Advances in GIST

1. Advances in GIST
D Raghunadharao MD DM FAPAS FRCP FACP

2. KIT (CD117) receptor tyrosine kinase structure and common mutations found in GIST.
Arrows indicate the corresponding mutations in the exons.

3. KIT (CD117) gene structure and common mutations in GIST
Arrows indicate the positions of common mutations in the KIT gene

4. KIT and PDGFRA downstream signalling pathways

5. Sensitivity of KIT mutations to approved TKIs
green = sensitive; red = resistant; IM = imatinib; SU = sunitinib; RE = regorafenib;
ABD = ATP-binding domain; AL = activation loop.

6. Schematic distribution of KIT or PDGFRA receptor mutations,
frequency of mutations and TKI

7. Location & frequency of primary mutations in
KIT and PDGFRA

8. Molecular classification of GISTs

9. Treatment algorithm for patients with resectable GIST
and mutational profiling

10. High-risk features
1. Tumour rupture
2. Diameter >10 cm
3. Mitotic rate >10 per 50 HPF
4. Mitotic rate >5/50 HPF and diameter >5 cm;
5. Mitotic rate >5/50 HPF and diameter >2 cm and
non-gastric GIST
6. Diameter >5 cm and non-gastric GIST

11. Treatment algorithm for patients with unresectable or
metastatic GIST and mutational profiling

12. How to interpret mutation data in GIST
Mutation Treatment Implication
KIT exon 11 Sensitive to Imatinib & Regorafenib
KIT Exon 9 Responsive to higher dose of Imatinib, sunitinib sensitive
Secondary KIT Mutations:
Exons 13, 14, 17, 18
Sunitinib sensitive
PDGFR D842V (exon 18) Imatinib resistant, dasatinib sensitive
KIT/PDGFRA WT Imatinib resistant, dasatinib sensitive, regorafenib
sensitive, if SDH - deficient
SDH: succinyl dehydrogenase

14. TKIs for imatinib-resistant GIST
Study Drug Population N Response
Sunitinib Imatinib resistant 312 TTP 27 weeks
Sorafenib Imatinib & Sunitinib resistant 38 ORR 68%
Nilotinib Imatinib & Sunitinib resistant 248 No difference in PFS or OS
Sorafenib Imatinib & Sunitinib resistant 41 ORR 37.6%
Dasatinib Imatinib & Sunitinib resistant 47 PR 32%
Abbreviations: TTP time to progression; ORR overall response rate; PR partial response

15. Study Drug Population Number Response
Regorafenib Imatinib & Sunitinib resistant 33 SD 86%
Masitinib First Line 30 PFS 41 months
Crenolanib Selective for D842V mutation Blocks Kinase activity of
PDGFRA D842V
PTK
787/ZK222584
Imatinib resistant 15 ORR 67%
AMG 706 Imatinib resistant 138 ORR 33%
Abbreviations: SD stable disease; PFS progression free survival; ORR overall response rate
New TKIs for GIST

16. Novel agents for GIST
Drug Class Indication No Response
Everolimus mTOR Inhibitor TKI resistant 58 PFS 29%
Everolimus mTOR inhibitor Refractory GIST 15 ORR 27%
Sirolimus mTOR Inhibitor D842V mutation 3 Some activity
Ganetespib HSP90 inhibitor Failure of prior therapy 26 SD 52%
Retaspimycin HSP 90 inhibitor Failure of TKIs 47 Too toxic
Perifosine AKT pathway
inhibitor
Imatinib resistant 41 Minimal activity
Abbreviations: SD stable disease; PFS progression free
survival; ORR overall response rate

17. NCCN Guidelines