies against PD-1 prevent the binding of inhibitory ligands PD-L1 or PD-L2 Antibodies against PD- L1 prevent the ligand from binding to PD-1 or B7-1 Topalian et al, Current Opinion in Immunology 2012; 24:

73 Immune checkpoint inhibitors. Who are the main players? Almost all NSCLC data is from conference abstracts / presentations, and not from published trials 73

74 Leading PD-1 and PD-L1 antibodies Anti PD-1 Nivolumab Bristol-Myers Squib IgG4 Pembrolizumab Merck IgG4 (humanized) Anti PD-L1 Atezolizumab Genentech / Roche IgG1 Durvalumab MedImmune / AstraZeneca Modified IgG1 74

75 Leading PD-1 and PD-L1 antibodies Drug Number Response rate Nivolumab % Pembrolizumab % Atezolizumab 52 23% Durvalumab % Brahmer et al, ASCO 2014; Garon et al, ESMO 2014; Horn et al, WCLC 2013; Brahmer et al, ASCO

76 A year ago we were asking? Are these an exciting news story that will not turn into anything? 76

77 A year ago we were asking? Are these an exciting news story that will not turn into anything? 77

78 A year ago we were asking? Are these an exciting news story that will not turn into anything? Or will it be a true winner? 78

79 These drugs are here to stay 2 nd line treatment advanced squamous cell lung cancer Brahmer et al, NEJM 2015; 373 (2) :

80 These drugs are here to stay 2 nd line treatment advanced non-squamous cell lung cancer Paz Ares, ASCO Slide courtesy of BMS 80

81 Are these drugs well tolerated? In general yes Grade 3-4 toxicities in only 7% cases (compared to 55% in docetaxel) Immune-related side effects uncommon Hypothyroidism Pneumonitis Colitis Administered iv every 2-3 weeks (depends on which drug) 81

82 2015 State of Play Patients with advanced NSCLC and good PS Line EGFR positive ALK positive ROS1 positive Wildtype NSCLC 1 st Gefitinib / Erlotinib Afatinib Crizotinib Crizotinib Platinum doublet CT Main Maintenance pemetrexed 2 nd 3 rd gen TKI 2 nd gen ALK Pemetrexed or Docetaxel Nivolumab 3rd Erlotinib 82

83 For those who In summary Get to see a medical oncologist Are fit for treatment There are now multiple treatment options, and often well tolerated An exciting time in thoracic oncology However we must advocate for the whole lung cancer population 83

84 Thank you for your attention 84