Nieuwe patiëntenselectie, nieuwe targets, nieuwe drugs. Hans Gelderblom, LUMC NVMO-Post-ASCO 20 juni 2013, Ermelo

Transcriptie

1 Nieuwe patiëntenselectie, nieuwe targets, nieuwe drugs Hans Gelderblom, LUMC NVMO-Post-ASCO 20 juni 2013, Ermelo

2 Building bridges to conquer cancer Dus: verbanden zien Patientenselectie: DPD Nieuwe targets Nieuwe drugs

3 3-4% DPD deficiëntie 80% ernstige toxiciteit (Ahmed #3627)

4 (Ahmed #3627)

5

6 Prospectieve studie

7 Alternatieven voor genotyperen DPD activity in PBMCs Uracil breath test Uracil loading dose Endogenous Uracil/DHU Duur en niet overal beschikbaar Duur en niet overal beschikbaar Sampling, Uracil niet commercieel beschikbaar Circadiaan ritme TDM Risico toxiciteit 5-FU test dosis Courtesy Jesse Swen LUMC

8 Individualization of fluoropyrimidine therapy DNA Test 100% dose DPD EM 50% dose DPD IM + dose titration Drug B DPD PM Patiënten niet meer behandelen met 5-FU, CAP (of Tegafur) zonder screening op DPYD

9 Building bridges to conquer cancer Dus: verbanden zien Patientenselectie: liquid biopsy Nieuwe targets Nieuwe drugs

10 Simpele biomarkers niet vergeten WHO LDH Toxiciteit Bv huid (EGFRi) Bv hypertensie (VEGFi) Bv Hyperlipidemie/glycemie (mtori) Presented by:

11

12

13 Probleem: heterogeniteit Baseline: KIT exon 9 mutation 1 maand op imatinib 9 mnd op imatinib Exon 9 + resistance mutation #1 E9 + resist mutation #2 E9 + resist mutation #3

14 Limitations of tumor biopsies and a possible new solution Tumor ( tissue ) biopsies may be problematic for a number of reasons Heterogeneity Availability (only certain tumors, or areas of any given tumor can be sampled) Biopsies are often invasive in patients with solid tumors, which can be located deep in internal organs Tumor cells are constantly dying and releasing DNA into the bloodstream Sophisticated blood assays may allow a comprehensive analysis of all of the mutations in any given patient Such liquid biopsies may circumvent the limitations and risks of tumor-based DNA analysis from solid tissue biopsies

15 Mutational analysis of plasma DNA from patients in the phase III GRID study of regorafenib vs placebo in tyrosine kinase inhibitor-refractory GIST: correlating genotype with clinical outcomes George D. Demetri, MD Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School On behalf of GRID Study Team: Michael Jeffers, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Leahy, Margaret von Mehren, Heikki Joensuu, Giuseppe Badalamenti, Martin Blackstein, Axel Le Cesne, Patrick Schöffski, Robert G Maki, Jianming Xu, Toshirou Nishida, Iris Kuss, Paolo G Casali (Study supported by Bayer HealthCare)

16 Regorafenib is a structurally distinct inhibitor of multiple kinases relevant to GIST and other cancers N H H N N N N H 3 C O Imatinib N N CH 3 Percent control N N H O NH O Sunitinib N H F Binding inhibition F Cl F F N H O N H Regorafenib F O N O N H Percent control 0% <0.1% 0.1 1% <1 5% <5 10% <10 35% Wilhelm SM et al. Int J Cancer 2011; 129: Murphy EA et al. PNAS 2010; 107: Karam MW et al. Nat Biotechnol 2008; 26:

17 PFS probability Regorafenib significantly improved PFS vs placebo (blinded central review, primary endpoint in phase III GRID trial) 1.00 Median PFS (95% CI) Number of events Regorafenib, N= months ( ) 81 (61%) Placebo, N= months ( ) 63 (95%) 0.75 Hazard ratio (95% CI): 0.27 ( ) 1-sided p-value: < Placebo Regorafenib Days from randomization Demetri GD et al. Lancet 2013; 381:

18 Mutational analysis of circulating DNA in plasma via BEAMing technology Beads, Emulsions, Amplification, Magnetics (done with Inostics): Laboratory steps: pre-amplification, emulsion PCR, hybridization, flow cytometry Detection of tumor-associated mutations using circulating free DNA from plasma Exquisitely sensitive detection: 1 mutant allele in 10,000 normal alleles Ideal concept to detect emergence of multiple gene mutations which can make GIST resistant to targeted therapies Richardson AL, Iglehart JD. Clin Cancer Res 2012; 18:

19 Conclusions Primary KIT mutations, as well as secondary KIT mutations associated with resistance to TKIs, were readily detectable in plasma DNA via BEAMing KIT mutations associated with TKI resistance were more readily detected in plasma (47%) than in tumor tissue (12%) The majority (75%) of KIT resistance mutations were localized in the activation loop domain High concordance rate was noted between patient-matched plasma and tumor tissue DNA mutation assays Correlative analysis showed benefit of regorafenib over placebo independent of primary or secondary mutation status despite small sample sets Too few patients had mutations in PDGFRA, KRAS, or BRAF for meaningful subgroup analysis

20 Building bridges to conquer cancer Dus: verbanden zien Patientenselectie Nieuwe targets Nieuwe drugs

21 [TITLE] Presented By Howard A. Burris, MD at 2013 ASCO Annual Meeting

22 [TITLE] Presented By Howard A. Burris, MD at 2013 ASCO Annual Meeting

23 [TITLE] Presented By Roy S. Herbst, MD, PhD at 2013 ASCO Annual Meeting

24 [TITLE] Presented By Gary K. Schwartz, MD at 2013 ASCO Annual Meeting

25 [TITLE] Presented By Jayesh Desai, MBBS, FRACP, MD at 2013 ASCO Annual Meeting

26 [TITLE] Presented By Jayesh Desai, MBBS, FRACP, MD at 2013 ASCO Annual Meeting

27 Building bridges to conquer cancer Dus: verbanden zien Patientenselectie Nieuwe targets Nieuwe drugs: (anti-pd-1) en enkele voorbeelden

28 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

29 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

30 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

31 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

32 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

33 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

34 [TITLE] Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting

35 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

36 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

37 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

38 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

39 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

40 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

41 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

42 [TITLE] Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting

43 Building bridges to conquer cancer: Bruggen bouwen tussen de successen* * Vertaling concepten van ene naar andere tumor * Betere selectie patient (DPD, NRAS/KRAS, tumor profiling) * Nieuwe drugs en targets (Anti-PD-1)