Advances in cancer target pathways
Roma 8 aprile 2016
KIT/PDGFRA pathway
KIT 80-85%
PDGFRA 5-10%
Wild-type (10%-15%)
Dominio di
legame col
ligando
Dominio di
legame col
ligando
-Stem cell factor
-Plateled derived
growth factor
M
Membrana
M
Esone 9: 13%
TKI
M
Esone 11: 66%
Esone 13: 1.2%
(Esone 14: mutazioni secondarie di resistenza
TKII
M
Esone 17:0.6%
(Esone 18: mutazioni secondarie di resistenza
Citoplasma
M
M
Esone 12: 1.5%
Esone 14: 0.3%
M
Esone 18: 5.6%
La risposta ad imatinib dipende dal tipo e dalla localizzazione delle mutazioni.
Alcune mutazioni del 2° dominio tirosin chinasico sono intrisecamente imatinib-resistenti.
Molecular overview in GIST
GIST
KIT mutant (75%)
PDGFRA mutant (10%)
KIT/PDGFRA wild-type (10-15%)
Primary mutations in:
Exon 8
Exon 9
Exon 11
Secondary mutations
Exon 13
Exon 17
Primary mutations in:
Exon 12
Exon 14
Exon 18
Secondary mutations
SDH DEFICIENT (50%)
IGF1R positive
Quadruple WT(30%)
(SDH COMPETENT)
BRAF/RAS/NF1 mutant(15%)
IGF1R negative
IGF1R negative
Therapeutic Strategy
• Malattia localizzata operabile
• Malattia localizzata non operabile
Biopsia per assetto mutazionale
Imanitinib
Neoadiuvante
Chirurgia
+/Terapia adiuvante
• Malattia metastatica
Ricaduta
Terapia sistemica +/Chirurgia/ RF
Miettinen risk classification
Risk classifications ‘’post-Miettinen’’
Counter maps
Risk 60-80%
Risk 80-90%
Joensuu H, et al. 2012
Adjuvant treatment: from less to more
1 year imatinib 400 mg vs placebo
RFS 98%
RFS 83%
DeMatteo RP, et al. 2009
1 years vs 3 years imatinib 400 mg
high risk Fletcher 2002 or tumour rupture
Results:
3 years RFS 87% vs 60%
5 years RFS 66% vs 48%
Ricerca
5 years OS 92% vs 82%
Comments:
1. Cure o long remission?
2. Incongruence of high risk definition (34% al
100%)
3. Discontinuation rate (36% vs 16%)
Joensuu H, et al. 2012
Adiuvant therapy
How long and what objective?
Patients identification : mitotic rate, size, location and
sensitive kinase genotype
No treatment for low risk
Treatment for high risk (excluding PDGFRFA D842V) and for
WT decision case based
Intermediate risk (> 30%-50%) treatment for sensitive
mutations
Advanced Disease
KIT and PDGFRa genotype
Overall
survival
Event
free
survival
Exon 11
Exon 9
No mutation
Heinrich, M. C. et al. J Clin Oncol; 21:4342-4349 2003
Exon 11
Exon 9Exon 9
No mutation
KIT and PDGFRA genotype: metaGIST
Analysis of Predictive Factors
PFS: KIT exon 9 mutation was the only significant predictive
factor for the benefit of high-dose therapy (P = .012).
Within patients with KIT exon 9 mutations, PFS was significantly
longer for patients treated with the high-dose arm (P = .017).
For patients without such mutations, no difference was observed
between treatment arms.
OS: none of the investigated cofactors showed any predictive
value, and no significant advantage of high-dose therapy
(P = .15,) was documented in patients with KIT exon 9 mutations
Metagist Group ; JCO 2010
Treatment discontinuation
PFS 2 years
80% vs 16%
BRF14 trial of French Sarcoma Group shows that imatinib interruption in advanced
GIST results in rapid progression in most patients
Le Cesne et al. Lancet Oncol 2010
TUMOR HETEROGENEITY
Genetic heterogeneity in cholangiocarcinoma: a major challenge for
targeted therapies
Giovanni Brandi, Andrea Farioli, Annalisa Astolfi, Guido Biasco and Simona Tavolari
Oncotarget 2015
•
•
•
Fundamental contribution of secondary KIT mutations to TKI resistance in GIST
Heterogeneity of resistance mutations within and between mets from individual pts
Secondary KIT domain mutation are found in over 80% of pts
KIT and PDGFRA secondary mutations
Maleddu A, et al. Cancer Treat Rev 2009
Secondary mutations occur in
GIST with primary mutation on
KIT exon 11 and 9
Most frequent secondary
mutations in KIT exon 13, 14,
17+ 18
Secondary mutations in
PDGFRA are rare
Secondary mutations usually
occur in the same receptor:
( except 2 cases of KIT primary mutations
(exon 11 and exon 9) followed by PDGFRA
secondary mutations (exon 18 and 14)
GIST KIT/PDGFRA WT do
not develop secondary
mutations
Additional events in GIST beyond KIT/PDGFRA receptors
identified by NGS study
“Oncogenes amplification+Oncosuppressors reduction”
Schedule 50 mg/die 4 weeks on /2 off
TTP of cross over arm was similar to originally
sunitinib arm
OS not significant ( cross over allowed)
Sunitinib discontinuation at PD?
CONTINUED SUNITINIB TREATMENT AFTER PROGRESSIVE DISEASE (PD) IN A WORLDWIDE TREATMENT-USE TRIAL OF PATIENTS (PTS)
WITH GASTROINTESTINAL STROMAL TUMOR (GIST)
Background
Continuous kinase inhibition has been posited as important for optimizing outcomes of pts with kinase-mutant-driven cancers such as
GIST. The outcomes of pts who continued on treatment after PD vs those who stopped after PD were compared using data from a
worldwide treatment-use study of sunitinib in GIST.
Methods
This open-label study was designed to provide access to and assess the safety and efficacy of sunitinib (starting dosing schedule: 50 mg/d;
4 wk on treatment, 2 wk off in 6-wk cycles) in pts with advanced imatinib-resistant/intolerant GIST (enrollment: 9/2004 − 12/2007).
Treatment was continued for as long as there was evidence of disease control in the judgment of the investigator; survival was monitored
for ≤2 y post-treatment or until 7/2008, whichever came first. In this post hoc analysis, pts were dichotomized based on whether sunitinib
treatment was continued or stopped after PD.
Results
At final data cutoff (10/2011), 1124 of 1131 pts enrolled had received ≥1 dose of sunitinib on study. Of these pts, 380 continued and 324
stopped sunitinib treatment after PD. The groups were generally well balanced for baseline demographics except for gender (proportion
male: 67% vs 59%) and pts with ECOG PS 0 (44% vs 35%). Pts who continued on treatment after PD generally
received sunitinib longer than those who did not continue post-PD (median 9 vs 4 cycles started). Median OS among pts who remained on
treatment after PD was 22.8 months (95% CI: 20.4 − 24.7) and 13.2 months (95% CI: 11.7 − 14.5) among those who did not
continue sunitinib after PD. The most common treatment-related AEs in both groups were diarrhea, fatigue, and hand − foot syndrome,
which were mainly grade 1/2 and occurred at a higher rate among pts who continued sunitinib after PD than among those who stopped
treatment after PD (49% vs 35%; 48% vs 41%; and 39% vs 31%, respectively).
Conclusions
Results of this analysis suggest that pts with GIST who continued on sunitinib after PD exhibited a better clinical outcome (longer OS) than
those who stopped treatment after PD, although the potential impact of differing pt characteristics and selection bias cannot be ruled out
in this retrospective analysis.
OS= 22 vs 13 m
Regorafenib as third line … waiting Ponatinib ?
Garner AP, Clin Cancer Res 2014
Demetri G, Lancet Oncol 20012
Median PFS 12
weeks (4,8 months
vs 1 m)
Regorafenib
120 mg
Ponatinib
30 mg
OS= ns ( cross over allowed)
Rechallenge imatinib: RIGHT study
81 pz randomizzati 1:1 a ricevere imatinib
(dopo il fallimento di imatinib e sunitinib) o
placebo
Dopo un follow-up mediano di 5·2 mesi la PFS
è risultata 1.8 mesi con imatinib versus 0·9
mesi con placebo (p=0·005).
37 (93%) pazienti del braccio placebo hanno
effettuato cross over al braccio imatinib
dopo progressione.
Role of KIT and PDGFRA genotype
Response prediction:
>KIT exon 11 good response to imanib
>KIT exon 9 requires higher dose imatinib, better response to sunitinib
>PDGFRA D842V resistance to imatinib
>KIT/PDGFRA WT confers generally resistance to imatinib, better response to
sunitinib
Prognosis:
> KIT 11 mutations associated to shorter survival in pre-imatinib era
 deletions (codons 557 and/or 558) associated to poorer outcome in comparison
to missense mutations
> KIT 9 located in the small intestine, associated to poorer outcome
> PDGFRA mutations usually have a good prognosis
Metastatic WT GIST: flow chart of treatment
KIT/PDGFRA WT SDH deficient
PDGFRA D842V mutant
Regorafenib
Nannini M, Cancer Treat Rev 2011
SDH complex
SDH complex: regulates the respiratory chain in mithocondria membrane
controls hypoxia and angiogenesis
SDHA mutations in KIT/PDGFRA WT GIST
JNCI 2011
9 of the 34 patients with
KIT/PDGFRA wild-type GIST
carried mutations in one of the four
subunits of the SDH complex with a
prevalence for SDHA (6 patients in
SDHA, 2 in SDHB, 1 in SDHC)
Overexpression of IGF1R
(Rnaseq;WT; IHC)
Not by amplification but by epigenetic
(miRna, hypomethilation?)
Pantaleo MA, Eur J Hum Genet 2013
RATIONALE FOR TARGETING IGF/IGF RECEPTOR PATHWAY
IN CHOLANGIOCARCINOMA
Liver
Alvaro et al. Am J Pathol. 2006
ICC
Gatto and Alvaro World J Gastrointest Oncol 2010.
Crenolanib (anti PDGFRa mutation)
CELL Lines
New putative drugs in Pi3K GIST ( BYL 719)
PI3K (H1047L) + KIT exone 11
(K558_e562del)
High cell growth arrest by PIK3 inhibitors in 4
GIST cell lines resistant to imatinib,
BYL + Imatinib: Phase Ib / closed
: ( combination: safety)
Bauer S, Oncogene 2007
1/87 GIST patients
Daniels M, et al. Cancer Lett 2011
Take home message
Treatments of GIST should be decided on molecular basis
In advanced setting the treatments should be continous
Three lines of treatments in a rare tumors for metastatic disease
+ rechallenge at definitive failure
Adjuvant therapy should be indicated after a careful risk of relapse evaluation
KIT/PDGFRA WT GIST should be studied for SDH or BRAF mutations