Update über molekulare Tests beim NSCLC. Martin Früh Onkologie und Hämatologie Kantonsspital St. Gallen

Transkript

1 Update über molekulare Tests beim NSCLC Martin Früh Onkologie und Hämatologie Kantonsspital St. Gallen

2 «Driver» Alterationen: Obligat: EGFR ALK..... RCTs vorhanden! Titel der Präsentation Tissue should be prioritized for EGFR and ALK testing EGFR and ALK results should be available within 2 weeks (10 working days) Lindenman, J Thor Oncol 2013

3 Inzidenz Onkogen-abhängiger Malignome Titel der Präsentation

4 Randomisierte Studien mit EGFR Erstlinien-TKIs bei EGFR- Mutation Studie Studienarm N Ansprechrate Progressionsfreies Überleben (Monate) Gesamtüberleben (Monate) NEJ002 1 Gefitinib Chemotherapy %* 31% 10.8 * WJTOG 2 Gefitinib Chemotherapy %* 32% 9.2 * OPTIMAL 3 Erlotinib Chemotherapy %* 36% 13.7 * 4.6 NS NS EURTAC 4 Erlotinib Chemotherapy %* 15% 9.7 * LUX 3 5 Afatinib Chemotherapy %* 22.1% 13.6 * LUX 6 6 Afatinib Chemotherapy % 23% 11 * *: p<0.001 NR: nicht rapportiert NS: nicht signifikant 1 NEJM 2010, 2 Lancet Oncol 2010, 3 Lancet Oncol 2011, 4 Lancet Oncol 2012, 5 JCO 2013, 6 Lancet Oncol 2014

5 Welches ist der beste EGFR TKI? Erlotinib vs. Gefitinib (CTONG0901) PFS Gefitinib 10.4 m Erlotinib 13.0 m P 0.1, HR 0.81 ( ) OS Gefitinib 20.1 m Erlotinib 22.9 m P 0.25, HR 0.84 ( ) n=240

6 LUX lung esmo Afatinib versus gefitinib as first-line treatment for patients with advanced non-small cell lung cancer harboring activating EGFR mutations: LUX-Lung 7

7 ! of LUX-Lung 7

8 in LUX-Lung 7

9 Präklinische Synergie mit Angiogeneseinhibitoren Naumov, Cancer Res 2009

10 PFS probability Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer: An open-label randomized trial PFS 100 (n=150) Erlotinib + bevacizumab Erlotinib Median (months) HR (95% CI) 0.54 (0.36, 0.79) p-value* *log-rank test, two-sided 40 Number at risk EB E Time (months) Seto Lancet 2014

11 Change from baseline (%) A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M mutation. Median PFS: 13.8 months (m) (95% CI ) 16 m (95% CI 13.1-not estimable) for T790M m (95% CI ) for T790M PD SD PR CR N=109 All T790M+ T790M- CR 7 (6.4) 3 (8.1) 4 (5.6) PR 76 (69.7) 23 (62.2) 53 (73.6) SD 18 (16.5) 9 (24.3) 9 (12.5) PD 3 (2.8) 0 (0.0) 3 (4.2) NE 5 (4.6) 2 (5.4) 3 (4.2) Stahel et al. Ann Oncol 2015; 26 (suppl 6): abstr 3BA

12 Tumor Resistenz bei EGFR Mutation Yu and Riely, CCR 2013 and 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, Akhavan, Cancer Discov 2013;

13 T790M Mutation Yun PNAS 2007

14 Rociletinib and Osimertinib in T790+ NSCLC N=127, ORR 61% N=46, ORR 59% Sequist and Jänne N Engl J Med 2015

15 Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer cfdna at progression (NGS testing) 26 positive for an EGFR-sensitizing mutation 12 (46%) had NO T790M Seven patients had detectable C797S (27% del 19 only), all WITH T790M 1 BRAF V600E, 1 PIK3CA, 1 MET ampl, 1 Her2 ampl., all with NO T790M Kombinationstherapien? Oxnard Abstr WCLC 2015

16 2. Resistenzmutation (C797S) Matthew CCR 2015

17 EML-4 ALK Gen Rearrangement Jüngere (median 59 Jahre) Adenokarzinome p.os.

18 18 EML-4 ALK Gen Rearrangement 1st Generation ALKi Crizotinib (Xalkori) 56% > 2 Vortherapien! 2nd Generation ALKi: Ceritinib (Zykadia) Titel der Präsentation n= 114 ORR: 58% PFS 7.0 months Kwak N Engl J Med 2010 Shaw N Engl J Med 2014

19 ALK+ Patienten mit Zweitgeneration ALKi (n=141) Duruisseaux, abstr 33.01, WCLC 2015

20 Erworbene Resistenz auf Crizotinib Unknown (ALK +) 13% Unknown (ALK -) 6% EGFR Muta on 12% ALK Muta on 31% Titel der Präsentation KRAS Muta on 19% ALK Muta on + CNG 6% ALK CNG 13% Camidge, ASCO 2013

21 Lorlatinib Bauer WCLC 2015

22

23

24 Klinisch wichtige seltene Mutationen 24

25

26 ROS1 Rearrangement Takeuchi Nature 2012

27 ROS1 in «triple negative» AdenoCa 23.5% to 40% of pulmonary adenocarcinomas are EGFR-/KRAS-/ALK- Incidence of ROS1 7.4% % 2 1 Mescam-Mancinia Lung Cancer Go J Thor Oncol 2013

28 28 Crizotinib in ROS1+ N=50 ORR 72% PFS 19 months Titel der Präsentation Shaw N Engl J Med 2014

29 G2032R Resistance Mutation Awad N Engl J Med 2013

30 Overcoming G2032R ROS1 Recistance Mutation? Cabozantinib Lorlatinib Katayama Clin Cancer Res 2015 Zou PNAS 2015

31 BRAF Mutation Nur ca. 50% V600E!

32 Dabrafenib in patients with BRAF V600E-mutant advanced non-small Phase II cell study lung cancer BRF (NSCLC): of A multicenter, dabrafenib open-label, in BRAF phase V600E II trial (BRF113928) mutation positive non-small cell lung cancer patients Responders in 2 nd line N=25 Progressed, n (%) 12 (48) Ongoing, n (%) 13 (52) Duration of response Number of prior systemic anti-cancer therapy regimens for metastatic disease: 1 2 Median, months (95% CI) 11.8 (5.4, NR) <6 months, n (%) 11 (44), 4 ongoing >6 months, n (%) 14 (56), 9 ongoing >9 months, n (%) 10 (40), 8 ongoing >12 months, n (%) 6 (24), 4 ongoing Median PFS a, months (95% CI) 5.5, (2.8, 7.3) Duration of treatment (months) ORR 32% DCR 56% (n=78) *62% of patients progressed or died Planchard et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA38_PR

33 Hyman N Engl J Med 2015 Prospective Cohort with Vemurafenib in BRAF V600E mutated NSCLC (n=20) months

34 Dabrafenib plus trametinib in patients with BRAF V600E mutated metastatic NSCLC ORR 63%, DCR 88% Planchard et al. J Clin Oncol 2015; 33 (suppl): abstr 8006

35 MET Amplification

36 Crizotinib for MET amplification Ou, J Thor Oncol 2011

37 % Change from baseline Efficacy and safety of crizotinib in patients with advanced c- MET-amplified non-small cell lung cancer 1 CR and 4 PRs have been observed with crizotinib among 12 patients to date Low MET Intermediate MET High MET n=2 n=6 n= Disease progression Stable disease Partial response b Complete response b c c Threshold for partial response categories of amplification: MET/CEP7 ratio (Low), >2.2-<5 (Intermediate) and 5 (High) 100 a Confirmed objective responses b Based on investigator assessment c Two patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001)

38 Incidence of RET Translocation «enriched» 8 of 51 lung (15%) adenocarcinomas negative for EGFR, KRAS, ALK, ROS1 Varella-Garcia J Clin Oncol 31, 2013 (suppl; abstr 8024) 5/32 (15%) never-smoking history, adenocarcinomas (WT EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, AKT, ALK ROS1) Drilon J Clin Oncol 31, 2013 (suppl; abstr 8067) «semi-enriched» 24 of 842 (2.8%) EGFR mut non-squamous cell ca. Yoh et al. Ann Oncol 2014; 25 (suppl 4): abstr 1227PD «unselected» 7 of 944 (0.7%) unselected NSCLC Platt J Clin Oncol 31, 2013 (suppl; abstr 8045)

39 Clinical response of RET+ patients Vandetanib: 3/3 SD (2 shrinkages) 1 Vandetanib: 2/2 SD, Sunitinib: 2/2 PD 2 Cabozantinib: 2/3 PR 3 39 Platt J Clin Oncol, 2013 (suppl; abstr 8045) 1, Varella-Garcia J Clin Oncol, 2013 (suppl; abstr 8024) 2, Drilon Cancer Discovery

40 Vandetanib und RET (CCDC6-RET Fusion) Falchook J Clin Oncol 2014

41 Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers (n=16) Cabozantinib (n=16) ORR, % (95%CI) 38 (15, 65) PR, n (%) Confirmed Unconfirmed 7 (44) 6 (38) 1 (6) Median PFS, months (95% CI) Median OS, months (95% CI) 7 (5, not reached) 10 (8, not reached) Drilon et al. J Clin Oncol 2015; 33 (suppl): abstr 8007

42 Her2 mutated NSCLC Lapatinib: 2/2 PD Trastuzumab 1/1 PR Afatinib 2/3 SD, 1/3 PR Mazières J Clin Oncol 2013

43 % change in sum LD % change in sum LD PUMA trial 4201 for HER2 mutation PD bp exon 20 insertion 3bp exon 20 insertion 9 bp exon 20 insertion A775_G776Ins YVMA Exon 20 insertion G776VC P780_Y781Ins GSP S310F Unspecified PD PD PD SD SD PD SD 0 SD SD SD SD PD 0 SD SD SD SD SD SD SD SD SD SD SD -50 PFS 2.9 months -50 PFS 4.0 months PR PR PR -100 Neratinib -100 Neratinib + temsirolimus September 2014, Madrid, Spain esmo.org Courtesy of B. Besse and J. Mazières esmo.org

44 ETOP NICHE Studie September 2014, Madrid, Spain esmo.org esmo.org

45 MET exon 14 splicing site mutation 3/4 responders crizotinib (n=3, PR) capozantinib (n=1, SD) Gehäuft bei sarcomatoiden Karzinomen (8/36, 22%, Liu Abstr 8020) Awad J Clin Oncol 2016, Shea J Thor Oncol 2016, Paik Cancer Disc 2015, Liu ASCO 2015

46 Entrectinib bei NTRK1 Rearrangement Farago J Thor Oncol 2015

47 Systemtherapie Verbesserung durch SUBTYPISIERUNG 47 Ansprechrate Medianes Überleben (Monate) Ohne Chemotherapie 0% 6 Monotherapie 15% 7 Doublet 25% 8-10 Doublet+ Bevacizumab 35% 12 Doublet+ Cetuximab 36% 12 EGFR-TKI bei EGFR+ 75% 24 Crizotinib bei ALK+ 57% 24 Osimertinib/Rociletinib bei T790M+ >50% >40? Ceritinib bei ALK+ >50% 34

48 Zusammenfassung 30-40% der nicht-plattenepitehlialen NSCLC besitzen eine potentiell onkogene «Driver» Mutation Randomisierte Studien zeigen einen Benefit bezüglich ORR, PFS und QoL bei EGFR und ALK Identifikation weiterer Titel «selteneren» der Präsentation molekularen Mutation und Einschluss in Studienprotokolle ist entscheidend Erneute molekulare Testung bei Progression ermöglicht die Behandlung mit neuen wirksamen Substanzen (z. B. 790M)