METHOD OF PARTICIPATION

Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials:• Pre-activity Survey

– Located at the front of your syllabus• CME Evaluation with Post-activity Survey

– Located at the back of your syllabus

M E T H O D O F PA R T I C I PAT I O N

Disclosures

• The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests is located on page 5 of your syllabus

• The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests is provided on page 5 of your syllabus

• The relevant financial relationships reported by the non-faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests is located on page 5 of your syllabus

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Educational Objectives

At the conclusion of this activity, participants should be able to demonstrate the ability to:• Understand the recently updated clinical practice guidelines for

GIST• Review the treatment options for patients with very early stage

disease (micro-GIST), localized disease, and metastatic disease

• Discuss surveillance strategies for patients with resected or metastatic GIST and understand the clinical spectrum of resistance

• Develop a multidisciplinary treatment approach for the management of GIST

Pre-activity Survey

• Please take out the Pre-activity Survey from your packet• Your answers are important to us and will be used to help

shape future CME activities• It is important that you fill out the information at the top of

the form:– Please select the best answer(s) for the questions below:– Degree: _MD/DO _ Nursing Professional _ PharmD

_Other:_____________________________ – Specialty: _ Oncology _ Pathology _ Internal Medicine

_Other:_____________________________

Please rate your level of confidence in personalizing treatment strategies for patients with metastatic GIST:

1 2 3 4 5Not confident Extremely confident

Pre-activity Survey Question 1

Pre-activity Survey Question 2Neoadjuvant imatinib should NOT be considered for:

A. Unresectable or borderline resectable tumorsB. Tumors that would NOT clearly exhibit an improvement

in surgical morbidity with neoadjuvant therapyC. Tumors that would require extensive multi-visceral

resectionD. Potentially resectable metastatic disease


A healthy 39-year-old male was diagnosed with 4 x 4.5 cm gastric mass with liver metastases. Core needle biopsy reveals spindled cell GIST with KIT exon 11 mutation. He responded to imatinib 400 mg/d but a solitary lesion progressed after 18 months of therapy. What is the most reasonable treatment recommendation for this patient?

A. Biopsy progressing lesionB. Switch patient to sunitinib 37.5 mg/dC. Increase imatinib to 800 mg/dD. Consider local therapy, such as arterial embolization,

radiofrequency ablation, or surgical resection


A healthy 58-year-old male was diagnosed with a 9 cm, small-intestine, KIT exon 9 mutant GIST with peritoneal sarcomatosis. He received imatinib 800 mg/d and had regression by size and contrast enhancement on CT for 3 years. What therapy would you recommend for this patient at this patient?

A. Discontniue imatinibB. Continue imatinib 800 mg/dC. Switch to sunitinib 37.5 mg/d


Which of the following novel targeted therapies is NOT a reasonable option for a patient with GIST who has progressed following imatinib therapy?

A. Clinical trialB. RegorafenibC. PazopanibD. Temozolomide

GIST Overview• Most common GI sarcoma

– 0.2% of all GI tumors, but 80% of GI sarcomas

• Distinct clinical and histopathologic entity– Highest incidence in the

40-to-60-year-old age group

– Similar male/female incidence

– Many misclassified

• About 4,000 - 5,000 newly diagnosed GIST patients per year in the US

• Clinical presentation is variable– Pain, hemorrhage, anemia, anorexia,

nausea, perforation

Median Overall Survival in Metastatic GIST (Circa 1990)

Fletcher CD et al. Hum Pathol. 2002;33:459-465.Joensuu H et al. Lancet Oncol. 2002;3:655-664. Miettinen M et al. Pol J Pathol. 2003;54:3-24.Nilsson B et al. Cancer. 2005;103:821-829.

GIST Subtypes

• Kit mutation – ~80% of GISTs– Exon 11 (~70%): codon

557-558– Exon 9 (~10%)

• PDGFR mutation – ~10% of GISTs– Exon 12– Exon 18 D842V (resistant)

Blay et al. Discov Med. 2012;13:357-367.

• SDH-B deficient• Raf V600E• NF-1• Ras • PI3K• IGF-1R overexpressed• “Wild-type”

GIST Chemotherapy Trials

REGIMEN NO. OF PATIENTS PARTIAL RESPONSE N (%)

DOX + DTIC 43 3 (7%)DOX + DTIC +/– IF 60 10 (15%)IF + VP-16 10 0 (0%)Paclitaxel 15 1 (7%)Gemcitabine 17 0 (0%)Liposomal DOX 15 0 (0%)DOX 12 0 (0%)DOX or docetaxel 9 0 (0%)High-dose IF 26 0 (0%)EPI + IF 13 0 (0%)Various 40 4 (10%)DTIC/MMC/DOX/CDDP/GM–CSF 21 1 (5%)Temozolomide 19 0 (0%) TOTAL 280 19 (6.8%)

DOX = doxorubicin; DTIC = dacarbazine; IF = ifosfamide; CDDP = cisplatin; VP16 = etoposide; EPI = epirubicin; NR = not reported Dematteo RP et al. Hum Pathol. 2002;33:466-477.

GIST Pathology

• GIST is believed to share several characteristics with ICC– Neuromuscular pacemaker cell of the GI tract– Found in myenteric plexus throughout GI tract– Expression of CD34 in ~80% of cases– Expression of KIT (CD117) in ~95% of cases

ICC = interstitial cells of Cajal

Corless CL et al. J Clin Oncol. 2004;22:3813-3825.Sircar K et al. Am J Surg Pathol. 1999;23:377-389.

Extracellular Domain (exon 9, 10.2%)

Juxtamembrane Domain (exon 11, 66.1%)

Tyrosine Kinase Domain I (exon 13/14, 1.2%)

Tyrosine Kinase Domain II (exon 17, 0.6%)

= common mutation site

ATP

Kit Receptor Structure

Adapted from D’Amato G et al. Cancer Control. 2005;12:44-56.

ATP

ProliferationSurvival

AdhesionInvasion

MetastasisAngiogenesis

ADP

+

P

Kit Receptor Phenotype

ATP

ProliferationSurvival

AdhesionInvasion

MetastasisAngiogenesis

Imatinib

= imatinib contact point

Adapted from D’Amato G et al. Cancer Control. 2005;12:44-56.

Clinical Trials of Imatinib in GIST

Study Phase N OR CR PR SD PD OS(2 yr)

TTP(median) PFS

van Oosterom, 2001 I 36 53% 0% 53% 36% 11% - - -

von Mehren, 2002 II 147 63% 0% 63% 19% 12% - 72 wks -

Verweij, 2003 II 27 71% 4% 67% 18% 11% - - 73% (1 yr)

Rankin, 2004 III 746

-400 mg daily 48% 3% 45% - - 78% - 50% (2 yr)

-800 mg daily 48% 3% 45% - - 73% - 53% (2 yr)

Verweij, 2004 III 946

-400 mg daily 50% 5% 45% 32% 13% 69% - 44% (2 yr)

-800 mg daily 54% 6% 48% 32% 9% 74% - 52% (2 yr)

Personal Communication. Jon Trent, MD, PhD.

Phase III Trials 400 mg/d vs 800 mg/d Imatinib in Advanced GIST

Benjamin RS et al. Proc Am Soc Clin Oncol. 2003;22:814. Abst. 3271.Rankin C et al. Proc Am Soc Clin Oncol. 2004;23:815. Abst. 9005.Verweij J et al. Proc Am Soc Clin Oncol. 2003;22:814. Abst. 3272.Blanke C et al. J Clin Oncol; 2008;26:620.

Followfor

Survival, PFS

Imatinib(400 mg/d)

Imatinib(800 mg/d)

PDMetastatic or unresectable

GIST

• US Intergroup SWOG S0033 Study• EORTC 62005 Study

MetaGIST: PFS

Gastrointestinal Stromal Tumor Meta-analysis Group (MetaGIST). J Clin Oncol. 2010;28:1247-1253.

400 mg800 mg

Time (Mos)

HR=0.89P=0.04

PFS

(%)

CASE 1: EARLY-STAGE GIST

• 55-year-old male; otherwise healthy• Presented at local health care facility in 1/2011 c/o upper

abdominal pain/early satiety x past six weeks• Underwent evaluation including abdominal CT scan and

upper endoscopy• Endoscopy revealed a 4 x 4.5 cm gastric mass with mucosal

erosion. Needle biopsy demonstrated blood; not diagnostic• Referred to tertiary care center for further evaluation by

multi-disciplinary team

Case 1: Presentation

Case 1: Discussion Point 1

First diagnostic test to be performed: A. CT scan of chest, abdomen, and pelvisB. EUS for needle biopsyC. CT-directed core needle biopsyD. Open operation to excise tumorE. Laparoscopic inspection and incisional biopsy

Answer: A

CT scan 1/2011 demonstrates a >10cm mass with areas of necrosis. Tumor extends into the gastrosplenic ligament; no metastatic disease.

Case 1: CT Scan Imaging; 1/2011


Mass appears to be resectable. What will the initial management strategy include?A. CT-directed biopsyB. EUS/FNAC. Resect mass as excisional biopsyD. Presentation at multi-disciplinary solid tumor

– management conference

E. IMRT-configured external beam radiotherapy

Answer: D

Biopsy of Suspected GIST; Initial Management

• Endoscopic ultrasound guided fine needle aspiration preferred to image-directed percutaneous core needle biopsy; less danger of rupturing fragile GIST capsule

• Biopsy needed prior to neoadjuvant non-surgical therapies to confirm malignancy

NCCN Guidelines, v 1.2013.

NCCN Guidelines For Pathologic Assessment of Suspected GIST

• Morphological dx is requisite standard of care• Ancillary techniques

– IHC: 95% express CD117; 80% express CD34– Molecular genetic testing for mutations in KIT (80% incidence) or

PDGFRA (10% incidence) genes; 10%-15% w/o either mutation• Tumor size and mitotic rate (but not gene mutational status) inform

prognosis• The pathology report should include anatomic location, size, and an

accurate assessment of the mitotic rate measured in the more proliferative area of the tumor

• Mutational analysis may predict response to therapy with tyrosine kinase inhibitors


Initial Management Strategies

• If not a GIST, but some other type of malignancy, non-surgical therapies might be the optimal first steps

• For GIST, consider neoadjuvant imatinib ONLY if surgical morbidity could be reduced by downstaging the tumor preoperatively

• NOTE: Neoadjuvant imatinib may prohibit accurate assessment of recurrence risk

NCCN Guidelines, v 1. 2013.

Tumor Genotype and Imatinib Dose Selection

Gastrointestinal Stromal Tumor Meta-analysis Group (MetaGIST). J Clin Oncol. 2010;28:1247-1253.

Neoadjuvant Imatinib• Consider for:

– Unresectable or borderline resectable tumors– Tumors that would require extensive multi-visceral resection– Potentially resectable metastatic disease

• RTOG 0132/ACRIN 6665 Trial– Multicenter Phase II trial

RTOG = Radiation Therapy Oncology Group ; ACRIN = American College of Radiology Imaging Network Van den Abbeele AD et al. J Nucl Med. 2012;53:567-574. Eisenberg BL et al. J Surg Oncol. 2009;99:42-47.

Group A Group BResponse to pre-operative therapy (RECIST) 7% PR, 83% SD, 10% unknown 4.5% PR, 91% SD, PD 4.5%

Estimated 2-year PFS 82.7% 77.3%Estimated 5-year PFS 57% 30%Estimated 2-year OS 93.3% 90.9%Estimated 5-year OS 77% 68%Type of resection R0 77%

R1 15%R2 8%

R0 58%R1 5%R2 32%Unspecified 5%

RTOG0132/ACRIN 6665Results

Eisenberg BL et al. J Surg Oncol. 2009;99:42-47. Wang et al. Presented at ASCO 2011: Abstract 10057.

RTOG0132/ACRIN 6665Surgical Complications

Eisenberg BL et al. J Surg Oncol. 2009;99:42-47.

Surgical Complications (n = 45)

Wound infection 3 6.7

Hemorrhage requiring blood or blood product

2 4.4

Respiratory event 5 11.1

Cardiac event 3 6.7

Surgical death 1 2.2

Anastomotic disruption 1 2.2

Other surgical complication 15 33.3

Abscess (intra-abdominal) 2 4.4

Neoadjuvant Imatinib: MDACC ExperienceRetrospective Review (46 patients)

• 11 patients with locally advance primary– Median pre-op treatment 12 mos– 1 CR, 8 PR– All 11 underwent complete surgical resection– Median f/u 19.5 mos

All 11 alive 10/11 disease free

Andtbacka RH et al. Ann Surg Oncol. 2007;14:14-24.

• 35 patients with locally advanced or metastatic GIST– 11 patients able to undergo complete resection– Patients demonstrated to have a partial response to pre-

operative therapy much more likely to undergo complete resection (91% vs 4%)

– At median f/u 30 mos, all 11 patients completely resected were alive (6/11 with recurrence at a median of 15 mos)

Neoadjuvant Imatinib: MDACC ExperienceRetrospective Review (46 patients)

Andtbacka RH et al. Ann Surg Oncol. 2007;14:14-24.

Neoadjuvant Imatinib: Summary

• Neoadjuvant treatment with imatinib is feasible• Data from retrospective series and RTOG 0132/ACRIN 6665

indicate neoadjuvant therapy may reduce tumor bulk and permit resection of initially unresectable or borderline resectable tumors

• Resection should be considered following a radiographic indication of response (before tumor progression)

• Currently no consensus on use of neoadjuvant therapy– Generally for patients with marginally resectable tumors or

whose resection would be associated with significant morbidity

Case 1: Multi-disciplinary Assessment

Our patient is resectable with negative margins, but significant risk of morbidity w/ multi-visceral resection; prior to initiating imatinib therapy:• Obtain baseline CT or MRI• Consider baseline PET scan; if GIST PET-avid provides additional marker to assess response to systemic therapy


Case 1: Gastric GIST PET-CT (3/1/11)

Started on imatinib 400 mg/day; assess for progression vs cytoreduction. Proceed to surgery for bleeding, severe GI symptoms, GIST progression


CT scan 8/11 demonstrating that GIST is smaller and more necrotic, consistent with treatment effects

Case 1: CT Scan Re-imaging; 8/2011

• Patient began experiencing imatinib side effects – Fatigue– Edema– Nausea

• Imatinib dose decreased to 200 mg/day• Could consider sunitinib if serious imatinib side effects• CT scan repeated 2 months later

Case 1: Gastric GIST Treatment Effects

Gleevec (imatinib mesylate) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2013.


CT scan 10/11 demonstrating marked additional cytoreduction (now ~ 5.5cm) with more necrosis; now probably resectable w/o multi-visceral ablation

Case 1: CT Scan Re-imaging; 10/2011

Principles of GIST Surgery

• Negative margins (R0) are goal; frozen section control

• GIST are friable; tumor capsule easily violated

• Usually LN (-); nodes not specifically resected

• Re-resection not performed if R1 margins on final pathology analysis


• Decision made for surgical resection at this juncture; surgical findings:– 3.6 cm mass in omentum; 10% necrotic– 5.0 cm mass involving greater curvature of stomach; 99%

necrotic • Adjuvant imatinib initiated w/ resumption of oral intake

post-operatively

Case 1: Discussion

NCCN Guidelines, v 1.2013

Imatinib in the Adjuvant Setting• 50% recurrence rates for GIST with surgery alone

• Cytotoxic chemotherapy ineffective for GIST

• Imatinib demonstrated to be effective

– ACOSOG Z9000 (Phase II)

– ACOSOG Z9001 (Phase III)

– Scandinavian Sarcoma Group XVIII (Phase III)

• FDA approved imatinib for completely resected GIST ≥3cm in size

Gleevec (imatinib mesylate) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2013.


• Imatinib (400mg/day) vs placebo following resection of localized, primary GIST

• 1 year of adjuvant therapy• Summary of results:

- 1-year RFS 98% - imatinib

- 1-year RFS 80% - placebo

- Recurrence in imatinib arm increases at 18mo (6mos following discontinuation of therapy)

Adjuvant Imatinib: ACOSOG Z9001Phase III, Double-blinded, Placebo-controlled, Multicenter Trial

• RFS was significantly improved in imatinib arm in each tumor size category (≥3cm <6cm; ≥6cm <10cm; ≥10cm)

• Grade 3 or 4 toxicity in 30.9% of pts in imatinib arm vs 18.3% pts in placebo arm

• Short follow-up time and crossover design did not permit evaluation for differences in overall survival

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

Adjuvant Imatinib: SSG XVIII

• Prospective, open-label, phase III trial• 400 patients with operable primary GIST

– >5cm, >5 mitoses/50 HPF• Primary outcome = RFS• Secondary outcome = OS, safety

Joensuu H et al. Presented at: ASCO 2011.

36 months 12 monthsImatinib (400mg/day)

n = 200 n = 200

5-year RFS Imatinib 66% Imatinib 48% P<0.0001

5-year OS Imatinib 92% Imatinib 82% P=0.019

Therapy generally well tolerated

Adjuvant Imatinib: Summary

• At least 3 years of therapy appears effective and safe

• Which patient subsets derive the most benefit from adjuvant imatinib?

• Still need to establish cutoffs for estimated risk of disease recurrence for which adjuvant therapy is recommended

Case 1: Post-operative Follow-up

• Continue imatinib in adjuvant setting; duration uncertain

• CT scanning q 3-6 months x 5 yr, then annually for life

Gronchi A et al. Cancer. 2010;116:1847-1858.

GIST Evaluation• Every 2-4 months• History and physical examination• Laboratory testing• Abdominal/pelvic CT with contrast

– Recommended for diagnosis and staging– Also useful for assessing common sites of metastasis (e.g. liver, peritoneum)– Every 2-4 months while on therapy

• 18FDG-PET– Determines tumor metabolic activity– Useful with IV contrast allergy or renal insufficiency– Useful when contrast CT evaluation indeterminate

McAuliffe JC et al. Ann Surg Oncol. 2009;16:910-919.Van den Abbeele AD. Oncologist. 2008;13:8-13.

18FDG-PET=fluorine-18-fluorodeoxyglucose positron emission tomography

61.3 HU11.3 HU

GIST Response to Therapy

Pre-imatinib Post-imatinib (8 weeks therapy)

McAuliffe JC et al. Ann Surg Oncol. 2009;16:910-919.Van den Abbeele AD. Oncologist. 2008;13:8-13.

CASE 2: METASTATIC GIST

• 58-year-old male; otherwise healthy• Diagnosed with a 9 cm small intestine, KIT exon 9 mutant

GIST with widespread peritoneal sarcomatosis• Patient received imatinib 800 mg/d• On CT the patient has had regression by size and contrast

enhancement for 3 years• Patient asks whether he can discontinue imatinib at this time• What would you tell the patient?

Case 2: Metastatic GIST

Case 2, Discussion Point 1

What would you recommend for this patient?

A. Discontinue imatinib

B. Continue imatinib 800 mg/d

C. Switch to sunitinib 37.5 mg/d

Answer: B

Continuous Target Inhibition BFR14 3-yr Randomization

RANDOMIZATION

Advanced/metastatic

GIST

STOP

Imatinib 400 mg

RCRPSD

3 yr

PD Imatinib 400 mg

2 yr

Blay JY et al. J Clin Oncol. 2007;25:1107-1113.

BFR14 3-yr RandomizationProgression-free Survival

Rate of PD at 6 months: 40%in STOP group at 9 months: 55% at 1 year: 75%

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27 30Months

Prob

abilit

y

CONT group 3 evts / 25 patients

1-year PFS: 87.7% (CI95 = 71.6 - 100.0)

STOP group17 evts / 25 patients

1-year PFS: 25.2% (CI95 = 6.3 - 44.0)

Log-rank test : P<0.0001

Median follow-up: 11 m(CI95: 4.8 – 13.8)

Adenis A et al. J Clin Oncol. 2008;26(suppl; abstr 10522).

RIGHT study: PFS

• Imatinib Rechallenge in Metastatic or Unresectable GIST

Kang YK et al. Lancet Oncol. 2013;14:1175-1182.

CASE 3: METASTATIC GIST

• 39-year-old male; otherwise healthy• Diagnosed with a 4 x 4.5 cm gastric mass with liver

metastases• Percutaneous core needle biopsy reveals spindled cell GIST

with 21 mitoses/50 hpf and KIT exon 11 mutation• Initiated on imatinib 400 mg/d• Initial response to imatinib, but progression of a solitary,

previously regressing lesion after 18 months of therapy

Case 3: Metastatic GIST


What would you recommend for this patient?

A. Biopsy progressing lesion

B. Switch patient to sunitinib 37.5 mg/d

C. Increase imatinib to 800 mg/d

D. Consider local therapy, such as arterial embolization, radiofrequency ablation, surgical resection

Answer: D

Limited Progression

Courtesy of Dr. R. DeMatteo.

Therapy by Type of Progression

• Limited or Nodular Progression– Hepatic artery chemoembolization– Hepatic radio-frequency catheter ablation– Surgical resection– Radiation therapy (esophageal or rectal)

• Widespread progression– Increase imatinib to 800 mg daily– Sunitinib– Clinical trial


Imatinib-resistant Metastatic GISTLimited Hepatic Progression

Kobayashi K et al. Am J Clin Oncol. 2009;32:574-581.

Progressing Lesion

Post-Embolization

Hepatic Arterial EmbolizationRadiographic Response Rates

• 14 patients with imatinib-resistant GIST and progressive liver metastases– Treated with hepatic arterial embolization or chemoembolization– 13 patients evaluable for radiologic response

RESPONSE BEST RESPONSE (Choi Criteria) BEST RESPONSE (RECIST)

Overall 54% 8%Complete 0% 0%

Partial 54% 8%

Stable 46% 92%

Progression 0% 0%

Kobayashi K et al. Am J Clin Oncol. 2009;32:574-581.

Efficacy and Safety of SunitinibIn Patients with Advanced GIST after Failure with ImatinibA Randomized Controlled Trial

Demetri GD et al. Lancet. 2006;368:1329-1338.

TIME TO TUMOR PROGRESSION


Patient develops widespread metastases in the liver and peritoneum. The patient’s metastatic tumor progressed at multiple sites on imatinib 800 and then on sunitinib 37.5 mg daily. What would you recommend?

A. Regorafenib 160 mg/dB. Participation in a clinical trial

Rationale for Novel Agents to Treat Imatinib-resistant GIST• Although imatinib revolutionized the initial management of advanced GIST, TKI

resistance eventually occurs in >85% of patients leading to progression of disease• Sunitinib can benefit GIST patients after failure of imatinib, but there is only one

approved therapy after failure of both imatinib and sunitinib

Casali PG, Reichardt P et al. Presented at: ESMO 2012; abstract 1478O.

OF F

TREATMENT

Disease progressionper independent blinded central

review

2 : 1

Regorafenib + best supportive care (BSC)

160 mg once daily 3 weeks on, 1 week off (n=133)

Placebo + BSC 3 weeks on,

1 week off (n=66)

RAND

OM I

ZAT

I ON

UnblindingCrossover offered for placebo arm or continued regorafenib for treatment

arm

Regorafenib (unblinded)until next progression

Metastatic/ unresectable GIST

patients progressing despite at least prior

imatinib and sunitinib

(n=236 screened; n=199 randomized)

GIST – Regorafenib In Progressive Disease (GRID): Study Design

Multicenter, randomized, double-blind, placebo-controlled phase III study global trial: 17 countries across Europe, North America, and Asia-Pacific Stratification: treatment line (2 vs >2 prior lines), geographical location (Asia vs “Rest of World”)

Progression-free Survival Comparison of Central Review vs Investigator Assessments

Surv

ival d

istrib

utio

n fu

nctio

n

00

0.25

0.50

0.75

1.00

50 100 150 200 250 300 350

Days from randomization

Regorafenib (central review)

Placebo (central review)

Regorafenib (investigator assessment)

Placebo (investigator assessment)


Overall Survival between GRID Study Arms

Estimating Crossover Impact via the Rank-preserving Structural Failure Time (RPSFT) Method

P valuesRegorafenib vs placebo (uncorrected): 0.199Regorafenib vs placebo (RPSFT corrected): 0.025

Days from randomization

Surv

ival d

istrib

utio

n fu

nctio

n

0

Placebo

0

0.25

0.50

0.75

1.00

50 100 150 200 250 300

Regorafenib

350 400

Placebo (RPSFT corrected)


Other Agents for IM-RES GISTCLASS AGENT TRIAL PHASE RESULTS

KIT Inhibitors

Sorafenib II PR=13%, SD=58% PFS=5 monthsDasatinib II PR=22%, SD=24% PFS= 2 monthsNilotinib I/II/III PR=10%, SD=37% PFS=3 months

Pazopanib II OngoingAxitinib ND ND

Raf Inhibitors Vemurafenib I ND

mTOR Inhibitors Everolimus II/III PR=2%, SD=43% PFS=3.5 months

PI3K Inhibitors Buparlisib (BKM120) I/II Recruiting

HDAC inhibitors Vorinostat NA NDPlacebo Various III PR=0% PFS=1- 1.5 months

HDAC=histone deacetylase; IGF-1R=insulin-like growth factor–1 receptor; MKI=multitargeted kinase inhibitor; mTOR=mammalian target of rapamycin.

Participant CME Evaluation

• Please take out the Participant CME Post-survey and Evaluation from the back of your packet

• If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few questions we will read through now measuring the knowledge and competence you have garnered from this program. The post-survey is located on page 1 of the evaluation form.

Participant CME Post-survey Question 1

As a result of attending this educational activity, please rate your level of confidence in personalizing treatment strategies for patients with metastatic GIST:

1 2 3 4 5Not confident Extremely confident

Participant CME Post-survey Question 2Neoadjuvant imatinib should NOT be considered for:

A. Unresectable or borderline resectable tumorsB. Tumors that would NOT clearly exhibit an improvement

in surgical morbidity with neoadjuvant therapyC. Tumors that would require extensive multi-visceral

resectionD. Potentially resectable metastatic disease


A healthy 39-year-old male was diagnosed with 4 x 4.5 cm gastric mass with liver metastases. Core needle biopsy reveals spindled cell GIST with KIT exon 11 mutation. He responded to imatinib 400 mg/d but a solitary lesion progressed after 18 months of therapy. What is the most reasonable treatment recommendation for this patient?

A. Biopsy progressing lesionB. Switch patient to sunitinib 37.5 mg/dC. Increase imatinib to 800 mg/dD. Consider local therapy, such as arterial embolization,

radiofrequency ablation, or surgical resection


A healthy 58-year-old male was diagnosed with a 9 cm, small-intestine, KIT exon 9 mutant GIST with peritoneal sarcomatosis. He received imatinib 800 mg/d and had regression by size and contrast enhancement on CT for 3 years. What therapy would you recommend for this patient at this patient?

A. Discontniue imatinibB. Continue imatinib 800 mg/dC. Switch to sunitinib 37.5 mg/d


Which of the following novel targeted therapies is NOT a reasonable option for a patient with GIST who has progressed following imatinib therapy?

A. Clinical trialB. RegorafenibC. PazopanibD. Temozolomide

Thank you for joining us today!

Please remember to turn in your evaluation form.

Your participation will help shape future CME activities.

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METHOD OF PARTICIPATION