Solange Peters, MD-PhD Cancer Center, Lausanne Switzerland EGFR AND NSCLC

Transcription

1 Solange Peters, MD-PhD Cancer Center, Lausanne Switzerland EGFR AND NSCLC

2 Interactive Clinical Case

3 History Maria José 1963 Since end 2010, progressive dyspnea Attends Emergency Room after 3 days with cough and fever >39 PMH: None DH: None Current smoker: 35 pack years

4 White left lung Chest X-Ray Additional Evaluations Bronchoscopy: no endobronchial lesion but extrinsic compression of LLL main bronchus -> Lavage and brushing negative Blood tests and hemogram normal except crp 200mg/l -> ad antibiotherapy co-amoxicillin

5 First Intervention Pleural effusion drainage by thoracoscopy (>2l, citrine exudative fluid) Multiple pleural biopsies Dg: Lung adenocarcinoma Poorly differentiated TTF1 +, CK7+, CK 5/6-, p63 -

6 p63 TTF-1 Lung Adenocarcinoma

7 CT scan (ct3 cn0 pm1)

8 PET/CT scan ct3 cn0 pm1

9 Brain MRI Normal Very well Baseline Symptoms Fully active, 2 small kids Mild persisting dry cough Performance status zero

10 Stage IV Lung Adenocarcinoma Heavy smoker 1)Cisplatin-pemetrexed 2)Ciplatin-pemetrexed-bevacizmab 3)Other platinum doublet 4)Other doublet with bev 5)EGFR mutation testing 6)ALK FISH

11 Stage IV Lung Adenocarcinoma Heavy smoker EGFR Exon 19 deletion (E746-A750)

12 Chemo or EGFR-TKI? Overall Response Rate (%) Cis/Pem Cis/Gem Erlotinib Platinum Doublet Scagliotti et al, JCO 2008 Rosell et al, Lancet Oncol. 2012

13 Clinical Course Grade 0 Rash PS 0 No toxicity Ongoing active smoking (!)

14 Restaging CT scan Baseline Post 4wks

15 Restaging CT scan Post 6 months Post 1yr

16 Restaging CT scan Post 12 months months Post 20 months

17 Audience Question: How should treatment be continued? Continue EGFR TKI therapy with close follow up Chemoradiotherapy Chemotherapy Continue EGFR TKI + Thoracic radiosurgery Thoracic radiotherapy Surgery

18 Cancer genome and driver genes 3142 genes mutated in Cancer (Sanger/COSMIC database) 10% (286) of these are driver genes (10% oncogenes, 90% tumour supressor genes affected) Oncogenes About 33 genes described within 12 core pathway By definition, same codon mutated in >2 different tumors Tumor Suppressor Genes 15% of mutations leads to truncation Cannot be inhibited by current approaches

19 2012 update on adenocarcinoma driver mutations KRAS Unknown EGFR NRAS MEK1 MET PTEN HER2 BRAF PIK3CA

20 2012 update on adenocarcinoma driver gene alterations EML4-ALK ALK REA RET REA ROS REA PTEN LOSS PIK3CA AMP Unknown HER2 AMP MET AMP

21 2012 update on squamous carcinoma driver mutations/ gene alterations PTEN PIK3CA KRAS AKT1 DDR2 Unknown LKB1 BRAF EGFR VIII HER2 MET AMP AMP CCND1 AMP EML4ALK PIK3CA AMP PTEN loss FGFR1 AMP SOX2 AMP FGFR2 MULTIPLE HER2 MET Squamous is even more complex grouping by pathways? Prez-Moreno, CCR 2012; Paik, ASCO 2012, TCGA, Nature 2012

22 Molecular standards in NSCLC Minimal testing Peters et al, Ann Oncol 2012

23 Epidermal growth factor receptor (EGFR) signaling pathway (1980) EGFR, HER2 Cell membrane SOS EGFR-TK PI3K Akt ATP P ATP GRB2 STAT MAPK RAS RAF MEK Gene transcription cell-cycle progression Nucleus Proliferation Survival signals Invasion Angiogenesis Metastasis

24 EGFR discovery - 11 patients in 2004 Lynch, NEJM 2004

25 Inhibition of EGFR signaling pathway with activating mutation (2004) EGFR, HER2 ATP EGFR Inhibitors (gefitinib, erlotinib) ATP ATP EGFR-TK pathways PI3K Akt Cell membrane SOS EGFR-TK ATP ATP P ATP GRB2 STAT MAPK RAS RAF MEK Gene transcription cell-cycle progression Nucleus Proliferation Activating mutation ( 15% of patients) Survival signals Invasion Angiogenesis Metastasis

26 Going through simple comparisions Comparison of overall survival between patients who began first-line systemic therapy before or after gefitinib approval (A) All patients (B) (B) Patients with EGFR mutations. Takano, JCO 2011

27 Mutations in the EGFR gene Confer sensitivity/resistance to EGFR TKIs EGFR transcript Unclear effect on sensitivity to EGFR TKIs P694X 18 Extracellular domain Exons 1 16 EGFR Tyrosinekinase domain Exon 17 Exons Exons D761Y 18 D770_N771 insnpg 20 T790M L858R Regulatory domain E709X G719A/S Deletions Transmembrane domain V700D L861X 21 L730F P733L G735S V738F V742A T751I S752Y D761N E746K A763V N765A S768I T783A L792P L798F G810S L833V N826S H835L L838V H850N T847I V851X I853T G863DA864T A859T E866K Riely, Clin Cancer Res 2006

28 Studies of EGFR TKIs versus chemotherapy as first-line therapy in EGFR Act Mut+ NSCLC Study EGFR TKI n Median PFS in TKI arm (months) OPTIMAL Erlotinib < First Signal Gefitinib IPASS Gefitinib < WJTOG 3405 Gefitinib < NEJSG 002 Gefitinib < EURTAC Erlotinib < LUX-3 Afatinib < P value HR

29 EURTAC: erlotinib first-line in EGFR mutation+ NSCLC Phase III study initiated by the Spanish Lung Cancer Group (GECP) Recruitment in Spain, Italy and France Erlotinib 150 mg/day until PD Chemonaïve advanced NSCLC EGFR mutation-positive (exon 19 or L858R) ECOG PS 0 2 R N=174 Primary endpoint: PFS Secondary endpoints: ORR, 1-year survival, OS, safety, QoL, localisation of PD ORR = objective response rate; QoL = quality of life Platinum-based doublet chemotherapy

30 EURTAC: PFS in ITT population 1.0 Erlotinib (n=86) Chemotherapy (n=87) PFS probability 0.8 HR=0.37 ( ) 0.6 Log-rank p< Patients at risk Erlotinib Chemo Time (months)

31 Sensitivity to EGFR-TKI according to different EGFR mutations N EGFR RR (%) PFS (months) OS (months) 278 Classical exon Wild-type Exon 20 insertion G L Uncommon mutations Wu, Clin Cancer Res 2011

32 The risk of a wrong selection: the TORCH study R a n d o m Standard First-line Chemotherapy* PD Second-line Erlotinib** First-line Erlotinib** PD Second-line Chemotherapy* 1:1 Experimental Strata: histology smoking status gender country (Italy, Canada) age ethnicity *Chemotherapy: Cisplatin, 80 mg/m2, day 1 Gemcitabine, 1200 mg/m2, day 1 and 8 every 3 weeks, for 6 cycles **Erlotinib: 150 mg/day p.o. until progression PRIMARY END-POINT: NON INFERIORITY FOR OS

33 Overall survival Patients Events Median OS Months (95% CI) Standard ( ) Experimental ( ) Hazard Ratio 1.36 (95%CI ) Log-rank test p = Patients at risk Standard Experimental

34 Mut+ NSCLC: EGFR-TKI Acquired Resistance Baseline Tumor regression (RR up to 90%) Progression (median 9 months) Cave disease Flare: Hospitalization and/or death attributable to disease progression after discontinuation of gefitinib or erlotinib and before initiation of study drug; >20% patients median time 8 months

35 Mechanisms of TKI acquired resistance Lovly and Pao, Science Trans Med 2012

36 Evolutionary modeling based on growth kinetics No comparative data evaluating rechallenge strategy No prospective customized trial in TKI resistant NSCLC BUT provisional evidences: accumulating retrospective data Chmielecki J, Sci Transl Med 2011

37 Continuation on TKI upon progression A strategy per se Oxnard, ASCO 2012

38 Continuation on TKI upon progression A strategy per se Faehling, ASCO 2012

39 Rechallenge with TKI Author TKI PR (%) SD (%) DCR (%) mpfs mos mos mos Tomizawa 10 N=20 GEF Koizumi 12 N=20 GEF Heon 12 N=24 GEF 30% ERLO 70% NR Tomizawa, Lung Cancer 2010; Koizumi, Clin Lung Cancer 2012, Heon ASCO 2012

40 EGFR resistance mediating mechanisms Combination chemotherapy + EGFR-TKI Change of EGFRTKI Chemotherapy IGF-Inhibitors Second Generation EGFR-TKIs PIK3 TKI Combination EGFR-TKI + EGFR AB HGF AB cmet TKI Met Mab Sequist et al, Sci Transl Med 2011

41 T790M: history of disease Found Germline (40%)! Discordant recent results! Erlotinib is still effective against tumours with de novo T790M n Median PFS (months) T790M T790M PFS probability T790M at baseline : 2.8% sequencing 25% MALDI-TOF 35% deep sequencing T790M at TKI resistance: 33.3% sequencing 83.3% MALDI-TOF Time (months) Rosell, CCR 2011

42 Overcoming EGFR T790M? Promising irreversible pan-her agents in overcoming resistance show unexpected discouraging activity

43 EGFR TKI resistant patients treated with cetuximab-afatinib: update Janjigian, ESMO 2012 Confirmed partial response: 30% (29 of 96 pts), identical in T790M subgroups Median duration of response: 8 months Clinical benefit (partial response or stable disease): 75% (72 of 96 pts)

44 Side-road (bypass tracks) resistance Pao, Nat Rev Cancer, 2010

45 Side-roads EGFR pathways shown to be activated - MET amplification HGF over expression PIK3CA mutations PTEN loss FGRF overexpression AXL overexpression CRKL amplification NFkB activation BRAF mutation Yano, JTO 2011; Sos, Cancer Res, 2011; Ware, PLoS one 2010, Zhang Nat Gen 2012; Ohashi PNAS 2012; Tabara, Plos one 2012; Ng, Nat Med 2012

46 Wilson, Nature 2012

47 Other EGFR TKI resistance biological processes - Anti-apoptotic pathway (BIM deletion) Loss of EGFR mutant gene Transformation to SCLC EMT Yano, JTO 2011; Sos, Cancer Res, 2011; Ware, PLoS one 2010, Zhang Nat Gen 2012; Ohashi PNAS 2012; Tabara, Plos one 2012; Ng, Nat Med 2012

48 Conclusions: EGFR activating and sensitizing mutations in NSCLC The majority of lung adenocarcinoma in Caucasian patients harbor potentially druggable genetic oncogenic alteration EGFR alteration and TKI availability has opened an new era of customized treatment dramatically modifying the survival of selected patients Resistance mechanisms open the complexity of further treatment development at various levels: Tumour heterogeneity Pathways signaling redundancy and feed-back loops Clonal selection and kinetics of cancer cell populations Multiple concomitant drivers existence Need for TKI/targeted agents combination trials (phase I, vertical or horizontal blockade of pathways)

49 Conclusions: EGFR activating and sensitizing mutations in NSCLC (2) Other strategies targeting apoptotic pathways, HSP function, and anticancer immune response are emerging and seem promising in NSCLC, in combination or not with available approaches. A similar picture, with some more complexity, is emerging on lung squamous cell carcinoma Further progress mandates a move from unselected NSCLC trial designs to molecularly-driven clinical trials Such trials will require the building of large, flexible and international collaborative groups

50 Thanks for your attention