Nieuwe patiëntenselectie, nieuwe targets, nieuwe drugs
Hans Gelderblom, LUMC NVMO-Post-ASCO 20 juni 2013, Ermelo
Building bridges to conquer cancer Dus: verbanden zien • Patientenselectie: DPD • Nieuwe targets • Nieuwe drugs
3-4% DPD deficiëntie 80% ernstige toxiciteit
(Ahmed #3627)
(Ahmed #3627)
Prospectieve studie
Alternatieven voor genotyperen • DPD activity in PBMCs
• Uracil breath test • Uracil loading dose • Endogenous Uracil/DHU
• TDM •
Courtesy Jesse Swen LUMC
• Duur en niet overal beschikbaar • Duur en niet overal beschikbaar • Sampling, Uracil niet commercieel beschikbaar • Circadiaan ritme • Risico toxiciteit 5-FU test dosis
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
Building bridges to conquer cancer Dus: verbanden zien • Patientenselectie: “liquid biopsy” • Nieuwe targets • Nieuwe drugs
Simpele biomarkers niet vergeten • WHO • LDH • Toxiciteit – Bv huid (EGFRi) – Bv hypertensie (VEGFi) – Bv Hyperlipidemie/glycemie (mTORi)
Presented by:
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
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
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)
Regorafenib is a structurally distinct inhibitor of multiple kinases relevant to GIST and other cancers N
H N N H3C
N
H N
F
O
N N
CH3
O
N
Imatinib Percent control
N H
O Cl
NH O
F N H
Sunitinib Binding inhibition
F F
O
O N H
N H
N
N H
F
Regorafenib Percent control 0% <0.1% 0.1–1% <1–5% <5–10% <10–35%
Wilhelm SM et al. Int J Cancer 2011; 129: 245–255 Murphy EA et al. PNAS 2010; 107: 4299–4304 Karam MW et al. Nat Biotechnol 2008; 26: 127–132
Regorafenib significantly improved PFS vs placebo (blinded central review, primary endpoint in phase III GRID trial)
Regorafenib, N=133
Placebo, N=66
4.8 months (4.1–5.8)
0.9 months (0.9–1.1)
Median PFS (95% CI)
1.00
PFS probability
Number of events 81 (61%) 0.75
63 (95%)
Hazard ratio (95% CI): 0.27 (0.19–0.39) 1-sided p-value: <0.0001 Placebo Regorafenib
0.50
0.25
0
0
50
100
150
200
Days from randomization
Demetri GD et al. Lancet 2013; 381: 295–302
250
300
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: 3209–3211
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
Building bridges to conquer cancer Dus: verbanden zien • Patientenselectie • Nieuwe targets • Nieuwe drugs
[TITLE]
Presented By Howard A. Burris, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Howard A. Burris, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Roy S. Herbst, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Gary K. Schwartz, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Jayesh Desai, MBBS, FRACP, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Jayesh Desai, MBBS, FRACP, MD at 2013 ASCO Annual Meeting
Building bridges to conquer cancer Dus: verbanden zien • Patientenselectie • Nieuwe targets • Nieuwe drugs: (anti-PD-1) en enkele voorbeelden
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Ryan Bruce Corcoran, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Cathy Eng, MD at 2013 ASCO Annual Meeting
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)
