Overview of Lung Cancer :Perspectives from Cancer Genotype. Ji-Youn Han, MD, PhD. Center for Lung Cancer National Cancer Center

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1 Overview of Lung Cancer :Perspectives from Cancer Genotype Ji-Youn Han, MD, PhD. Center for Lung Cancer National Cancer Center

2 Histologic classification of lung cancer

3 Therapeutic plateau reached with chemotherapy in NSCLC Platinum-based doublets (3 rd generation) Response rate 20-30% Median time to progression 3-4 months Median overall survival 8-10 months

4 Lung Cancer: high incidence & high mortality

5 주요암의 5 년생존율추이 : 전체

6 How many genes are altered in a typical solid tumor? ~10 Vogelstein 2010 AACR

7 EGFR as an anti-cancer target 1980s 1990s 1 st generation EGFR-TKIs Tumor type EGFR expression Head & neck cancer 80-95% NSCLC 40-80% Breast cancer 14-91% Colon cancer 25-77% Ovarian cancer 35-70% Pancreatic cancer 30-50%

8 Response rate, % Phase II results of gefitinib in previously treated advanced NSCLC (2002) 30 Vertical bars represent 95% CI mg 500 mg 250 mg 500 mg IDEAL 2 USA 3 rd -linesetting (n=216) IDEAL 1 Japan and Europe 2 nd or 3 rd line setting (n=210) Kris JAMA 2003;290:2149- Fukuoka JCO 2003;21:223

9 Japan & US approvals of Gefitinib Japan full approval granted July 2002 Indication: Inoperable or recurrent non small cell lung cancer. US accelerated approval granted May 2003: IRESSA is indicated as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies. The effectiveness of IRESSA is based on objective response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. US Phase III for full regulatory approval (ISEL: OS superiority vs placebo)

10 Subpopulations & response to gefitinib in NSCLC Group Responses P Study Women vs. Men 19% vs. 3% IDEAL 2 1 Japanese vs. Caucasian Adenocarcinoma vs. Others Non-smoker vs. Former/current 28% vs. 10% IDEAL % vs. 4% IDEAL % vs. 8% <0.001 MSKCC 3 1 Fukuoka et al, JCO 2003; 2 Kris et al, JAMA 2003; 3 Miller et al, JCO 2004

11 Iressa Survival Evaluation Lung Cancer (ISEL) Previously treated (failure of 1 2 previous chemo-regimens) stage IIIB/IV NSCLC with PS 0 3 (n=1692) R Gefitinib 250mg/day (n=1129) Placebo (n=563) Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival (PFS), response rate (RR), safety, quality of life (QoL), duration of response Thatcher et al. Lancet 2005;366:1527

12 BR.21 Previously treated (failure of 1 2 previous chemo-regimens) stage IIIB/IV NSCLC with PS 0 3 (n=731) R 2 1 Erlotinib 150mg/day (n=488) Placebo (n=243) Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival (PFS), response rate (RR), safety, quality of life (QoL), duration of response Shepherd F, et al. N Engl J Med 2005;353:123 32

13 Phase III results of Gefitinib & Erlotinib in previously treated advanced NSCLC EGFR-TKI Trial Patients Survival ORR Gefitinib ISEL 1692 (HR=0.89 [95% CI: ]) 8% vs. 1% Erlotinib BR (HR=0.70 [95% CI: ]) 9% vs. 1% HR and 95% CI Favours active agent Favours placebo

14 Timeline of EGFR-targeting in NSCLC Iressa approval in Japan Final ISEL results shows no survival benefit with Iressa Iressa approval in US Tarceva approval in US AstraZeneca restricts Iressa use in US to those previously taking Iressa with demonstrated benefit

15 Why gefitinib failed in the United States? Sharma et al. Nature Reviews Cancer 2007; 7,

16 Survival & response rates by subgroup analysis (ISEL) Thatcher et al. Lancet 2005;366:1527

17 EGFR mutations in NSCLC (2004) Mutations associated with drug resistance Mutations associated with drug sensitivity Nat Rev Cancer 2007;7:16-181

18 Effects of EGFR-TK domain mutations on the ATP-binding cleft Wild type Mutant form Enhanced kinase activity Increased sensitivity to TKI Gazdar AF et al. Trends Mol Med 2004;10:481

19 EGFR mutations in NSCLC Somatic mutation in EGFR-TK domain More common in never- or light-smokers 30-40% of Asians 10-15% of Caucasians Oncogenic addiction Oncogenic in NIH3T3 cells & mice Exquisite sensitivity to EGFR-TKIs

20 Prospective non-randomized studies of NSCLC with EGFR mutations treated with EGFR-TKIs Author # screened EGFR mutations Agent RR (%) PFS (M) First-line Inoue Gefitinib Paz-Ares Erlotinib Tamura Gefitinib Asahina Gefitinib Sequist Gefitinib Kim Gefitinib Second-line Sutani Gefitinib First - & second or more-line Rosell (16.6%)-217Tx Erlotinib Kim et al. Lung Cancer 2010, Rosell et al. NEJM 2009;361:958

21 Iressa Pan-Asia Study (IPASS) Randomization period: March 2006 October 2007 Patients Chemo-naïve Age 18 years Adenocarcinoma Never or ex-light smokers Life expectancy 12 weeks WHO PS 0-2 Measurable stage IIIB / IV Gefitinib (250 mg / day) 1:1 randomization Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # ** Cross-over permitted End points Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression Mok et al. NEJM 2009

22 Comparison of PFS by EGFR mutation status Mok et al. NEJM 2009

23 Phase III trials comparing gefitinib versus chemotherapy as first-line therapy in EGFR mutant NSCLC Study N TKI Chemo Primary endpoint NEJ002 G719X X19 L858R L861Q 198 Gefitinib TC PFS WJTOG3405 X19 L858R 172 Gefitinib DP PFS OPTIMAL X19 L858R 152 Erlotinib GC PFS EURTARC X19 L858R 146 Erlotinib Platinum +G or D PFS T: paclitaxel, C: carboplatin, G: gemcitabine, D: docetaxel, P: cisplatin

24 First-line EGFR-TKI vs. Chemo in EGFR mutant NSCLC NEJ002 (N=228) WJTOG3405 (N=172) OPTIMAL (N=165) EURTAC (n=174) Gefitinib PC Gefitinib DP Erlotinib GC Erlotinib Chemo (n=114) (n=114) (n=86) (n=86) (n=83) (n=82) (n=86) (n=88) ORR (%) P<.001 P<.0001 P<.0001 Median PFS (M) HR=0.30 HR=0.489 HR=0.16 HR=0.37 (95% CI: ) (95% CI: ) (95% CI: ) (05% CI: ) P<.001 P<.0001 P<.0001 P<.0001 Median OS (M)

25 Timeline of EGFR-targeting in NSCLC EGFR mutations identified in NSCLC 1990s Quinazoline EGFR Inhibitors discovered Erlotinib approved for NSCLC Gefitinib FDA approval was withdrawn Gefitinib approved for EGFR-M NSCLC EGFR mutation screening Gandi & Janne Clin Cancer Res 2012

26 Irreversible EGFR-TKIs: 2 nd generation EGFR-TKIs Agent Type EGFR IC 50 (nm) HER2 IC 50 (nm) Other targets Gefitinib Reversible NA Erlotinib Reversible NA Afatinib Irreversible HER-4 Neratinib Irreversible HER-4 Dacomitinib Irreversible 6 46 HER-4 Theoretical advantages of 2 nd -generation irreversible EGFR-TKIs Higher affinity for EGFR-TKI domain Irreversible TK blockade More complete EGFR signaling blockade by inhibiting HER2 or HER4 Modest in-vitro activity to T790M mutation Yun CH et al. PNAS 2008;105:2070 Suda K et al. JTO 2009; 4:1-4

27 Irreversible EGFR-TKIs in clinical trials HKI-272 (EGFR+HER2) XL647 (EGFR, HER2, VEGF) BIBW2992 (EGFR+HER2) PF (EGFR+HER2+HER4) RR 3% in TKI-resistant pts Intriguing response in G719X RR 2% in TKI-resistant pts (Sequist, JCO 2010) (Pennell, Chicago Lung 2008) RR 7% in TKI-resistant pts 2M PFS advantage (3.3 vs.1.1m) RR 7% in TKI-resistant pts (Miller, ESMO 2010) (Janne, ASCO 2009)

28 Afatinib in EGFR mutant NSCLC: LUX Lung-3

29 Response rate: Afatinib vs. PemCis

30 PFS: Afatinib vs. PemCis

31 Toxicity: Afatinib vs. PemCis Afatinib PemCis AE leading to discontinuation 23 (10%) 16 (14%) Drug-related AE leading to discontinuation 18 (8%) 13 (12%)

32 EML4-ALK fusion gene

33 Natural history of ALK-positive NSCLC 3-7% of NSCLC Adenocarcinoma : acinar, papillary, cribriform, mucin-producing, signet-ring cell Never or light smoking status Younger: median 51 years Minimal overlap with other oncogenic driver mutations Excess of hepatic mets & pleural/pericardial effusion at presentation

34 Diagnosis of ALK-rearranged NSCLC Fluorescence In Situ Hybridization (FISH) Camidge DR et al. Clin Cancer Res 2010;16: FISH characteristics Criteria for positivity Number of cells counted At least 50 cells % of positive signals > 15% Distance between 5 (green) & 3 (red) signals Greater than 2 signal diameter separation Presence of single 3 ALK signal only (single red) Yes Presence of single 5 ALK signal only (green only) No Ignatius Ou SH. 2011;5:471

35 Treatment of ALK-rearranged NSCLC ALK-TKI Sasaki T & Janne PA: Clin Cancer Res 2011;17:

36 Crizotinib

37 Crizotinib efficacy in ALK-rearranged NSCLC Efficacy A (n=119) PROFILE 1005 (n=136) ORR (CR+PR) [95% CI] 61% (2%+59%) [52-70%] 50% (1%+49%) [42-59%] Duration of response (range) 11.2 ( ) M 9.8 ( ) M Median PFS (95% CI) Median OS OS rate at 12M 10 M (8-15M) Not reached yet 81% Camidge DR, et al. J Clin Oncol 2011; 29 Suppl: Abstract 2501 Crino L et al. J Clin Oncol 2011;29 Suppl: abstract 7514

38 Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer NEJM 2013

39 EGFR Timeline EGFR mutations identified in NSCLC 1990s Quinazoline EGFR Inhibitors discovered Erlotinib approved for NSCLC Gefitinib approved for NSCLC ALK Timeline Crizotinib developed Responses seen in ALK+NSCLC Treated on phase I study of crizotinib EML4-ALK discovered in NSCLC Crizotinib approved for ALK+-NSCLC Gandi & Janne Clin Cancer Res 2012

40 Cost of Cancer Drugs: What Price for What Benefit? Simple measures of efficacy could be based on the amount of time a new drug prolongs life. If survival is prolonged by more than 6 months and/or by more than onethird of the patient s life expectancy (eg, months or months), this would be considered extremely effective and would put the drug price in a higher range for example, over $50,000 per year, but not more than $75,000. A drug that prolongs survival by 3 to 6 months and/or by 25% to 33% of life expectancy (eg, months or months) would be considered beneficial and priced modestly perhaps between $30,000 to 50,000 per year. Finally drugs that demonstrate statistically significant survival benefits of 2 months or less and less than 25% prolongation of life expectancy would be considered to have minimal efficacy and priced below $30,000 a year.

41 2 nd generation ALK inhibitors in under investigation Crizotinib AP26113 LDK378 CH ALK IC 50 24nM 0.62nM 0.15nM 1.9nM Other targets C-Met EGFR T790M ROS-1 IGF1R - ORR (crizotinib-naïve) 60.8% (n=143) 50% (n=4) 60% (n=35) 93.5% (n=46) ORR (crizotinib-resistant) 75% (n=16) 57% (n=79) 2nd Generation ALK Inhibitors (NSCLC) Very Difficult to Beat Xalkori on Response Rate Penetration of the Blood Brain Barrier & Increased Potency Could Lead to Better Efficacy Xalkori should be beatable front-line, not on ORR but PFS.

42 Xalkori TM (Crizotinib) 성분함량 성상 흰색또는연한노란색의분말이든흰색 / 분홍색의경질캡슐 효능효과 ALK-positive locally advanced or metastatic NSCLC Based on response rate 작용기전 Selective ATP competitive RTK-inhibitor (ALK, c-met, RON) 허가 2011 년 12 월 29 일한국 : ALK- 양성국소진행성또는전이성비소세포폐암의치료

43 Crizotinib: Absorption Peak plasma time: median 4 to 6 hours (following a single dose of crizotinib) Steady state: within 15 days (repeated 250mg twice a day) Bioavailability: mean 43% (range: 32% to 66%) following a single dose The solubility of crizotinib decreases with increasing ph & its bioavailability may be reduced with coadministration with drugs that elevate gastric ph. XALKORI can be administered with or without food A high-fat meal reduced crizotinib AUC and C max by approximately 14%. Poorly penetrate blood-brain barrier

44 Crizotinib: common side effects ( 25%) Vision problems (62-64%) These problems usually happen within 2 weeks of starting XALKORI flashes of light blurred vision light hurting eyes new or increased floaters nausea (53-57%) diarrhea (43-49%) vomiting (40-45%) hands and feet swelling (28-38%) constipation (27-38%) Grade 3-4 adverse reactions in at least 4% of patients in both studies : ALT increased & neutropenia

45 Dose modification: hematologic toxicities CTCAE Grade XALKORI Dosing Grade 3 Withhold until recovery to Grade 2, then resume at the same dose schedule Grade 4 Withhold until recovery to Grade 2, then resume at 200 mg twice daily In case of recurrence, withhold until recovery to Grade 2, then resume at 250 mg once daily. Permanently discontinue in case of Grade 4 recurrence. Hematologic toxicities except lymphopenia (unless associated with clinical events, e.g., opportunistic infections)

46 Dose modification: non-hematologic toxicities CTCAE Grade Grade 3 or 4 ALT or AST elevation with Grade 1 total bilirubin (TB) XALKORI Dosing Withhold until recovery to Grade 1 or baseline, then resume at 200 mg twice daily a Grade 2, 3 or 4 ALT or AST elevation with concurrent Grade 2, 3 or 4 TB elevation (in the absence of cholestasis or hemolysis) Any Grade pneumonitis b Grade 3 QTc prolongation Grade 4 QTc prolongation Permanently discontinue Permanently discontinue Withhold until recovery to Grade 1, then resume at 200 mg twice daily a Permanently discontinue a In case of recurrence, withhold until recovery to Grade 1, then resume at 250 mg once daily. Permanently discontinue in case of further Grade 3 or 4 recurrence. b Not attributable to NSCLC progression, other pulmonary disease, infection, or radiation effect.

47 Complex renal cysts Crizotinib 치료받은환자중 8명 (1% 미만 ) 에서복합성신낭종이보고됨 [ 아시아인환자 6명 (2% 미만 )] 치료를시작한이후 2-8개월이내에보고 8명중 2명의환자에서진단당시옆구리통증 어떤환자에서도뇨분석이상이나, 신장애가보고되지는않았음 종양재평가시및옆구리통증이나타나는경우에신낭종에대한방사선촬영모니터링 ( 예. CT, MRI 등 ) 을수행해야함 신낭종으로진단된환자는신기능검사와영상검사를사용한모니터링을고려해야함

48 Case 1 (Female/57 세 ) NSCLC (ADC) stage IV: Dx 1) Gemcitabine+cisplatin X 2: PD 2) : PF (Crizotinib)

49 Baseline After C4: Lt renal cortical cyst

50 Left kidney subcapsular lesion (C6) Tract seeding after aspiration (C10) Liver cystic lesion (C6) Multiseptated cyst (C10)

51 Clizotinib C10 Hold Crizotinib Alimta C2

52 Clizotinib C10 Hold Crizotinib Alimta C6

53 Clizotinib C10 Hold Crizotinib Alimta C6

54 Xanthogranulomatous perinephritis

55 ROS1 1.7% (18/1,073) Younger Never-smoker Adenocarcinoma Asians Good response to crizotinib Bergethon K et al. JCO 2012;30:

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57 Actionable targets in lung adenocarcinomas

58 Actionable targets in squamous cell lung cancer % unknown 100% unknown

59 Summary: 1 st line therapy Testing for EGFR mutation & ALK rearrangements is critical before initiating 1 st -line treatment in advanced NSCLC. Strive to ensure enough cellular material is collected during the initial biopsy for molecular analysis. Platinum-based chemotherapy is still the standard therapy for pan-negative NSCLC.

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61 First-line treatment for pan-negative (EGFR/ALK/ROS1 negative) NSCLC Questions. What is your preferred non-protocol first-line regimen for patients with pan-negative lung adenocarcinoma? 1) Pemetrexed + Cisplatin (or Carboplatin) 2) Gemcitabine+ Cisplatin (or Carboplatin) 3) Platinum-based chemotherapy + Bevacizumab 4) Erlotinib

62 Pem/Cis vs Gem/Cis in 1 st line NSCLC: Survival by histology Nonsquamous histology Months Squamous histology The treatment-by-histology interaction analysis (P=0.001) Scagliotti, et al. J Clin Oncol 2008;26:3543 Months

63 Maintenance chemotherapy Question A patient with advanced lung adenocarcinoma receives 4 cycles of cisplatin/pemetrexed and has had a partial response on CT scan. He has tolerated therapy well but has a grade 1 peripheral neuropathy and grade 2 anemia. ECOG PS of 1 At this point, you would recommend: 1) 2 more cycles of cisplatin/pemetrexed 2) Continuation maintenance with single-agent pemetrexed 3) Switch maintenance with erlotinib 4) Switch maintenance with docetaxel 5) Observation with close follow-up, implementing second-line treatment upon progression

64 Continuous maintenance therapy with pemetrexed (PRAMOUNT) Therapy at PD 58% 58% (PEM 4%)

65 Switch maintenance therapy Trial Year induction Maintenance PFS OS (M) Therapy at progression Tx No Tx No Median P Median P SATURN 2010 Platinum -based X Erlotinib % 12.3 wk Placebo % (EGFR-TKI 16%) 12.0 < wk JMEN 2009 Platinum -based X PEM % 4.0 mo Placebo % (PEM 19%) 13.4 < mo Fidias 2009 GCb X Docetaxel 153 NR 5.7 mo 12.3 <.001 Observation 156 Docetaxel 63% 2.7 mo

66 Factors predicting benefit from maintenance chemotherapy Factors Response to 1 st -line therapy Examples JMEN: CR/PR-OS HR 0.81, SD-OS HR 0.68 SATURN: CR/PR-OS HR 0.94, SD-OS HR 0.72 PARAMOUNT: CR/PR-PFS HR 0.48 (95% CI, ), SD-PFS HR 0.74 (95% CI, ) PS ECOG PS of 0 or 1 Likelihood of therapy at PD Histology Molecular characteristics Fidias: OS was similar in immediate vs. delayed docetaxel SATURN: Adenocarcinoma-OS HR 0.77 (95% CI, ) SQCC-OS HR 0.86 (95% CI, ) JMEN: PFS & OS benefits were confined to nonsq histology The clinical benefit of EGFR-TKI was greatest in EGFR-mutant NSCLC. ATLAS trial: KRAS wild-pfs HR 0.67 ( ), KRAS mutant-pfs HR 0.93 ( )

67 AVAPERL PARAMOUNT PointBreak study

68 Continuous maintenance therapy Survival from maintenance randomization (ITT) PARAMOUT POINTBREAK AVAPERL PRONOUNCE PEM+CP PEM+CP PEM+CB+A Pac+CB+A PEM+CP+A PEM+CP+A PEM+CB PEM+CB+A Median PFS (M) PEM Placebo PEM+A A PEM+A A PEM PEM+A P < < Median OS (M) (maintenance group) 13.9 (16.9) 11.0 (14.0) 12.6 (17.7) 13.4 (15.7) P PEM, pemetrexed; CP, cisplatin; CB, carboplatin; A, Avastin (bevacizumab); Pac, paclitaxel; NR: not reached

69 Second-line treatment for pan-negative (EGFR/ALK/ROS1 negative) NSCLC Questions. What is your preferred non-protocol 2nd-line regimen for patients with pan-negative NSCLC? 1) EGFR-TKI 2) Chemotherapy

70 TAILOR Study Design Advanced/ recurrent Prior platinum -based doublet EGFR wild type KRAS wild type ECOG PS 0-2 R 1:1 Docetaxel 75 mg/m 2 IV d 1, 21 or 35 mg/m 2 IV d 1, 8, 15, 28 Erlotinib 150 mg oral daily CROSS- OVER NOT ALLOWED Stratification: Minimization approach Center Recurrent/progressive disease Prior chemotherapy regimen (pemetrexed vs. gemcitabine vs. vinorelbine) ECOG PS (0-1 vs. 2) Adequacy of tissue sample (optimal vs. suboptimal) Garassino MC, et al. J Clin Oncol. 2012;30. Abstract LBA7501.

71 TAILOR: PFS in Intent-to-Treat Group Docetaxel (n=94) Erlotinib (n=92) P CR 4.3% 0 PR 9.6% 2.2% SD 27.6% 20.6% PD 58.5% 77.2% RR (CR+PR) DCR (CR+PR+SD) 13.9% 2.2% % 22.8% Garassino MC, et al. J Clin Oncol. 2012;30. Abstract LBA7501.

72 DELTA: Docetaxel vs. Erlotinib Advanced NSCLC Prior 1-2 regimens ECOG PS 0-2 EGFR M test R 1:1 Docetaxel 60 mg/m 2 IV Q 3 wks Erlotinib 150 mg oral daily Stratification: Minimization approach Gender PS Histology Institution Okano et al ASCO.

73 DELTA: PFS in Intent-to-Treat Group Docetaxel (n=85) Erlotinib (n=106) P CR 0 0 PR 20.0% 5.6% SD 50.6% 47.2% PD 29.4% 47.2% RR (CR+PR) DCR (CR+PR+SD) 20.0% 5.6% % 70.6% 0.017

74 EGFR-wild type lung adenocarcinomas are heterogeneous!

75 Summary First-line EGFR-TKI Therapy & for patients with EGFR mutations Particular sensitive to EGFR-TKIs: higher RR & longer PFS Improved toxicity profile & QOL of EGFR-TKIs compared to chemotherapy 2 nd generation EGFR-TKI? Chemotherapy is better for EGFR wild type NSCLC in any setting EGFR wild type NSCLCs are not homogenous (ALK, ROS-1, RET, KRAS, etc) Test for other potentially actionable genetic alterations Both continuation & switch maintenance chemotherapy have demonstrated favorable toxicity profile, prolongation of PFS, & -in some instance, an OS benefit. There are still considerable controversies in maintenance therapy Economic consideration Additional toxicity with maintenance therapy In the absence of clear-cut survival advantage or differential improvement in symptoms, it may difficult to justify extending therapy instead of delaying.

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