Whom to treat and how long to treat after resection of GIST

Professor John R Zalcberg

Chief Medical Officer & Director, Division of Cancer Medicine

Peter MacCallum Cancer Centre

Chair, Australasian Gastro-Intestinal Trials Group

Disclosures

Novartis Pfizer Bayer Amgen BMS

Research / Travel Support / Advisory Board

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

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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.

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Specific KIT Mutations Have Prognostic Importance

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

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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.

Risk Stratification of Primary GIST: Miettinen (AFIP)

Original source: Miettinen M, Lasota J. Semin Diagn Pathol. 2006;23:70-83.

Data are based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.

† Denotes small numbers of cases. ≈ Tumour size categories combined for both duodenal and rectal GISTs because of small numbers. ∂ No tumours of such category were included in this study.

Nomogram to Predict RFS Following Complete Surgical Resection of Primary GIST

Gold JS et al. Lancet Oncol. 10; 1045-1052, 2009

Risk Classification – Room for Refinement

1. Wardelmann E et al. Virchoves Arch. 2007;451:743-749.2. Joensuu H. Hum Path. 2008;39:1411-1419.3. Dei Tos AP et al. J Clin Oncol. 2009;27(suppl). Abstract 10555.

Additional factors:

- Mutational status1

- Rupture2

- Necrosis3

Joensuu H et al. Lancet Oncol, 13; 265-274, 2012

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 events

5 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 events

5 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

ParametersPlacebo(n=354)

Imatinib(n=359)

Tumour size, n (%)

>3 and <6 cm 149 (42.1%) 143 (39.8%)

>6 and <10 cm 119 (33.6%) 123 (34.3%)

>10 cm 86 (24.3%) 93 (25.9%)

Margins, n (%)

R0 330 (93.2%) 325 (90.5%)

R1 23 (6.5%) 34 (9.5%)

Unknown 1 (0.3%) 0 (0.0%)

Tumour origin, n (%)

Stomach 235 (66.4%) 209 (58.2%)

Small intestine 102 (28.8%) 125 (34.8%)

Rectum 5 (1.4%) 5 (1.4%)

Other 12 (3.4%) 18 (5.0%)

Unknown 0 (0.0%) 2 (0.6%)

R0 – negative microscopic margins; R1 – positive microscopic margins

Patient characteristics (continued)

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

Random

assignment

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

Patient dispositionCategory 12 Months 36 Months

No. (%) No. (%)

Randomized (Feb 2004 to Sep 2009) 200 200

Included in ITT Population* 199 198

- No GIST at pathology review 5 (3) 10 (5)

- GIST metastases at study entry 13 (7) 11 (6)

Included in Efficacy Population 181 177

Included in Safety Population 194 198

- On treatment at data collection cut-off 0 (0) 19 (10)

Discontinued assigned treatment 29 (15) 63 (32)

- GIST recurred during treatment 4 (2) 12 (6)

- Adverse event 15 (8) 27 (14)

- Other reason 10 (5) 24 (12)

*3 patients who withdrew consent excluded

Baseline characteristics (ITT)Characteristic 12-Mo group 36-Mo group

Median age (range) - years 62 (23-84) 60 (22-81)

Male - (%) 52 49

ECOG performance status 0 - (%) 85 86

Gastric primary tumor - (%) 49 53

Median tumor size (range) - cm 9 (2-35) 10 (2-40)

Median mitosis count - /50 HPFs 10 (0-250) 8 (0-165)

Tumor rupture - (%) 18 22

GIST gene mutation site - (%)*

- KIT exon 9 6 7

- KIT exon 11 69 71

- KIT exon 13 2 1

- PDGFRA (D842V) 13 (10) 12 (8)

- wild type 10 8

*Available for 366 (92%) out of the 397 tumors

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

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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

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100%

Years

Treatment safety

Category 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.

Phase 3 Adjuvant Trial (EORTC 62024): Overview

EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.

ObjectivesObjectives

Primary Time to secondary resistance

Secondary Overall survival Relapse-free survival Relapse-free interval Drug safety

TreatmentTreatment

Imatinib 400 mg/day for 2 years

Inclusion criteriaInclusion criteria

Intermediate- or high-risk GIST Completely resected KIT-positive GIST

Phase 3 Adjuvant Trial (EORTC 62024): Design

Follow for 5 years after treatment to evaluate TTSR, PFS, and OS

Observation(for 2 years)

Imatinib (400 mg/day for 2 years)

aDue to progression or unacceptable toxicity.

TTSR, time to secondary resistance; PFS, progression-free survival; OS, overall survival

EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.

Complete resection of

primary GIST

Discontinued treatmenta

Post-Resection Evaluation of Recurrence-Free Survival for Gastro-Intestinal Stromal Tumors Treated with Adjuvant Imatinib:

PERSIST-5

Phase II

N = 85 patients

Primary objective: Recurrence-free survival

Imatinib 400 mg/d x 5 years

Resected GIST >2 cm and mitotic rate >5

orNon-gastric primary >5 cm

Register

Adapted DeMatteo

Conclusions from SSGXVIII *

In GIST, 3 years of adjuvant imatinib are better than one in terms of

recurrence-free and overall survival

Three years of post-operative imatinib treatment represent the new

gold standard for patients with resected “high-risk” GISTs

The overall risk at which adjuvant imatinib should be commenced

requires further clarification

* Adapted from discussion by Charles Blanke, ASCO 2011