updates da Sidney NSCLC stadi iniziali Il trattamento adiuvante: focus on EGFR Dr Giuseppe L. Banna A.O. Cannizzaro Catania Hotel Guinigi

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1 Post-IASLC updates da Sidney NSCLC stadi iniziali Il trattamento adiuvante: focus on EGFR Dr Giuseppe L. Banna A.O. Cannizzaro Catania Hotel Guinigi

2 Conflitti di interesse Ai sensi dell art art del Regolamento applicativo dell Accordo Stato-Regioni , dichiaro che negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con i seguenti soggetti portatori t di interessi i commerciali in campo sanitario: i Italfarmaco Lilly Roche In fede, Giuseppe Luigi i Banna

3 Overall survival by ypathological stage TNM 7 edition (No. NSCLC Pts =81,015) Non esiste un cancro del polmone a buona prognosi! Goldstraw P et al J Thorac Oncol 2007; 2:

4 Recurrence following resection Kris MG WCLC 2013

5 Gene signature-directed ACT The 15-gene expression signature to guide decisions for ACT in stage IB/II NSCLC could be highly costeffective Wong KiM, WCLC 2013

6 Storia della chemioterapia adiuvante 1995: RCTs controversi underpowered LCCG meta-analisi (MA) Trend NS per chemioterapia CDDP-based N.7 RCTs powered - Beneficio significativo per ACT (3+/4-) LACE MA Lancet MA - Beneficio significativo per ACT Long-term results RCTs (JBR.10-IALT) - Beneficio i ed effetti a lungo termine Primi trials con targeted therapies

7 MA LACE (RCTs following 1995) Median follow-up 5.2 years Score card for Adjuvant CT HR 0.89 (95% CI, ; P=.005) AB at 5 ys of 5.4% Stage HR IA 1.40 IB 0.93 II 0.83 IIIA 0.83 ALPI BLT IALT JBR.10 HR 0.84 (95% CI, ; P<.001) AB at 5 ys of 5.8% ANITA CALGB ECOG NOT TESTED NEGATIVE POSITIVE Pignon J-P et al, J Clin Oncol 2008

8 NSCLC-CG (MRC) Lancet RCTs da 1 Gennaio No RCTs con alchilante >1 yr 34 RCTs 8447 pts F.U. median 5.5 yr HR 0.86 (95% CI, ; P<.0001) AB at 5 ys of 4% 13 RCTs 2660 pts F.U. median 6.4 yr HR 0.88 (95% CI, ; 0 P=.009) AB at 5 ys of 4% NSCLC MACG, Lancet 2010

9 LACE NAVELBINE MA LACE 5 trials (ALPI, BLT, ALT, JBR.10, ANITA) 4584 pts Absolute survival benefit of 8.9% at 5-years LACE NAVELBINE 4 trials (BLT, ALT, JBR.10, ANITA) 1888 pts Absolute survival benefit of 8.9% at 5-years Survival (%) Chemotherapy Control +5.3% Surv vival (%) NAVELBINE + cisplatin Control +8.9% p= Time (years) N.B: NNT per LACE = 1/19, per LACE NVB =1/11, ovvero da a pts vivi in più a 5 yr 20 0 p= St I: +1.8% St II: % St IIIA: % Time (years) Pignon, JCO 2008; Douillard, JTO 2010

10 Lung e non-lung cancer death IALT Non correlata con: - Età(<65vs vs. 65) - Stage - PS - Dose di CDDP HR 1.34 (95% CI, ; P=.06) No effect of PORT LACE The absolute effect of CT at 5 ys: - of f69%f 6.9% for lung cancer death - of 1.4% for non lung cancer death* (*pulmonary/cv disease, CT tox.; 1st 6 mo.) Pignon J-P et al, J Clin Oncol 2009 Arriagada R et al, J Clin Oncol 2010

11 Long-term results IALT FU median 7.5 ys JBR.10 FU median 9.3 ys HR 0.91 HR 0.78 (95% CI, ; P=.10) (95% CI, ; P=.04) AB at 5 ys of 3.9% AB at 5 ys of 11% Arriagada R et al, J Clin Oncol 2010 Butts CA et al, J Clin Oncol 2010

12 ACT adoption - Population-based retrospective cohort study (Ontario) - Surgical resection (6570 pts) from 2001 to Preadoption and postadoption p cohort cut-off Adoption: from 7% to 31% (P<.001) (Only 16% 70 yr treated; more likely to receive ACT younger age, less comorbidity, shorther length of surgical stay in hosp., more extensive surgery) - Hospitalization rate unchanged at 6-12 mo. (34 vs. 33%) and mo. (50 vs. 50%) ( 24 mo. of surgery 33% red. in % of pts admitted to hospital for metastatic disease (P<.001) Conferme: Traslazione del beneficio da RCTs a societal benefit senza incremento in tossicità (validità esterna di RCTs) Rapida adozione della CT adiuvante 4-yr OS from 52.5% to 56.1% Booth CM, J Clin Oncol 2010

13 ACT adoption - ISA survey IIIB IIIA IIB Indication for adjuvant chemotherapy by stage N. 51 (78%) 61 (94%) 56 (86%) - 46-item questionnaire (yr 2008) - 78 physicians - 68 out of 98 Italian Centers (53% North 4 % South-Centre-Islands) - Disclosed adherence to GL 97% - 3 confirmation questions by 65 phys. IIA 48 (74%) N. 10 N. N. 28 (43%) IB 9 (14%) 2 3 (5%) NA 0 (0%) (29%) (22%) Preferred adjuvant chemotherapy regimen 50 (64%) N (2%) not indicated 0 (0%) Expected NNT estimation (28%) N (33%) 25 (32%) (2%) 33 (51%) (6%) (1%) 1 (1%) 50 not indicated 0 (0%) 9 (14%) Known NNT estimation Cis-Vin Cis-Gem Carbo-Pac Carbo-Gem >1 regimen Banna GL et al on behalf of all ISA Investigators, Lung Cancer 2011

14 Key ypoints of ACT NSCLC has not a good prognosis ACT is beneficial in stage II-IIIA ACT is beneficial in PS 0-1 (not in PS=2) Probably beneficial in elderly (>70 ys) pts Probably beneficial in tumors >4 cm Most evidence with CDDP-Vinorelbine Rapid adoption in clinical practice Possible non-lung cancer death Long term results are important

15 ACT guidelines Guideline Source Consensus: ACCP Chest 2007;132 ESMO Annals of Oncology 21 (Supplement 5): v103 iv115, 2010 ASCO J Clin Oncol 27: , 2009 published online at on November 16, AIOM NCCN Novembre Version Ontario J Clin Oncol 25 (34) 2007 published online at AIOT Stages II-IIIA, good PS and surgery outcome, young patient Grey area: Stage IB (TNM v6.0) Partner of cisplatin Elderly patient ACT vs. NACT Research area: Treatment personalization Modified - Courtesy of Bria & Cecere F, 2011

16 AB, NNT, HR (+RCTs & MAs) RCTs #Pts OS AB HR (95% CI) p NNT IALT % 0.86 ( ) <.03 1:25 JBR % 0.70 ( ).022 1:8 ANITA % 0.79 ( ).013 1:12 LACE % 0.89 ( ).004 1:19 LCCG % 0.86 ( ) <.001 1:25 Le misure assolute sono più comprensibili dai pazienti rispetto ad HR: da studi di comunicazione in BC, se si utilizza HR è più probabile che i pazienti preferiscano la chemioterapia ma meno probabile bil che ne abbiano compreso il reale beneficio i Chao C et al, J Clin Oncol 2003

17 AB, NNT, HR & Pazienti da MAs Beneficio i assoluto= 4-5.4% 54% NNT 1:25= pts vivi i NNT= 1:19/25 RR= dall 11 al 14% NNT 1:19= pts 5 yr NSCLC MACG, Lancet 2010

18 Need of personalization of treatment Selection and treatment of a target tumor driver Tailoring chemotherapy based on individual id molecular l markers (ERCC1, BRCA1, RRM1, TS, genomic alterations) Targeting microenviromental factors S Mayor, BMJ 2007

19 Need of personalization of treatment Selection and treatment of a target tumor driver EGFR S Mayor, BMJ 2007

20 EGFR TKIs in advanced NSCLC

21 EGFR directed adjuvant therapy Can we extrapolate these findings to use EGFR TKIs in patients with earlier stages (I-IIIA) IIIA) disease, which h could potentially ti improve long-term survival?

22 EGFR target population: p size Hirsch, WCLC 2013

23 Inter-/Intra-Tumoral heterogeneity

24 Intra-Tumoral heterogeneity Mizoguchi K, WCLC 2013

25 Tumor-driver genes

26 Role of different EGFR mutations

27 Challenges in EGFR-directed AT Size of target population p (10-15%) Inter- and intratumoral heterogeneity Role of driver for EGFR mutation Role of different EGFR driver mutations (i.e. sensitinzing, or not, mutations)

28 EGFR-directed AT in unselected pts? In patients not selected based upon EGFR mutation status, adjuvant EGFR TKIs do not improve survival

29 NCIC CTG BR.19 study

30 SWOG 0023 study

31 NCIC CTG BR.19 study

32 NCIC CTG BR.19 study Median duration of treatment with gefitinib was 4.8 mo. vs. 8.9 with placebo

33 NCIC CTG BR.19 study

34 NCIC CTG BR.19 study = 4%

35 Apparent detrimental effect Possible explanation: The study is underpowered; the gefitinib arm did poorly by chance alone The study is underpowered with EGFR mutation- positive patients Duration of treatment with gefitinib may have been to short to see therapeutic effect The EGFR pathway may play a less important role in early disease and tumours are not as dependentd on this pathway as oncogenic driver as later stage disease Liam CK, WCLC 2013

36 Detrimental effect in untargeted PRIME Study First-line chemotherapy in CRC TORCH First-line CT or erlotinib for advanced NSCLC C

37 Real detrimental effect: an hypothesis

38 Real detrimental effect: an hypothesis Acquired resistance for EGFR in NSCLC

39 Acquired resistance with EGFR TKI? Of 22 pts receiving adjuvant EGFR TKI, 14 recurring pts were retreated with median TTP of 10 mo. and ORR 73% BUT: - T790M more common in recurrent cancer while receiving adjuvant TKI (67% vs. 0, p=0.011)

40 RADIANT study Start date: Sep 2006 Estimated study completion date: June 2006 Primary completion date: april 2013 (final data collection date for primary outcome measures) Up to 4 cycles of ACT after surgery Enrollment complete 80% of pts EGFR+ve by IHC or FISH 12% EGFRmut+ve

41 EGFR-directed AT in selected pts In patients selected based upon EGFR mutation status, adjuvant EGFR TKIs do improve survival?

42 Retrospective data from MSKCC

43 Retrospective data from MSKCC Patients with EGFR-mutant lung cancer who received an adjuvant EGFR TKI had a numerically superior DFS, however, this difference was not significant, HR 0.53 (95%CI: , p=0.06) Patients with EGFR-mutant lung cancer who received an adjuvant EGFR TKI showed a numerically superior OS, however, this difference was not significant, HR 0.62 (95%CI: , p=0.296)

44 Retrospective data MSKCC (updated) Pts received EGFR TKIs both in the adjuvant setting, and at recurrence 45% of the pts 45% of the pts received erlotinib or gefitinib following ACT

45 Retrospective data MSKCC (updated) Patients with EGFR-mutant lung cancer who received an adjuvant EGFR TKI had a longer DFS than those who did not receive an adjuvant EGFR TKI, HR 0.43 (95%CI: , p=0.001) Patients with EGFR-mutant lung cancer who received an adjuvant EGFR TKI showed a numerically superior OS, however, this difference was not significant, HR 0.50 (95%CI: , 08 p=0.076) 076) 45% of the pts received erlotinib or gefitinib % p g following ACT

46 The SELECT phase II study

47 The SELECT study Conclusions: - Treatment with adjuvant erlotinib in EGFR mu+ve NSCLC is feasible - Some patients required dose reduction or discontinuation - The observed 2-yr DFS was 94%

48 The SELECT study In BR.19 study median duration of treatment with gefitinib was 4.8 mo. vs. 8.9 mo. with placebo In RADIANT study, median duration of erlotinib was 18.6 mo. In MSK pts, median duration of gefitinib or erlotinib was 16 mo.

49 Previous safety data

50 AT with EGFR-TKIs in EGFRmut+ve The potential role of adjuvant EGFR TKIs in patients with completely resected NSCLC that contains a sensitinzing mutation in EGFR remains uncertain No. of EGFR mutation positive patients have sufficient power to make firm conclusion about genotype-directed conclusion about genotype directed adjuvant therapy?

51 Which is the correct trial design? Example: TASTE study based on EGFR and ERCC1

52 The TASTE study

53 ALCHEMIST schema Kris MG, WCLC 2013

54 Driver mutations in NSCLC

55 Driver mutations & therapy in NSCLC

56 Other ongoing g trials in EGFR mut+ve Questions: - Should we optimise the feasibility of a prospective RCT comparing adjuvant EGFR TKIs with standard treatment by conducting it where there is an higher incidence of EGFR mutations, as in Asian populations? - Is DFS the right primary endpoint for RCT comparing adjuvant EGFR TKIs with standard treatment? - Which is the optimal duration for Which is the optimal duration for an adjuvant EGFR TKI therapy?

57 The example of imatinib for GIST

58 Other ongoing g trials in EGFR mut+ve

59 Other ongoing g trials in EGFR mut+ve Kris MG, WCLC 2013 Trial design innovations: -Primary endpoint: pathologic documentation of recurrence -Internet-based data collection -No pathology review needed mutation presence only required -No scan data collection needed -No blood testing needed

60 Neoadjuvant vs Adjuvant factors Factors favoring neoadjuvant therapy: Attacks micrometastases t at earliest time Better drug delivery and tolerability Ability to assess sensitivity of agents planned for adjuvant Platform for new agent testingti Surgical findings an outcome surrogate Time to identify unsuspected metastases and comorbidities before locall therapy Randomized trials equivalent or better Provides quicker answers Kris MG, WCLC 2013

61 Neoadjuvant vs Adjuvant EGFR TKI - 15% of pts with stage IIIA-NS disease - Ineligibile staging g (CT scan vs. EBUS) - RRR 40% - DCR 66.5%

62 EGFR-Ras pathway

63 JBR.10 & K-ras Mutazioni di RAS nel 24% dei pts (in 451 dei 482 pts) Trend non significativo in wtras per ACT In wtras: median OS di 66yrvs78yr In mutras: median OS di 7.8 vs 9.7 yr Butts CA et al, J Clin Oncol 2010

64 Adjuvant GI-4000 KRAS vaccine

65 Need of personalization of treatment Selection and treatment of a target tumor driver Tailoring chemotherapy based on individual id molecular l markers (ERCC1, BRCA1, RRM1, TS, genomic alterations) Targeting microenviromental factors S Mayor, BMJ 2007

66 PIII-RCTs on ACT with biomarkers Updates: - SCAT study has completed recruitment with 500 pts; maiority of resected NSCLC showed low levels expression BRCA1 (adeno<scc); customization required less dose reduction - ITACA study: 558 pts randomized from 26 institutions Massuti B, WCLC 2013 Novello S, WCLC 2013

67 Adjuvant chemo-immunotherapy

68 Hallmarks of LC adenocarcinoma

69 Reason for PRO at WCLC 2013 EGFR induces apoptosis and its exposition to EGFR positive patients potentially induces eradication of micrometastasis remaining after surgery For the EGFR positive patients, EGFR-TKI is superior to standard platinum-doublet in terms of safety and tolerability EGFR-TKI is the most potent anti-cancer drug for EGFR positive patients t at tthe moment, which hshows remarkable antitumor effect, prolongs PFS and improves QoL compared to platinum-doublet Therefore, despite the issue of ILD remains, EGFR-TKI is to be considered as an appropriate treatment option in adjuvant setting for the EGFR positive patients. In order to prove this point, West Japan Oncology Group (WJOG) is currently conducting IMPACT trial, which is a prospective Phase III study Nakagawa K, WCLC 2013

70 Conclusions It is unclear whether EGFR TKIs improve outcome over traditional ACT in NSCLC It is premature to recommend adjuvant EGFR TKI for EGFRmut+ve NSCLC patients outside clinical trials The optimal duration of adjuvant EGFR TKI therapy is yet to be defined What is the prognostic/predictive effect of rare mutations? Adjuvant EGFR TKI versus TKI at relapse in EGFR mutation positive patients? (trial primary endpoint OS vs. DFS) The quality of life of patients while on therapy and the financial cost involved also need to be considered

71 The best cure of NSCLC GRAZIE PER L ATTENZIONE!

72 Phase III Targeted Adjuvant Trials Trial Stage Therapy Target No. pts 1 EP BR.19 IB-IIIA Gefitinib (EGFR) 503 x 2 yr ND OS RADIANT I-IIIA Erlotinib x 2 yr EGFR-IHC+ 974 DFS E1505 IB( 4cm)- IIIA Chemo +/- Bevacizumab? 1500 OS MAGRIT IB-IIIA Vaccine x27mo MAGE-A DFS

73 PIII-RCTs ongoing g con biomarcatori Tailoring CT: ITACA (ERCC1, TS); SCAT (BRCA); TASTE (ERCC1) TASTE Intergroup Francophone de Cancerologie Thoracique Targeted therapies: RADIANT, ECOG E1505 MAGRIT (MAGE-A3)

74 RADIANT - biomarker outcomes 974 pts enrolled 17% EGFR mut 27% F, 10% M 46% Asian, 4% Black, 11% Caucasians 53% non smoker (S), 4% current S, 9% former S 28% adenocarcinoma, 4% Sqamous cell 16% KRAS mut 6% NS, 14% CS, 20% FS Richardson WCLC 2011 O28.01

75 BR.19 & Kras & EGFR FISH - K-ras in 350 pts 27% mutations - EGFR FISH in 348 pts 41% amplification - K-ras, EGFR FISH not prognostic - Baseline factors balanced - Stage II, never smoker and Asian more likely to have EGFR mutations Goss PASCO 2010, abstr 7005

76 Biomarcatori ERCC1 (IHC) (BioALT) vantaggio in OS ristretto a tumori ERCC1 negativi in IALT (prognostico negativo, predittivo positivo) (HR=0.76; 95% CI ) 1 Ras wild-type trend a favore di maggiore beneficio per cancer- specific survival da CT adiuvante in JBR.10 (non prognostico) 2 RRM1 and p53 mutations sono state testate in trials recenti 3 ALK fusion oncogenes (4%) e inibitori di ALK 4 Bio-LACE in corso 5 ; TUBB3 prognostic but not predictive 6 BRCA1 mrna levels: low-level correlato con OS dopo CDDP- based CT 7 ; high-level correlato con OS dopo taxane-based CT 8 TS maggiormente espresso in SCC 9 1. Olaussen KA et al, New Engl J Med Arriagada R et al, J Clin Oncol Chhatwani L et al, Proc Am Thorac Surg Bang Y et al, Proc. ASCO Douillard JY et al, J Clin Oncol Reiman T, Ann Oncol Taron M, Hum Mol Genet Quinn JE Clin Cancer Res Ceppi P, Cancer 2006

77 Early stages Predictive biomarkers

78 Early stages Prognostic biomarkers

79 HER-2 history What did work? Identification of a target tumor-driver Reliable biological characterization (IHC, FISH) Identificazione of active targeted drugs Optimal therapeutic strategy