Nieuwe patiëntenselectie met longcarcinoom als role model voor de medisch oncoloog Anne-Marie Dingemans POST ASCO NVMO 18 juni 2015

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1 Nieuwe patiëntenselectie met longcarcinoom als role model voor de medisch oncoloog Anne-Marie Dingemans POST ASCO NVMO 18 juni 2015

2 Disclosure belangen Dingemans (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Zie hieronder Bedrijfsnamen Roche Eli Lilly Boehringer Ingelheim Astra Zeneca Pfizer BMS Amgen Astra Zeneca Novartis MSD

onderzoeksgeld Honorarium of andere (financiële) vergoeding Zie hieronder

4 Oncogene Drivers in Adenocarcinoma Kerr KM. J Clin Pathol. 2013;66(10):

5 1st ESMO Consensus Conference in Lung Cancer: Lugano 2010 Felip, et al. Ann Oncol 2011

6 Resistentie mechanismen Yu HA, et al. Clin Cancer Res. 2013;19(8):

7 3 de generatie EGFR-TKI Mutatie specifiek, ook T790M Minder effect op EGFR-WT = minder bijwerkingen

8 AZD9291: Best Percentage Change in Target-Lesion Size. Jänne PA et al. N Engl J Med 2015;372:

9 Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive NSCLC patients Study objective To report data on the safety and efficacy of rociletinib, an oral inhibitor of mutant EGFR, on a subset of NSCLC patients with the T790M resistance mutation detected by plasma genotyping treated with rociletinib mg BID Study design An overall Phase I/II study was performed on 456 enrolled patients diagnosed with EGFR-mutant NSCLC In Phase II, T790M positive by central tumour genotyping was required Plasma EGFR status was assessed by BEAMing (Sysmex), a quantitative assay using emulsion PCR then flow cytometry Key results 456 patients received rociletinib and were included in the safety analysis 243 and 147 patients were T790M positive by centrally-confirmed tissue genotyping and plasma testing, respectively, and were analysed for efficacy Sequist et al. J Clin Oncol 2015; 33 (suppl): abstr 8001

enrolled patients diagnosed with EGFR-mutant NSCLC In Phase II, T790M positive by central tumour genotyping was required Plasma EGFR status was assessed by BEAMing (Sysmex), a quantitative assay

10 Quantitative and Sensitive BEAMing Test (Sysmex Inostics) Used for Plasma EGFR Mutation Testing Presented By Lecia Sequist at 2015 ASCO Annual Meeting

11 Plasma Testing for T790M has Good Sensitivity and Likely Good Specificity Presented By Lecia Sequist at 2015 ASCO Annual Meeting

12 Best Response to Rociletinib (All Doses) in Plasma T790M+ Patients Presented By Lecia Sequist at 2015 ASCO Annual Meeting

13 T790M Plasma Testing is a Viable Alternative to Tissue Testing Presented By Lecia Sequist at 2015 ASCO Annual Meeting

14 Rociletinib Activity Observed in Central T790M Negative Patients Presented By Lecia Sequist at 2015 ASCO Annual Meeting

15 Slide 21 Presented By Alex Adjei at 2015 ASCO Annual Meeting

17 Oncogene Drivers in Adenocarcinoma Kerr KM. J Clin Pathol. 2013;66(10):

18 Solomon BJ et al. N Engl J Med 2014;371: Progression-free and Overall Survival. Crizotinib versus chemotherapie eerste lijn 70% cross-over crizotinib

19 A Common Scenario Baseline After 9 months of crizotinib

20 A Common Scenario Most common site of progression on crizotinib 70%! Baseline After 9 months of crizotinib

Next Generation ALK TKIs 50% maximal inhibitory concentration (IC50) values of Ba/F3 cells dependent on expression of EML4-ALK (native) or kinase domain mutated EML4-ALK variants (n = 10).

21 Next Generation ALK TKIs 50% maximal inhibitory concentration (IC50) values of Ba/F3 cells dependent on expression of EML4-ALK (native) or kinase domain mutated EML4-ALK variants (n = 10). Data for each cell line are derived from at least 4 independent experiments (error bars = standard deviation). Dashed horizontal lines indicate the mean steady-state exposure concentrations of each drug corrected for the functional effects of protein binding at the recommended phase 2 doses: a Crizotinib: 250 mg BID, 259 nm 9 ; AP26113: b 180 mg QD, 899 nm and c 90 mg QD, 264 nm 10 ; d Ceritinib: 750 mg QD, 456 nm 11 ; e Alectinib: 600 mg BID, 277 nm 12 ; f n = 2 Ou SH. Drug Des Devel Ther. 2011;5: Shaw AT, et al. N Engl J Med. 2014;370(13): Ou S, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 44.

Activity of Other ALK TKIs ALK TKI Ceritinib LDK378 (Novartis) Alectinib CH5425802 (Roche) RR, % (n) Crizotinib Naïve RR, % (n)

5% (46) 60% (47) >14 AP26113 (Araid) 100% (7) 69% (45/65) 13 N=16 Felipe E, et al. Ann Oncol. 2014; Abstract 4380. Shaw AT, et al.

22 Activity of Other ALK TKIs ALK TKI Ceritinib LDK378 (Novartis) Alectinib CH (Roche) RR, % (n) Crizotinib Naïve RR, % (n) Crizotinib Resistant 72% (83) 56% (163) mpfs, m 9.0 ( ) 93.5% (46) 60% (47) >14 AP26113 (Araid) 100% (7) 69% (45/65) 13 N=16 Felipe E, et al. Ann Oncol. 2014; Abstract Shaw AT, et al. N Engl J Med. 2014;370(26): Gadgeel SM, et al. Lancet Oncol. 2014;15(10): Nakagawa K, et al. J Clin Oncol. 2013;31(Suppl): Abstract 8033; Gettinger, S, et al. ESMO 2014: Abstract 5146

23 Abstract 8008<br />Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673) Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

24 Long median progression-free survival in crizotinib-resistant ALK+ NSCLC patients Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

25 Marked activity of alectinib in ALK+ NSCLC patients with measurable CNS metastases Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

26 What About Resistance? Crizotinib RR 65% to 75%; Median PFS 8-11 Months Courtesy A. Shaw.

28 Ceritinib resistance is associated with ALK G1202R Ding eman s l post ASC O NVM O 18 juni 2015

29 Gerichte therapie: wat doen we na ASCO 2015 Re-biopsie bij progressie! EGFR mutatie T790M Hersenmetastasen Rol liquid biopsy ALK = lastige ziekte: Dynamisch komen en gaan van mutaties Let op hersenmetastasen RET/BRAF/MET etc: Trials! Verwijzen DRUP

30 Non-oncogene driven NSCLC Or non-druggable (KRAS?) = still majority of our patients

31 Docetaxel > BSC Shepherd F A et al. JCO 2000;18: Shepherd F A et al. JCO 2000;18:

32 NVMO 18 juni

33 Mutations in Cancer Cells Make Them Appear Different to the Immune System High mutational rates may contribute to increased immunogenicity Especially in smokers Lawrence MS, et al. Nature. 2013

34 Telegraaf

35 Lung cancer immunotherapy Landscape Cancer immunotherapy: any interaction with the immune system to treat cancer Active: priming of the immune system Passive: delivery of compounds that may use immune system Antigen- specific Non-antigen-specific -> AG-specific antibodies & cytotoxic T cells HOPE: Promising phase II data! -> enhancement of immune system cytokines checkpoint inhibitors Monoclonal antibodies cetuximab trastuzumab Adoptive cell transfer T cells engineering CARs Dendritic cells Cancer vaccination therapy Cancer immunomodulation therapy Targeted antibodies immunotherapy Cellular immunotherapy

36 Lung cancer vaccination phase 3 trials NSCLC Stage Trial Status IB-IIIA Stage IIIA-B following CRT MAGE-A3 ASCI MAGRIT target 2270 Tecemotide (L-BLP25) START target 1300 Belagenpumatucel-L STOP target 700 Recruited Recruited Recruited IIIb/IV following ChT regf target 1000 TG4010 TIME target 1000 Ongoing Ongoing Racotumomab (1E10) target 1082 Ongoing

37 Lung cancer immunotherapy Landscape Cancer immunotherapy: any interaction with the immune system to treat cancer Active: priming of the immune system Passive: delivery of compounds that may use immune system Antigen- specific Non-antigen-specific -> AG-specific antibodies & cytotoxic T cells -> enhancement of immune system cytokines checkpoint inhibitors Hype: phase I at ASCO! Monoclonal antibodies cetuximab trastuzumab Adoptive cell transfer T cells engineering CARs Dendritic cells Cancer vaccination therapy Cancer immunomodulation therapy Targeted antibodies immunotherapy Cellular immunotherapy

38 Nivolumab phase I Updated by Brahmer ASCO 2014 Abstract 8112 N=129 NSCLC across doses (1-3-10mg/kg): - ORR 17% - Median duration response 74 weeks - OS 9.6 month - 1- and 2-year survival 42% and 24% 3mg/kg ORR 9/37, OS 14.9 month Topalian SL et al. N Engl J Med 2012;366:

39 Brahmer J. et al. NEJM, June 2, 2015

41 Ding eman s l post RPh III Nivolumab vs Docetaxel in 2 nd line Sq NSCLC ASC O NVM O 18 juni

42 Nivolumab geeft significante verlenging overleving Brahmer J. et al. NEJM, June 2, 2015

43 Clinical activity of nivolumab vs docetaxel as second line treatment in advanced NSCLC Brahmer J. et al. NEJM, June 2, 2015

44 Tumor response and duration Brahmer J. et al. NEJM, June 2, 2015

45 Treatment related adverse events in > 5% of patients Brahmer J. et al. NEJM, June 2, 2015

46 En verlenging PFSree and overall survival Brahmer J. et al. NEJM, June 2, 2015

47 OS by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting

48 LCSS Average Symptom Burden Index: <br />Mean Change From Baseline While on Treatment Presented By David Spigel at 2015 ASCO Annual Meeting

49 NIVOLUMAB 2 de lijn Plaveiselcelcarcinoom

50 And not only in squamous.

51 Checkmate 057: phase III study nonsquamous NSCLC 2nd line stage IIIb/IV nonsquamous NSCLC Randomize 1:1 Nivolumab 3 mg Q 2wks Docetaxel 75 g Q 3wk End points: Primary: OS Secundary: PFS ORR Correlation PD-L1 Paz Arez, LBA 109 ASCO 2015

52 Nivolumab in non-squamous cell lung cancer

53 ASCO studie stop na interim analyse nivolumab docetaxel HR N ORR 19% 12% PFS ( ) OS ( ) P= OS PDL ( )

54 Slide 30 Presented By Scott Gettinger at 2014 ASCO Annual Meeting

55 SELECTION OF PATIENTS Histology PD-L1 expression Mutational status

56 IMMUNOTHERAPIE: DAGELIJKSE PRAKTIJK = morgen

57 NVALT: Immunotherapie voor Longkanker Criteria voor centra 1. > 20 pt per jaar 2. Regelmatig MDO waarin specialisten zitting nemen die bij immunotherapie noodzakelijk zijn (dermatoloog, MDL-arts, immunologisch georienteerd arts) 3. Patienten registratie verplicht 4. Ervaring met immunotherapie door deelname aan studies

58 CENTRUM- EN PARTNERZIEKENHUIZEN Centrumziekenhuizen voor longkanker: 1. Universitair Medisch Centrum Groningen 2. Universitair Medisch Centrum Maastricht 3. Erasmus Medisch Centrum Rotterdam 4. VU Medisch Centrum Amsterdam 5. NKI / Antoni van Leeuwenhoekziekenhuis Amsterdam Partnerziekenhuizen: 1. St. Antonius ziekenhuis, Nieuwegein 2. Catharina ziekenhuis, Eindhoven 3. Jeroen Bosch ziekenhuis, Den Bosch 4. Rijnstate ziekenhuis, Arnhem 5. Amphia ziekenhuis, Breda 6. Isala klinieken, Zwolle 7. Wever ziekenhuis, Heerlen

59 Goldman Sachs top disruptive themes

64 Van hype naar hoop naar werkelijkheid Of waarom u longarts had moeten worden.

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