5 th most commonly diagnosed cancer in Australia 89 of new cancer diagnoses In 2009 10193 cases 6034 men 4159 women Projection to 2020 13640 Mortality In 2010 most common cause of cancer death ID: 1041146
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1. Treatment in Advanced Non-Small Cell Lung Cancer
2. 5th most commonly diagnosed cancer in Australia8.9% of new cancer diagnosesIn 2009: 10,193 cases (6034 men, 4159 women)Projection to 2020 13,640MortalityIn 2010 most common cause of cancer death18.9% of cancer deaths8099 deaths ( 4934 men, 30165 women)Age of diagnosisAverage 71NSCLC| Epidemiology- Australia
3. NSCLC| Staging
4. Meta-analysis of 8 trials (778 patients) using cisplatin-based chemotherapy[1]Absolute improvement in survival of 10% at 1 yr[1]Median survival, BSC vs chemo: 4 vs 8+ mos, respectivelyMedian survival now 12+ mos in more recent trialsVEGF-targeted therapy plus platinum doublet[2]Quality-of-life benefit from chemotherapy[3]NSCLC| Chemotherapy: should we give it?1. NSCLC Collaborative Group, et al. BMJ. 1995;311:899-909. 2. Herbst R, et al. Clin Lung Cancer. 2009;10:20-27 3. Klastersky J, et al. Lung Cancer. 2001;34(suppl 4):S95-S101.4. Chambers et al. BMC Cancer. 2012; 12: 184
5. AgeElderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care aloneMay have higher toxic effects in bone marrow but derive the same survival benefitCo-morbiditiesNSCLC| Who should we give Chemotherapy to?Langer CJ, Vangel M, Schiller J, et al.: Age-specific subanalysis of ECOG 1594Langer CJ, Manola J, Bernardo P, et al.: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592
6. Performance StatusPatients with PS 2 have significantly worse median survival and overall survival when compared to patients with PS 0-1.NSCLC | The patient in front of youGradeECOG Performance Status0Fully active1Restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature2Ambulatory and capable of all self care. Up > 50% of waking hours3Capable of only limited self care, confined to bed or chair for > 50% of working hours4Completely disabled. Cannot carry on any self care. Totally confined to bed or chair
7. NSCLC | HistologySquamous cell carcinoma:(25% to 30%) Arise in early versions of squamous cells that line airways, tend to be central, near a bronchusStrongly linked to smokingAdenocarcinoma:(40%) More common in smokers ,but most common type of lung cancer seen in non-smokers. Women > men, and it is more likely to occur in younger people than other types of lung cancer.More peripheral, higher rates of metastases on presentationsLarge cell (undifferentiated) carcinoma: (10% to 15%) Rapid growth,
8. Heterogenous group of diseasesHistopathology and molecular characterisation guide treatmentDistinct prognostic and predictive implications NSCLC| Tumour Biology
9. AdenocarcinomaSquamous Cell CarcinomaCarboplatin & PemetrexedEGFR MutationEGFR WildtypeCarboplatin &GemcitabineErlotinibGefitinibAfatinibNSCLC| First line Therapy+/- Bevacizumab+/- Cetuximab+/- Cetuximab
10. Combination cytotoxic chemotherapy remains the backbone of initial systemic treatmentNSCLC| Absent Mutations
11. Meta-analysis: 65 trials (N = 13,601) between 1980-2001Compared efficacy ofDoublet vs single-agent regimensTriplet vs doublet regimensDelbaldo C, et al. JAMA. 2004;292:470-484.Survival OutcomeDoublet vs Single-Agent RegimensTriplet vs DoubletRegimens1-yr OSDoublet > single-agent OR: 0.80; 95% CI: 0.70-0.91;P < .001 5% absolute benefitTriplet = doublet OR: 1.01; 95% CI: 0.85-1.21;P = .88Median OSDoublet > single-agent MR: 0.83; 95% CI: 0.79-0.89;P < .001Triplet = doublet MR: 1.00; 95% CI: 0.94-1.06;P = .97NSCLC| Initial Systemic Therapy: how many drugs?
12. NSCLC| Which regimen?
13. First lineSecond lineThird lineMaintenanceNot approved1970198019902000MedianOS (mos)12+~ 6~ 2-4BSCSingle-agent platinumDoubletsBevacizumab + PCCarboplatin*1989ErlotinibPemetrexed2004Docetaxel1999PaclitaxelGemcitabine 1998Vinorelbine1994Docetaxel2002Bevacizumab2006Gefitinib2003Standard therapies*Label does not include NSCLC-specific indicationPemetrexed2008/2009 Histology-directed therapy~ 8-10 Cisplatin*19781. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.NSCLC| History of Therapy in Advanced NSCLC
14. Paclitaxel 225 mg/m2 over 3 hrs on Day 1Carboplatin AUC 6.0 mg/mL/min on Day 13-wk cycleDocetaxel 75 mg/m2 on Day 1Cisplatin 75 mg/m2 on Day 13-wk cycleGemcitabine 1000 mg/m2 on Days 1, 8, 15Cisplatin 100 mg/m2 on Day 14-wk cycleReference ArmPaclitaxel 135 mg/m2 over 24 hrs on Day 1Cisplatin 75 mg/m2 on Day 23-wk cycleECOG 1594: Comparison of 4 First-line Doublet Regimens in Advanced NSCLCStratified by:ECOG PS (0/1 vs 2)Weight loss in previous 6 mos (< 5% vs ≥ 5%)Disease stage (IIIB vs IV or recurrent)Brain metastases (yes vs no)Advanced-stage, previously untreated NSCLC patients(N = 1207)Schiller JH, et al. N Engl J Med. 2002;346:92-98.NSCLC| Which Chemotherapy?
15. Schiller JH, et al. N Engl J Med. 2002;346:92-98.1.00.80.60.40.20Proportion of patientsMos051015202530Survival by Treatment GroupAll Randomized CasesCisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxelNSCLC| Which Chemotherapy?
16. Patients with squamous cell cancer can have gemcitabine-based therapy, pemetrexed is not recommended and bevacizumab is contra-indicated. Patients with adenocarcinoma benefit from treatment with pemetrexed, EGFR inhibitors, and bevacizumab.NSCLC| Which Chemotherapy?
17. Doublet chemotherapy for 4-6 cycles is standardPlatinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Caveat: Patients with adenocarcinoma may benefit from pemetrexed. Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects.Non-platinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority. NSCLC| Chemotherapy overview
18. Antiangiogenesis: VEGF targeted (bevacizumab)EGFR-targeted antibody (cetuximab), TKI (erlotinib)Newer targets (ALK and others)Recent identification of “driver mutations” in 50% of NSCLC adenocarcinomasNSCLC| Additional Agents
19. Bevacizumab Antibody targeting vascular endothelial growth factor Can be added to standard first-line combination chemotherapy in non-squamous lung cancer. NSCLC| Bevacizumab
20. HypertensionBleeding HaemoptysisBrain metsSquamous cells more likely to bleedPoor wound healingNSCLC| Bevacizumab: Adverse Effects
21. Testing for EGFR can take time.Current recommendations are if patient has commenced CTx should continue and complete the treatment? Commence maintenance? Watchful waiting then commence once progressionIf toxic SEs can swap to EGFR TKI if possibleNSCLC| Unknown mutation status
22. NSCLC| Bevacizumab E4599Advanced NSCLC (stage IIIB or IV)- non- squamous Randomised to paclitaxel/ carboplatin or paclitaxel/carboplatin + bevacizumabExcluded brain mets and haemoptysisSandler A, et al. N Engl J Med. 2006;355:2542-2550.AVAiLAdvanced NSCLC (stage IIIB or IV)- non- squamous Randomised to cisplatin/gemcitabine + placebo/low dose bevacizumab/ high dose bevacizumabExcluded brain mets and haemoptysisConfirmed outcome with less spectacular resultsReck M, et al. J Clin Oncol. 2009;27:1227-1234..
23. Oncogenic ActivationEpidermal Growth Factor ReceptorAnaplastic Lymphoma Kinase geneMET as a therapeutic target in NSCLCNSCLC| Genotype Directed Therapy
24. Mutations within cancer cellsGenes essential for cell growth and survivalTransformativeInitiate the evolution of a non-cancerous cell- to malignancyNSCLC| Driver Mutations
25. Current molecular targets for NSCLC
26. NSCLC| Epidermal Growth Factor
27. 15% of NSCLC overallHigher rates withinAdenocarcinomaNon-smokerAsianWomenYoungNSCLC| EGFR
28. NSCLC| Single Agent EGFR TKIGefitinibIPASS trial (gefitinib v carboplatin/paclitaxel)EGFR not initially tested (clinical criteria only)Progression Free Survival (12 month)Overall SurvivalGefitinib25 (HR 0.74)18.8*Carboplatin/Paclitaxel717.4*
29. StatusTreatmentPFSOSEGFR +Gefitinib9.5 (HR 0.48)22EGFR+Carboplatin/Paclitaxel6.322EGFR -Gefinitib1.5 (HR 2.85)11.2EGFR -Carboplatin/ Paclitasel6.512.7NSCLC| IPASS trial
30. January 2002 October 2004 NSCLC| Results!
31. OPTIMALPFSOSErlotinib13.1Gemcitabine/ Carboplatin14.6NSCLC| ErlotinibEURTACPFSOSErlotinib9.719.3Platinum doublet5.219.5
32. ToxicityRashGI toxicities:DiarrhoeaPneumonitisHepaticHepatic failureHepatorenal syndromeNSCLC| Erlotinib
33. SomaticmutationSmallavasculartumorTumor secretion of proangiogenic factors stimulates angiogenesisRapid tumor growth and metastasisAngiogenic inhibitors may reverse this processFolkman J. N Engl J Med. 1971;285:1182-1186.NSCLC| Anti-Antiangiogenesis
34. Over time there is formation of acquired resistance50% of acquired resistance is due to T790M ? blocks binding of TKIs such as gefitinib and erlotinibIrreversible EGFR-TKIs in development (afatinib, HKI272, PF00299804, BMS690514)Kobayashi S, et al. N Engl J Med. 2005;352:786-792. Engelman JA, et al. Science. 2007;316:1039-1043. Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501. Bean J, et al. Clin Cancer Res. 2008;14:7519-7525.NSCLC| Acquired resistance to EGFR
35. Primary endpoint: OSSecondary endpoints: PFS, response, QoL, safetyMiller VA, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2010. Abstract LBPL3.Patients with stage IIIB/IV lung cancer, progression after 1-2 lines of chemo, ≥ 12 wks of erlotinib or gefitinib, and ECOG PS 0-2(N = 585)Afatinib 50 mg QD + BSC (n = 390)Placebo QD + Best Supportive Care (n = 195)Randomized 2:1 (double blind)NSCLC| Afatinib
36. Miller VA, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2010. Abstract LBPL3.Placebo (133 events): median PFS: 1.1 mos (95% CI: 0.95-1.68)Afatinib (275 events): median PFS: 3.3 mos (95% CI: 2.79-4.40)HR: 0.38 (95% CI: 0.306-0.475; log-rank P < .0001)1.00.80.60.40.20.0Estimated PFS Probability0369121518PFS Time Since Randomization (Mos)Pts at Risk, nPlaceboAfatinib1953901515246521693NSCLC| Afatinib
37. Miller VA, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2010. Abstract LBPL3.Placebo (144 deaths; 58.5%): median OS: 11.96 mos (95% CI: 10.15-14.26)Afatinib (244 deaths; 62.6%): median OS: 10.78 mos (95% CI: 9.95-11.99)1.00.80.60.40.20Estimated Survival Probability0369121524Time to Death Since Randomization (Mos)HR: 1.077 (95% CI: 0.862-1.346; log-rank P = .7428)Pts at Risk, nPlaceboAfatinib19539016934414228311221733691832182165122512NSCLC| Afatinib
38. Met amplification ~ 20% of acquired resistanceMultiple drugs in development (XL184 [cabozantinib], MetMab, ARQ197)Often combined with EGFR-TKIOther resistance mutations in EGFR reportedT854A, D761Y . . .NSCLC| Erlotinib
39. Soda M, et al. Nature. 2007;448:561-566. Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase that is normally not expressed in the lung.Fusions of ALK with another upstream partner, EML4, were found in NSCLC in 2007. EML4-ALK fusions result from diverse small inversions within the short arm of chromosome 2.Biologically, EML4-ALK fusions result in protein oligomerisation and constitutive activation of the kinase.ALK mutations are found in 4% of the NSCLC and occur more frequently in young and non-smoking patientsNSCLC| ALK rearrangement in NSCLC
40. CrizotinibDual selective inhibitor of ALK and c-METATP-competitive inhibitorOrally available small moleculePotent inhibition of cell growth and induction of apoptosis in NSCLC cell linesDemonstrated safety in dose-escalation studyTan W, et al. ASCO 2010. Abstract 2596. NSCLC| Crizotinib in ALK +ve NSCLC
41. Kwak and colleagues evaluated safety and efficacy of crizotinib in ALK-positive NSCLC patients (N = 82)Kwak EL, et al. N Engl J Med. 2010;363:1693-1703.Percent Change From BaselinePatient No.604020-40-10010204050607079300-20-60-80-30%PDSDPRCRNSCLC| Crizotinib in ALK +ve NSCLCz: Tumour response
42. Probability of PFSMosMedian follow-up for PFS: 6.4 mos (95% CI: 5.5-7.2)95% Hall-Wellner confidence limits1.000.750.500.25002.55.07.510.012.515.017.5Kwak EL, et al. N Engl J Med. 2010;363:1693-1703.NSCLC| Crizotinib in ALK +ve NSCLC
43. Visual disturbances include the appearance of flashing lights, floaters, and overlapping shadows Visual Symptom Assessment Questionnaire for patients in PROFILE 1005 – 63% (114/182) had experienced visual side effects by C#2 of crizotinib. Improved to 41% (46/112) by C#5.Kwak EL, et al. NEJM 2010; 363 (18): 1693-1703.Salgia R, et al. ASCO 2012. Abstract 7596.NSCLC| Crizotinib in ALK +ve NSCLC
44. Patients with EML4-ALK fusion NSCLC have a better OS with crizotinib than with standard therapyShaw AT, et al. Lancet Oncol 2011; 12 (11):1004-1012.Median OS – not reached ~ 18 monthsMedian OS – 6 monthsNSCLC| Crizotinib in ALK +ve NSCLC
45. September 2011 April 2012NSCLC| Crizotinib in ALK +ve NSCLC
46. EML4-ALK defines a new molecular subset of NSCLCPatients are more likely to be young, never/light smokers with adenocarcinomaCrizotinib results in a 6-month PFS of 72% and overall response rate of 57% at 6.4 monthsOngoing clinical trials to assess benefit of chemotherapy vs. targeted therapyOver time tumours can develop resistance2nd generation ALK TKIs and HSP90 inhibitors offer promise in patients with crizotinib resistanceNSCLC| Crizotinib in ALK +ve NSCLC
47. Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment ParadigmEGFRKRASUnknownALKBRAFPIK3CAERBB2MEK1ERBB2 AmplificationMET AmplificationNSCLC| Crizotinib in ALK +ve NSCLC
48. NSCLC| More Targets
49.