Harmesh Naik, MD. Hope Cancer Clinic HOW DO I MANAGE STAGE 4 NSCLC IN 2012: STATE OF THE ART

Transcription

1 Harmesh Naik, MD. Hope Cancer Clinic HOW DO I MANAGE STAGE 4 NSCLC IN 2012: STATE OF THE ART

2 Goals Discuss treatment options for stage 4 lung cancer: New and old Discuss new developments in personalized treatment Provide audience participation opportunities Present examples from patients treated locally Answer questions from audience 2

3 Disclosure No financial interest to report. 3

4 Chronology Monday December 17, 2012: Received phone call around 9 AM. Our Wednesday CME speaker has cancelled, can you please make a presentation? End result 48 hours later. Thanks for the opportunity to present this CME activity. 4

5 Scope of discussion Discussion is limited to stage 4 non small cell lung cancer Present overall summary data with few selected results from individual clinical trials 5

6 Lung cancer About 221,000 estimated new cases in 2011 Overall 5 year survival is 15%. 6

7 Stage distribution at diagnosis SEER data

8 Stage 4 NSCLC AJCC 7nth edition: Stage 4 includes Any T, Any N, M1a and M1b M1a: Malignant pleural or pericardial effusion, separate tumor nodules in contra-lateral lobe or pleural nodules M1b: extra thoracic mets 8

9 Trends in stage distribution D. Morgensztern et al: ASCO 2007, abst

10 Trends in stage distribution Could be related to better imaging FDG/PET and better brain imaging 10

11 A question How many of you think there will a cure for stage 4 Non small cell lung cancer in your lifetime? Please raise your hands. 11

12 Five year survival- stage 4 NSCLC 5 year survival is 3.7% Source : SEER database, NCI data ACS: data 5 year survival is 1% Compare to 88% 10 year survival of CT detected stage I cancer (N Engl J Med 2006; 355: ) 12

13 Performance status (PS) PS is among the most important prognostic factors for survival of patients with NSCLC. Helps in selecting patients eligible for aggressive therapy 13

14 ECOG PS Grade ECOG ECOG PERFORMANCE STATUS 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 Dead From ECOG.ORG 14

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16 A question How many of you think histology matters in selection of treatment for stage 4 Non small cell lung cancer? Please raise your hands. 16

17 A question How many of you think type of mutations matter in selection of treatment for stage 4 Non small cell lung cancer? Please raise your hands. 17

18 Example cases: year Asian male left lung Adenocarcinoma, mediastinal nodes + bilateral hilar nodes,?liver mets by PET, lytic femur mets. T4N2orN3M1, PS 1. No brain mets. What is the next test most likely to help in treatment decision? 1. ALK mutation assay 2. EGFR mutation assay 3. MET mutation 4. Oncotype mutation assay 5. None of above 18

19 Example cases: year Asian male left lung Adenocarcinoma, mediastinal nodes + bilateral hilar nodes,?liver mets by PET, lytic femur mets. T4N2orN3M1, PS 1. No brain mets. What is the most appropriate treatment 1. Paclitaxel-Carboplatin 2. Gemcitabine-Cisplatin 3. Vinorelbine-Cisplatin-Erbitux 4. Oral Erlotinib 5. Oral Crizotinib 19

20 Answers At the end of this talk 20

21 Traditional treatments Palliative Non curative One type of treatment fits all Types of Treatments: Palliative chemotherapy Palliative radiation Supportive care Hospice 21

22 Traditional treatments Good PS : Cisplatin-based chemotherapy improves survival and palliates disease-related symptoms. Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. 22

23 Traditional treatments The role of chemotherapy in patients with poor PS was less certain. 23

24 Meta-analysis: Single agent versus doublets 24

25 Second line therapy First line therapy Second line therapy Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival in patients with good PS. 25

26 Traditional treatments: Shortcomings Not based on histology all histological subtypes are treated same way Short courses of toxic chemotherapy No predictive parameters of response Not very effective Mostly frustrating to both patients and providers 26

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28 Modern treatments for stage 4 NSCLC Choices based on histology Maintenance therapy Individualized therapy based on molecular markers 28

29 Modern treatments for stage 4 NSCLC: A step forward More precise Less toxic Better responses 29

30 Histology based therapy NSCLC Squamous Non squamous 30

31 ECOG 4599: Non Squmaous Non Squmaous PC PC-BEV 31

32 ECOG 4599: Survival Alan Sandler, M.D., et al: N Engl J Med 2006; 355:

33 ECOG 4599 Understanding statistics Patients with PC-Bev are 53% more likely to be alive at 2 years Relative improvement Absolute benefit: 23% versus 15% (8% absolute difference) 33

34 Phase III study Cisplatin plus Gemcitabine (CG) with Cisplatin plus Pemetrexed (CP) First line in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer 34

35 Median survival: CP versus CG Giorgio Vittorio Scagliotti, MD et al: JCO July 20, 2008 vol. 26 no

36 Conclusions CP=CG non inferior overall CP better and less toxic in Non Squmaous CG better in Squmaous Changed standard of care 36

37 Histology based therapy Summary: Use of Pemetrexate and Bevacizumab containing regimen limited to non Squmaous histology Use Gemcitabine-platinum or Taxane- Platinum for Squmaous histology 37

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39 Maintenance therapy Continuing the initial combination chemotherapy : Non beneficial Pemetrexed : PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy regimen Benefit was not seen in patients with Squmaous histology 39

40 Maintenance therapy Oral Erlotinib Patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment Patients whose tumors with wild-type EGFR also obtained significant PFS and OS improvements 40

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42 New molecular markers EGFR ALK Therapy selection KRAS RRM1 ERCC1 42

43 Potential molecular markers for therapy selection EGFR Exon 19 mutations in adenocarcinoma EML4-ALK mutations RRM1 may predict Gemcitabine sensitivity ERCC1 may predict platinum resistance Multiple gene expression assays are in development 43

44 EGFR mutations EGFR mutations and over expression activates signaling pathways leading to cell growth and cell survival Exon 19 deletions and L 858R point mutations are common Seen in 10-15% Caucasians (higher in Asians up to 40%) T790M mutation indicates resistance to first generation EGFR inhibitors 44

45 EGFR mutations EGFR inhibitors (Gefitinib and Erlotinib) may benefit selected patients with EGFR mutations Patients with EGFR mutations particularly those from East Asia, females, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors as an alternative to first- or second-line chemotherapy. Median PFS was significantly longer in Erlotinibtreated patients than in those treated with chemotherapy (13 vs 4.6 months in Chinese study) 45

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47 EGFR Exon 19 mutation Excellent review: Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC: Helena Linardou et al: Nature Reviews Clinical Oncology 6, (June 2009) 47

48 Cetuximab Activity of Cetuximab (anti EGFR antibody) seems to be independent of EGFR mutations Currently EGFR mutation status is not used to decide Cetuximab eligibility 48

49 KRAS mutations Seen in up to 30% Caucasians (less in Asians) Mutated KRAS stimulates pathways downstream to EGFR pathways Predicts resistance to EGFR inhibitors Seen more in smokers Associated with poorer prognosis 49

50 EML4-ALK mutations ALK mutations are generally seen in EGFR negative and KRAS negative tumors Generally seen in younger patients, adenocarcinoma histology and never smokers Crizotinib (ALK TKI) helpful for patients whose tumors have mutated ALK over 50% response rates seen in early trials Predicts resistance to EGFR inhibitors 50

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52 Clinical correlation: How accurate Even though certain characteristics are associated with certain mutations, only molecular testing can reliably detect genetic mutations 52

53 Reflex testing Timely and resource saving and protocol driven for consistency Automatic testing for EGFR for all non squamous samples ALK testing for EGFR negative tumors Some labs start with KRAS if negative than EGFR assay and if negative than ALK assay 53

54 Reflex testing EGFR on all non sq + Erlotinib - Alk testing + Crizotinib - Chemo 54

55 NCCN Clinical Practice Guidelines 2012 Recommend EGFR and ALK mutation testing all recurrent or metastatic Adenocarcinoma, large-cell carcinoma, and NSCLC NOS. Do not recommend routine biomarker testing of pure squamous cell carcinoma 55

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57 What do I do: Histology based therapy NSCLC Squamous Non squamous EGFR + Erlotinib EGFR -ve ALK Gemplatinum Taxaneplatinum Vin-Cis- Cetuximab ALK + ALK -ve Crizotinib Pem-Cis Tax-Plt- Bev 57

58 What do I do: PS based therapy NSCLC Good PS Doublets Clinical trial Poor PS Single agent RT Palliative care Hospice 58

59 What do I do: Example of sequential therapy Good PS only Doublet Or clinical trial Or biological if mutation positive First line Second line Good PS only Single agent Rarely a doublet (if biological as first line) Or clinical trial Erlotinib Or Phase I or Hospice Third line 59

60 What is ahead in future More details More insight New genes and possibly new treatments 60

61 More details Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing : Marcin Imielinski, et al. : Cell - 14 September 2012 (Vol. 150, Issue 6, pp ). 61

62 More insight Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers : Ramaswamy Govindan et al: Cell - 14 September 2012 (Vol. 150, Issue 6, pp ) 62

63 Targetable pathways in squamous cell lung cancer PS Hammerman et al. Nature 489, (27 September 2012) The Cancer Genome Atlas (TCGA) Research Network study 63

64 Mutated genes in squamous cell lung cancer PS Hammerman et al. Nature 489, (27 September 2012) The Cancer Genome Atlas (TCGA) Research Network study 64

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66 Example case: year old female: Presents with solitary brain metastasis, Right lung mass, No other mets Non smoker, 20 years second hand smoke Treatments: Craniotomy and surgical removal of brain lesion Brain RT Surgical resection of T2N0 right lung lesion Adenocarcinoma histology Oral Erlotinib for 58 months maintenance Still in remission as of last month 66

67 Example case: yr Caucasian female, 50 year smoking history, 3 cm squmaous cell lung cancer, T2N0, had radiation. 20 months later has bilateral lung mets- stage 4 Treated with Paclitaxel-Carboplatin-Erbitux for six cycles. Six months alter progressive cancer in lungs Tumor tested for PI3 kinase- not eligible for inhibitor study Started Gemcitabine 67

68 Example cases: year Asian male left lung Adenocarcinoma, mediastinal nodes + bilateral hilar nodes,?liver mets by PET, lytic femur mets. T4N2orN3M1, PS 1. No brain mets. What is the next test most likely to help in treatment decision? 1. ALK mutation assay 2. EGFR mutation assay 3. MET mutation 4. Ecotype mutation assay 5. None of above 68

69 Example cases: year Asian male left lung Adenocarcinoma, mediastinal nodes + bilateral hilar nodes,?liver mets by PET, lytic femur mets. T4N2orN3M1, PS 1. No brain mets. What is the most appropriate treatment per NCCN guidelines 1. Paclitaxel-Carboplatin 2. Gemcitabine-Cisplatin 3. Vinorelbine-Cisplatin-Erbitux 4. Oral Erlotinib 5. Oral Crizotinib 69

70 Example cases: year Asian male left lung Adenocarcinoma, mediastinal nodes, bilateral hilar nodes,?liver mets by PET, lytic femur mets. T4N2orN3M1, PS 1. EGFR exon 19 mutation detected Started on Oral Erlotinib RT to femur lytic lesion 70

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