GIST. The new TKI revolution: unanswered questions César Serrano, MD PhD Vall d’Hebron Institute of Oncology (VHIO), Barcelona Outline

Background: where we are?

TKI revolution 2.0

Unanswered questions: where will we be? Outline

Background: where we are?

TKI revolution 2.0

Unanswered questions: where will we be? KIT/PDGFRA as primary drivers of oncogenic signal in GIST Overall Mutation Frequency (950 GISTs): 86% KIT (78.5%) PDGFRA (7.5% total)

Exon 9 (9%)

Exon 11 (67%) Exon 12 (2%)

Exon 13 (1%) Exon 14 (rare)

Exon 17 (1%) Exon 18 (5.5%)

Courtesy of Jonathan A. Fletcher TKIs currently approved for metastatic GIST disease

IMATINIB 2001 mPFS 20.4 mo ORR 51% Polyclonal emergence of KIT secondary resistance mutations

Serrano C et al, Br J Cancer 2019 TKIs currently approved for metastatic GIST disease

IMATINIB 2001 mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% Outline

Background: where we are?

TKI revolution 2.0

Unanswered questions: where will we be? TKIs currently approved for metastatic GIST disease

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo ORR 9.4% AVAPRITINIB (BLU-285) mPFS 3.7 mo ORR 20.0% TKIs currently approved for metastatic GIST disease

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo ORR 9.4% AVAPRITINIB (BLU-285) mPFS 3.7 mo ORR 20.0% Phase III INVICTUS trial ripretinib (DCC-2618) v. placebo ≥ 4L

Study design

Von Mehren M, et al. ESMO 2019 Phase III INVICTUS trial ripretinib (DCC-2618) v. placebo ≥ 4L

Benefit of ripretinib in mPFS

Von Mehren M, et al. ESMO 2019 TKIs currently approved for metastatic GIST disease

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo ORR 9.4% AVAPRITINIB (BLU-285) mPFS 3.7 mo ORR 20.0% Phase I NAVIGATOR study avapritinib (BLU-285)

Study design

Heinrich MC, et al. CTOS 2018 Phase I NAVIGATOR study avapritinib (BLU-285)

Avapritinib activity in PDGFRA D842V-mutant GIST

Heinrich MC, et al. CTOS 2018 Phase I NAVIGATOR study avapritinib (BLU-285)

Avapritinib activity in KIT and non-D842V GIST

mPFS 3.7 mo

Heinrich MC, et al. CTOS 2018 Outline

Background: where we are?

TKI revolution 2.0

Unanswered questions: where will we be? #1 Ripretinib and Avapritinib are potential new standard-of-care in metastatic GIST patients #1 Ripretinib and Avapritinib are potential new standard-of-care in metastatic GIST patients

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618)  KIT/PDGFRA ≥ 4L mPFS 6.3 mo  GIST WT ORR 9.4% AVAPRITINIB (BLU-285) ≥ 1L  PDGFRA D842V >12 mo / 84% ≥ 4L  KIT/non-D842V 3.7 mo / 20.0% #2 New trials in earlier lines #2 New trials in earlier lines

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo AVAPRITINIB ORR 9.4% AVAPRITINIB (BLU-285) Phase III >12 mo / 84% VOYAGER 3.7 mo / 20.0% #2 New trials in earlier lines

Avapritinib - 3L/4L in regorafenib-naïve GIST

mPFS 8.6 mo

Heinrich MC, et al. CTOS 2018 #2 New trials in earlier lines

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo RIPRETINIB ORR 4.5% RIPRETINIB (DCC-2618) Phase III mPFS 6.3 mo INTRIGUE ORR 9.4% AVAPRITINIB (BLU-285) >12 mo / 84% 3.7 mo / 20.0% #2 New trials in earlier lines

Ripretinib - 2L in sunitinib-naïve GIST

George S, et al. ESMO 2018 #2 New trials in earlier lines

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% AVAPRITINIB SUNITINIB 2006 mPFS 5.6 mo Phase III ORR 6.8% COMPASS REGORAFENIB 2012 ctDNA selection mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo ORR 9.4% AVAPRITINIB (BLU-285) >12 mo / 84% 3.7 mo / 20.0% #2 New trials in earlier lines

 Avapritinib - ≥ 4L best response based on KIT mutational profile determined by ctDNA

George S, et al. ESMO 2018 #2 New trials in earlier lines

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% SUNITINIB 2006 mPFS 5.6 mo ORR 6.8% REGORAFENIB 2012 mPFS 4.8 mo ORR 4.5% RIPRETINIB (DCC-2618) mPFS 6.3 mo ORR 9.4% AVAPRITINIB (BLU-285) CRENOLANIB v. PLACEBO Phase III >12 mo / 84% PDGFRA D842V CrenoGIST 3.7 mo / 20.0% #2 New trials in earlier lines

IMATINIB 2001 2020-2021? mPFS 20.4 mo ORR 51% AVAPRITINIB SUNITINIB 2006 mPFS 5.6 mo Phase III ORR 6.8% COMPASS REGORAFENIB 2012 ctDNA selection mPFS 4.8 mo RIPRETINIB ORR 4.5% RIPRETINIB (DCC-2618) Phase III mPFS 6.3 mo INTRIGUE AVAPRITINIB ORR 9.4% AVAPRITINIB (BLU-285) CRENOLANIB v. PLACEBO Phase III Phase III >12 mo / 84% PDGFRA D842V CrenoGIST VOYAGER 3.7 mo / 20.0% #3 How do these drugs work… in GIST patients? #3 How do these drugs work… in GIST patients?

 Avapritinib is highly selective against KIT/PDGFRA mutations in the activation loop.

Heinrich M, et al. CTOS 2018 #3 How do these drugs work… in GIST patients?

 Avapritinib is highly selective against KIT/PDGFRA mutations in the activation loop. Other biological mechanisms involved?

George S, et al. ESMO 2018 #3 How do these drugs work… in GIST patients?

KIT secondary mutations likely increase KIT kinase activity and ≥2L TKIs are unable to turn it off completely

IMATINIB REGORAFENIB

Heinrich M, et al. JCO 2006 George S, et al. JCO 2012 #3 How do these drugs work… in GIST patients?

 Ripretinib is a switch control inhibitor with broad activity against KIT/PDGFRA mutations.

Smith BD, et al. Cancer Cell 2019 #3 How do these drugs work… in GIST patients?

 Ripretinib is a switch control inhibitor with broad activity against KIT/PDGFRA mutations.

Smith BD, et al. Cancer Cell 2019 #3 How do these drugs work… in GIST patients?

PDGFRA D842V

Somaiah N, et al. CTOS 2017 #3 How do these drugs work… in GIST patients?

Is complex TKI-refractory GIST a challenge for ripretinib?

Baseline ctDNA mutational profile

George S, et al. ASCO 2018 #4 TKI-refractory GIST: is it all about KIT? #4 TKI-refractory GIST: is it all about KIT?

≥4L KIT inhibitors ripretinib and avapritinib are effective in KIT/PDGFRA-driven GIST… #4 TKI-refractory GIST: is it all about KIT?

≥4L KIT inhibitors ripretinib and avapritinib are effective in KIT/PDGFRA-driven GIST… but GIST disease evolves over time

Von Mehren M, et al. ESMO 2019 #4 TKI-refractory GIST: is it all about KIT?

 # KIT 2nd mutations ≥ 4L does not appear to be that high

Phase II Ponatinib in GIST ctDNA - BEAMing

Heinrich M, et al. ASCO 2014 #4 TKI-refractory GIST: is it all about KIT?

 Co-activation of RAS/MAPK and PI3K/mTOR pathways supplants effectively KIT/PDGFRA oncogenesis

• Patient with ~20 cm gastric GIST + liver met • KIT exon 11 E554-V559 deletion • “Neoadjuvant” imatinib 400mg • Mixed response

Week 6 Week 16 Week 24 Serrano C et al, J Clin Oncol 2015 #4 TKI-refractory GIST: is it all about KIT?

 Co-activation of RAS/MAPK and PI3K/mTOR pathways supplants effectively KIT/PDGFRA oncogenesis

• Patient with ~20 cm gastric GIST + liver met • KIT exon 11 E554-V559 deletion • “Neoadjuvant” imatinib 400mg • Mixed response

Week 6 Week 16 Week 24 Serrano C et al, J Clin Oncol 2015 #4 TKI-refractory GIST: is it all about KIT?

 Co-activation of RAS/MAPK and PI3K/mTOR pathways supplants effectively KIT/PDGFRA oncogenesis

Region #1 Region # 2 Region #3 Responding Progressing Progressing 0 mit/50hpf 60 mit/50hpf 55 mit/50hpf

KIT Exon 11 E554-V559del PTEN C124S KRAS G12R KIT Ex13 T670I

Serrano C et al, J Clin Oncol 2015 #4 TKI-refractory GIST: is it all about KIT?

 Co-activation of RAS/MAPK and PI3K/mTOR pathways supplants effectively KIT/PDGFRA oncogenesis

Region #1 Region # 2 Region #3 Responding Progressing Progressing 0 mit/50hpf 60 mit/50hpf 55 mit/50hpf

KIT Exon 11 E554-V559del PTEN C124S KRAS G12R KIT Ex13 T670I

Serrano C et al, J Clin Oncol 2015 KIT

PI3K RAS

By-pass of KIT driver through KIT- independent conjoined activation of KIT downstream pathways

KIT

PI3K RAS

Serrano C et al, J Clin Oncol 2015 #5 Any future after the future?

 Old strategies for new drugs?

STRATEGY EXAMPLE  Pan-KIT inhibitors Ripretinib  Mutation-specific inhibitors Avapritinib  KIT protein stability HSP90i; IM + HDACi  KIT downstream pathways IM+PI3Ki; IM+MEKi  Adaptation to KIT inhibition IM+FGFRi  KIT heterogeneity Sunitinib + regorafenib  Immunotherapy IM + ipilimumab #5 Any future after the future?

 ctDNA-guided treatment in GIST patients

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Serrano C et al, CTOS 2018 Conclusions / Remarks

We are currently assisting to a golden-age with paradigm- shifting drugs tested in clinical trials.

Avapritinib targets for the first-time ever PDGFRA D842V mutation.

Ripretinib novel MoA targets KIT receptor heterogeneity.

Future efforts will focus on agents targeting alternative resistance mechanisms involved in KIT/PDGFRA signaling. Thanks to the patients and their families

¡MUCHAS GRACIAS!

[email protected] @DrCeSarcoma