Lungcancerbiologi en uppdatering. Stéphanie Mindus, specialistläkare Lung- och Allergisektionen, Akademiska sjukhuset, Uppsala

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1 Lungcancerbiologi en uppdatering Stéphanie Mindus, specialistläkare Lung- och Allergisektionen, Akademiska sjukhuset, Uppsala

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3 Strålbehandling Stort behov av nya lungcancerbehandlingar! Immunterapi

4 Targeted Therapies Science. 2002;297(5578): Nana-Sinkam. Chest. 2013;143(5_suppl):e30S-e39S.

5 Tumördrivande mutationer vid NSCLC J Clin Oncol 2013; 31: abst 8019

6 Testing for all genetic alteration is recommended NGS and multiplex techniques are recommended

7 LuxLung 3 Response rate 56% vs 23%

8 Lux Lung 3&6. ASCO Presenter: James Chih-Hsin Yang

9 ORR (%) Profile Crizotinib ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P< Crizotinib (n=173 b ) Chemotherapy (n=174 b ) Treatment Shaw AT, et al. N Engl J Med 2013;368:

10 Lung Cancer 76 (2012) 1 18

11 Vilka tester på vilket tumörmaterial? ALK translocation EGFR mutation MET Herbst RS, Hirsch FR. Lancet 373 (2009)

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13 Internationella guidelines Society Targeted therapy recommended Molecular pathology ACCP yes yes NCCN yes yes ESMO yes yes ASCO, ATS, CAP, NiCE, ERS; National societies yes (n.e.) (yes) (n.e.) Fr. Rainer Wiewrodt. ERS 2014 Kerr et al. Annals of Oncology 2014, 25: , 2014 (September 2014)

14 EGFR och ALK-testning i klinisk praxis 89% 71% 50% 40% 50% 36% all Univ. 14% Pul. Clinic 3% ALK EGFR ALK EGFR ALK Normative force of financial needs and dependencies Reimbursement; stable price even in case of increasing number of mutations Fr. Wiewrodt. ERS 2014

15 Geografiska skillnader ERS White Book 2013

16 Resistensmekanismer EGFR Mut+ EML4-ALK+ Small cell + MET 1% Small cell 1% Small cell + T790M 2% MET+ T790M 3% Unknown 18% MET amplification 3% HER2 8% HER2 + T790M 4% T790M 60% Unknown * Target gene alteration (29%) Bypass track activation (45%) * inc. L1196M ALK amplification ALK mutation EGFR mutation CKIT amplification Unknown *more than one resistance mechanism Common themes Second site mutations in target (e.g., T790M / L1196M) Use of alternative signalling pathways (e.g., MET / EGFR) Fr. Cotrot ERS 2014

17 Behandling av förvärvad EGFR-resistens 1 st generation gefitinib, erlotinib 2 nd generation afatinib, dacomitinib 3 rd generation AZD9291, CO-1686 drugs core binding Efficacy on T790M in vitro Efficacy on T790M+ NSCLC patients quinazoline reversible No No quinazoline irreversible Yes No pyrymidine irreversible Yes Yes

18 Behandling av förvärvad TKI-resistens AZD rd generation TKIs Phase I study with expansion cohort Patients with EGFR-mutated NSCLC, progression upon TKI, n = 232 T790M+ = 60% ORR = 53% (65% in T790M+ pts, 22% in T790M- pts), DCR = 83% Complete Response Partial Response No response Toxicity Few rash and diarrhea No DLT 6 ILD Fr. Cotrot. ERS 2014

19 Resistensmekanismer vid ALK+ Camidge, Doeble. Nature Rev

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21 ASCEND-1 trial: activity of LDK378 in advanced crizotinib naïve and resistant ALK+ NSCLC Antitumor Activity PFS Shaw AT, NEJM 2014 Kim D et al., ASCO 2014

22 Immunologisk behandling vid lungcancer

23 Olika behandlingsformer AKTIV PASSIV Tumörvacciner Manipulerad mikromiljö Adoptive T cell Transfer Antikroppar Check point-blockad Paroll D. et al. JEM 2013 Tartour and Zitvogel. Lancet 2013

24 Passiv Immunoterapi Släcker nyckelfunktioner i tumörceller Markera tumörceller för destruktion via ADCC (antibodydependent cell mediated toxicity m h a makrofager, neutrofiler och NK-celler) Levererar toxiner till tumörceller Släcker inhibitionen av antitumorala lymfocyter Cetuximab: monoklonal Anti-EGFR-Ak SSP1: rekombinerat immunotoxin mot mesotheliom

25 Check point-hämmare Immunmodulering för att undvika T-cells medierade skador CTLA-4 Ipilimumab PD-1 Nivolumab (PD-L1)

26 All Squamous Non-squamous Survival Carbo-paclitaxel 8.3 Phased ipi 12.2 (HR 0.87) HR 0.48 HR 1.17 Concurrent ipi 9.7 (HR 0.99) HR 1.02 HR 0.96

27 Stadium IV NSCLC (BMS , anti-pd-1 10mg/kg) Från Albelda SM. ERS 2014

28 Pågående studier med PD-1/PD-L1 Immune Checkpoint Hämmare Antibody Molecule Company Development Stage PD-1 BMS /MDX- 1106/ONO-4538 Fully human IgG4 mab Bristol-Myers Squibb Phase II multiple tumors CT-011 Humanized IgG1 mab Target Phase II multiple tumors MK-3475 Humanized IgG4 mab Merck Phase I AMP-224 B7-DC/IgG1 fusion protein Amplimmune Phase I PD-L1 MDX-1105/BMS Fully human IgG4 mab Bristol-Myers Squibb Phase I PD-L1 MPDL3280A Fully human IgG1 mab Genentech Phase I Från Albelda SM. ERS 2014

29 Tumörvacciner Syftar till att stimulera immunförsvaret mot en specifik antigen (DNA, RNA, peptid ) DNA, protein, vektor eller cell injiceras i patienten tillsammans med ett immunstimulerande cytokin

30 Tumörvaccinstudier & NSCLC Property of Antigen Vaccine Randomized Phase 2 Phase 3 MAGE 3 (MAGRIT GSK) Ca-testes antigen on about 40% of pts Protein with adjuvant Tested in adjuvant setting- incr. OSp= pts Initial results 2200 pts NEG MUC1 (TG4010) Overexpres-sed in most pts Vaccinia virus exp. MUC1 and IL2 Some OS benefit with chemorx- 148 pts 1000 pt trial underway MUC1 Tecemotide START Merck Serano 25 AA peptide from MUC1 plus adjuvant START1 (P3) negative START pts in combination with concurrent ChemoRad TGF-b (Lucanix) TGF inhibits ability of tumor cells to be immunogenic TGF-b antisense RNA transduced into 4 allogeneic cell lines used for vaccination Some OS benefit= p= pts enrolled Results reported as NEG Racotumomab NeuGcGM3 tumorassociated ganglioside an- anti-idiotype antibody that mimics NeuGcGM3 Some OS benefit (1.5 mo) in advanced pts pt trial underway

31 Summering Molekylärpatologisk testning är kliniskt användbar EGFR och ALK skall bedrivas upfront på Non-Squamous NSCLC Immunterapi visar lovande resultat, ffa check point blockad Kvarstående frågor och komplicerande faktorer: Adekvat tumörmaterial Rebiopsi efter 1 st line med specifik hämmare? Skivepitelcancer? Etiska frågeställningar: Multiplex/NGS: bördan av att veta för mycket Hur dyr får lungcancerbehandling vara?

32 Tack för uppmärksamheten!