Συστηματικη θεραπεία όγκων GIST

ΑΛΕΞΗΣ ΣΤΡΙΜΠΑΚΟΣΠαθολόγος Ογκολόγος

Δ/της Δ’Ογκολογικής ΚλινικήςΕυρωκλινική Αθηνών

EPIDEMIOLOGY

GIST represents a form of sarcoma that comprises approx. 1% to 3% of all malignant GI tumors.

GIST occurs predominantly in adults . The incidence has been slightly higher in men than

women. Small asymptomatic GISTs are found at autopsy in

more than 50 % of individuals over the age of 50 GIST treatment trials estimate an annual incidence

of 4,500 – 6,000 new cases (USA)

Συστηματική θεραπεία όγκων GIST

Επικουρική θεραπεία

Θεραπεία προχωρημένης νόσου– Unresectable

• ?potentially resectable– metastatic

Risk of Recurrence After Resection of Primary GIST

DeMatteo RP et al. Cancer. 2008;112:608-615.

Approximately 40% of patients who undergo complete resection of primary GIST have a recurrence within 5 years

0102030405060708090

100

1 Year 2 Years 5 Years 10 Years

Rec

urre

nce-

Free

Sur

viva

l, %

Risk Assessment

Accurate assessment of risk of aggressive malignant behaviour in GIST poses a challenge1

Morphologic features most predictive of outcome1,2

- Mitotic index - Tumour size

Tumour site and rupture also affect risk of recurrence and progression2,3

Mutational status is useful in predicting treatment response in the metastatic setting4,5

?applicable in the adjuvant setting

1. Fletcher CD et al. Hum Pathol. 2002;33:459-465.2. Demetri GD et al. J Natl Compr Cancer Netw. 2007;5(suppl 2):S1-S29.3. Miettinen M, Lasota J. Arch Pathol Lab Med. 2006;130:1466-1478. 4. Debiec-Rychter M et al. Eur J Cancer. 2006;42:1093-1103. 5. Heinrich MC et al. J Clin Oncol. 2003;21:4342-4349.

Primary GIST: Risk Factors for Recurrence After Surgery

Adapted with permission from DeMatteo RP et al. Cancer. 2008;112:608-615.

Rates of RFS were independently predicted by mitotic index, tumour size, and tumour location

Overall Survival by Risk Group

AFIP, Armed Forces Institute of Pathology.Adapted with permission from Goh BKP et al. Ann Surg Oncol. 2008;15:2153-2163.

Cum

ulat

ive

Surv

ival

Specific KIT Mutations Have Prognostic Importance

RFS in 127 patients with completely resected localized GIST based on mutation type

Prop

ortio

n R

ecur

renc

e-Fr

ee

Years After Resection

1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3 4 5 6 7 8 9 10

P<0.001

KIT exon 9 mutation (n=4)

KIT exon 11 DEL557/8 (n=35)No mutation (n=29)

KIT exon 11 PM/INS (n=32)

Other KIT exon 11 deletion (n=17)PDGFRA mutation (n=8)

DeMatteo RP et al. Cancer. 2008;112:608-615.

Imatinib: Selective TKI Targeting KIT, PDGFRA, and Abl

Approved for treatment of unresectable, advanced KIT-positive GIST[33,34] and as adjuvant therapy for resectable GIST[35]

32. Rubin BP, et al. Lancet. 2007;369:1731-1741. 33. Demetri GD, et al. N Engl J Med. 2002;347:472-480. 34. Blanke CD, et al. J Clin Oncol. 2008;26:626-632. 35. DeMatteo RP, et al. Lancet. 2009;373:1097-1104.

Mechanism of action: Imatinib binds to the same site as ATP, thereby preventing phosphorylation of downstream substrates and inhibiting KIT or PDGFRA signaling [32]

Imatinib Mesylate

N

N

N

HN

HN

NN

O CH3So3HInhibition of KIT activated signal transduction, causing reduced GIST proliferation or induction of apoptosis

KIT-activated signal transduction resulting in GIST proliferation

and survival

P

PADP P Y Substrate

ADPP

PP

IMATY SubstrateADPADPP

PP

P

PP

A B

IMAT

ADPP

PP

Y Substrate

Επικουρική θεραπεία

Adjuvant Studies of Imatinib

Trial N Phase Regimen Setting Primary Endpoint Statusa

ACOSOG Z90001 107 2 Imatinib 400 mg/d Adjuvant OS 4-year results

ACOSOG Z90012 708b 3 Imatinib 400 mg/day vs placebo Adjuvant RFS 2-year

results

Nilsson3 23 2 Imatinib 400 mg/day vs historical control Adjuvant RFS 3-year

results

LI J4 105 N/AdImatinib 400 mg/day vs control (refused

therapy)Adjuvant RFS 2-year

results

Kang B5 47 2 Imatinib 400 mg/day (until progression) Adjuvant RFS 2-year

results

EORTC 620246 900 3 Imatinib 400 mg/day vs observation Adjuvant TTSR Enrollment

Completed

SSGXVIII/AIO6 400 3 Imatinib 400 mg/day12 vs 36 months Adjuvant RFS Reported

1. DeMatteo RP et al. ASCO GI Cancers Symposium; 2004. Abstract 8. 2. DeMatteo RP et al. J Clin Oncol. 2005;23:818s. Abstract 9009. 3. Nilsson B et al. Br J Cancer. 2007;96:1656-1658. 4. Li J et al. J Clin Oncol. 2009;27(suppl). Abstract 10556. 5. Kang Y et al. J Clin Oncol. 2009;27(suppl). Abstract e21515. 6. ClinicalTrials.gov. Accessed August 26, 2009.

ACOSOG Z9001: Trial Schema

(Phase III)778 patients

Placebo(354 randomised)

(345 treated)

87 discontinued treatment early

Imatinib (359 randomised)

(337 treated)

97 discontinued treatment early

30 events5 GIST-unrelated deaths

713 patients randomised

• Phase III, randomised, double-blind, placebo-controlled multi-centre trial

IM 400 mg/day or placebo for 1 yr

70 events5 GIST-related deaths

3 GIST-unrelated deaths

DeMatteo RP et al. Lancet. 2009; 373: 1097-1104

ACOSOG Z9001: Study Design/Methods

Key Eligibility Criteria:• Patients ≥18 years with localised and primary GIST• KIT-positive tumours ≥3 cm• Complete surgical resection

Endpoints:• Primary: Recurrence-free Survival (RFS)• Secondary: Overall Survival (OS) and safety

Other Key Elements:• Dose modifications upon grade 3 or 4 events• PD patients unblinded:

- If placebo IM 400 mg/day or- If IM 400 mg/day IM 800 mg/day

Median follow-up: 19.7 months

Estimated 1-year RFS (95% CI):

Imatinib: 98% (96-100)Placebo: 83% (78-88)

HR = 0.35 (0.22-0.53)p < 0.0001

CI, confidence interval; HR, hazard ratio

Events experienced:

Imatinib: 8.0% (30) Placebo: 20.0% (70)

Recurrence-free Survival (RFS)*

*All randomised patients were included in the analysis; recurrence-free survival was defined as the time frompatient registration to the development of tumour recurrence or death from any cause. Intention-to-treat analyses were done for recurrence-free survival (ie, analysed patients by randomised group).

• Imatinib adjuvant therapy results in significantly longer RFS in each of the tumour size categories compared to placebo

Recurrence-free Survival (Tumour size)

size >10cm

size >3 and <6 cm size >6cm and <10cm

• No difference in OS between imatinib and placebo adjuvant therapies

Overall Survival (OS)*

*All randomised patients were included in the analysis; Overall survival was defined as the time from patient registration to death from any cause. Intention-to-treat analyses were done for overall survival (ie, analysed patients by randomised group).

Imatinib at 400 mg/day is safe and well tolerated when administered as adjuvant therapy after complete resection of primary GIST

Adjuvant imatinib resulted in an improvement in RFS in patients with all tumour sizes

- Especially relevant for high-risk patients (e.g. tumour size ≥10 cm or high mitotic rate) since this patient population has a 50% higher chance of recurrence at 2 years without adjuvant therapy

OS between imatinib and placebo groups comparable at this time A longer follow-up period is likely required to observe differences

Ongoing trials in the adjuvant setting are under way to determine appropriate treatment duration of imatinib and impact on OS

– SSGXVIII/AIO – EORTC 62024

Summary

Adjuvant Imatinib: Beyond 1 Year of Treatment

Imatinib 400mg/d for 12 months

An open-label Phase III study

Imatinib 400mg/d for 36 months

Follow-up

Follow-up

SSGXVIII: Study design

Randomassignment 1:1Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture

SSGXVIII: Objectives

Primary: RFS

Time from randomization to GIST recurrence or death

Secondary objectives included:

SafetyOverall survival

SSGXIII: Key inclusion criteria

Histologically confirmed GIST, KIT-positive

High risk of recurrence according to the modified Consensus Criteria*:

– Tumor diameter >10 cm or – Tumor mitosis count >10/50 HPF** or – Size >5 cm and mitosis count >5/50 HPFs or– Tumor rupture spontaneously or at surgery

*Fletcher CD et al. Hum Pathol 2002; 33:459-65 **HPF, High Power Field of the microscope

SSGXVIII: Recurrence-free survival (ITT)

No. at risk (n=397)

36 Months of imatinib 198 184 173 133 82 39 8 0 12 Months of imatinib 199 177 137 88 49 27 10 0

60.1%

47.9%

86.6%

65.6%

36 Months

12 Months

Hazard ratio 0.46 (95% CI, 0.32-0.65)

P <.0001

0 1 2 3 4 5 6 70

20

40

60

80

100%

Median follow-up time 54 months

Years

Subgroup No. of patients Hazard ratio (95% CI), RFS P valueAge ≤65 256 0.47 (0.30-0.74) .001 >65 141 0.49 (0.28-0.85) .01Sex Male 201 0.46 (0.28-0.76) .002 Female 196 0.46 (0.28-0.76) .002Tumor site Stomach 202 0.42 (0.23-0.78) .005 Other 193 0.47 (0.31-0.73) <.001Tumor size ≤ 10 cm 219 0.40 (0.23-0.69) <.001 >10 cm 176 0.47 (0.29-0.76) .002Mitoses/50 HPF (local) ≤ 10 mitoses 209 0.76 (0.43-1.32) .33 > 10 mitoses 154 0.29 (0.17-0.49) <.001Mitoses/50 HPF (central) ≤ 10 mitoses 256 0.58 (0.34-0.99) .04 > 10 mitoses 137 0.37 (0.23-0.61) <.001Tumor rupture No 318 0.43 (0.28-0.66) <.001 Yes 79 0.47 (0.25-0.89) .02Tumor mutation site KIT exon 9 26 0.61 (0.22-1.68) .34 KIT exon 11 256 0.35 (0.22-0.56) <.001 Wild type 33 0.41 (0.11-1.51) .16 Other 51 0.78 (0.22-2.78) .70

0.1 1.0 10

36 mo better 12 mo better

0.1 1.0 10

Clinical Risk Factors and Risk-Reduction with 3 Years of Adjuvant Imatinib

Risk Factor No. Patients Hazard Ratio (95% CI, RFS)

P-Value

TUMOUR SITE

Gastric 202 0.42 (0.23-0.78) 0.006

Non-Gastric 195 0.47(0.31-0.73) <0.001

SIZE

<10 cm. 219 0.40 (0.24-0.69) <0.001

>10 cm. 176 0.47 (0.29-0.76) 0.002

Mitoses/50 HPF

<10 238 0.53 (0.30-0.94) 0.03

>10 133 0.36 (0.22-0.59) <0.001

No. at risk (n=397)36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0

SSGXVIII: Overall survival (ITT)

Hazard ratio 0.45 (95% CI, 0.22-0.89)

P = .019

96.3% 92.0%

94.0%

81.7%

36 Months

12 Months

0 1 2 3 4 5 6 70

20

40

60

80

100%

Years

Treatment safetyCategory 12-month group

(n=194)No. (%)

36-month group (n=198)No. (%)

P

Any adverse event 192 (99) 198 (100) .24

Grade 3 or 4 event 39 (20) 65 (33) .006

Cardiac event 8 (4) 4 (2) .26

Second cancer 14 (7) 13 (7) .84

Death, possibly imatinib-related 1* (1) 0 (0) .49

Discontinued imatinib, no GIST recurrence

25 (13) 51 (26) .001

*Lung injury

Most frequent adverse events

Adverse event Any Grade P Grade 3 or 4 P

12 Mo % 36 Mo % 12 Mo % 36 Mo %

Anemia 72 80 .08 1 1 1.00Periorbital edema 59 74 .002 1 1 1.00

Elevated LDH* 43 60 .001 0 0 -

Fatigue 48 48 1.00 1 1 .62

Nausea 45 51 .23 2 1 .37

Diarrhea 44 54 .044 1 2 .37

Leukopenia 35 47 .014 2 3 .75

Muscle cramps 31 49 <0.001 1 1 1.00

Conclusions

Compared to 1 year of adjuvant imatinib, 3 years of imatinib improves

- RFS - Overall survival

as treatment of GIST patients who have a high estimated risk of recurrence after surgery.

Adjuvant imatinib is relatively well tolerated; severe adverse events are infrequent.

Θεραπεία προχωρημένης νόσου

Beyond imatinib

Sunitinib in GIST: Selective Targeting of VEGFR and KIT

Mechanism of action: Sunitinib binds to the same site as ATP, thereby preventing phosphorylation of downstream substrates and inhibiting VEGFR, PDGFR, KIT, CSF-1R, and FLT signaling

Approved for treatment of GIST after disease progression on or with intolerance to imatinib

38. Wolter P, et al. Acta Oncol. 2010;49:13-23. 39. Faivre S, et al. Nat Rev Drug Discov. 2007;6:734-745.

PDGFRA PDGFRB KIT FLT3CSF R(FMS)

VEGFR(FLT)

VEGFR2(FLK)

VEGFR3(KDR/FLT4)

Regorafenib: Novel Multitargeted TKI Regorafenib has a wide spectrum of

target inhibition: KIT; PDGFR; VEGFR-1, -2, -3; TIE2; RET, fibroblast growth factor receptor 1; RAF; and p38 MAPK[63]

Phase II study (N = 33) in metastatic GIST: 4 PRs, 22 SD ≥ 22 wks, median PFS: 10 mos[63]

Phase III GRID study[64]

– Significant PFS improvement vs placebo in 199 pts with metastatic or unresectable GIST and progression on imatinib and sunitinib

– Most common grade 3/4 events:hand-foot skin reaction, hypertension, diarrhea

63. George S, et al. J Clin Oncol. 2012;30:2401-2407.64. Demetri G, et al. ASCO 2012. Abstract LBA10008.

Prop

ortio

n W

ithou

t Pro

gres

sion 1.00

0.75

0.50

0.25

00 50 100 150 200 250 300

Days From Randomization

PlaceboRegorafenib

HR: 0.27 (95% CI: 0.19-0.39)1-sided P < .0001

Regorafenib(n = 133)

Placebo(n = 66)

Median PFS, mos (95% CI)

4.8 (4.1-5.8)

0.9 (0.9-1.1)

Events, n (%) 81 (60.9) 63 (95.5)

Treatment algorithm in metastatic GISTKIT exon 9 mutation1–4 KIT/PDGFRA wild-type1–4KIT exon 11 mutation1–4

1. Reichardt P, et al. ASCO 2014 (abstract 10549)2. Heinrich MC, et al. J Clin Oncol 2008;26:5352–5359

3. Debiec-Rychter M, et al. Eur J Cancer 2006;42:1093-1103

4. The ESMO/European Sarcoma Network Working Group.

Ann Oncol 2014;25 (Suppl 3): iii21–iii26

*Switch treatment upon confirmed progression

*

*

*

*

*

*

*

*

*

*

Imatinib 400 mgImatinib 800 mg Imatinib 400 mg

Imatinib 800 mg Sunitinib

Sunitinib Sunitinib

Regorafenib Regorafenib

Imatinib 800 mg

Sunitinib

Regorafenib

Sunitinib