method of participation
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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
Pre-activity Survey Question 3
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
Pre-activity Survey Question 4
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
Pre-activity Survey Question 5
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
Case 1: Discussion Point 2
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
NCCN Guidelines, v 1.2013.
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
NCCN Guidelines, v 3.2012.
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
NCCN Guidelines, v 1.2013.
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.
NCCN Guidelines, v 1.2013.
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
NCCN Guidelines, v 1.2013.
• 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.
NCCN Guidelines, v 1.2013.
• 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
Case 3: Discussion Point 1
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
NCCN Guidelines, v 1.2013.
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
Case 3: Discussion Point 2
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)
Casali PG, Reichardt P et al. Presented at: ESMO 2012; abstract 1478O.
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)
Casali PG, Reichardt P et al. Presented at: ESMO 2012; abstract 1478O.
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
Participant CME Post-survey Question 3
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
Participant CME Post-survey Question 4
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
Participant CME Post-survey Question 5
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!
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