Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C.

From Here to Eternity: Optimal Duration of Post-Operative Therapy for Patients with Resected Gastrointestinal Stromal Tumors Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C. Chief, Medical Oncology, University of British Columbia Vice-President, British Columbia Cancer Agency

SSGXVIII: 12 versus 36 Months of Adjuvant Imatinib in GIST • Background on treatment of GISTs • Metastatic disease • Adjuvant • SSGXVIII methodology and validity of conclusions • Questions raised by SSGXVIII • Adjuvant treatment of other tumours • Conclusions and issues outstanding

April 5, 2001

B2222: Imatinib Treatment of Patients with Advanced GISTs is Highly Effective von Mehren et al., Proc Am Soc Clin Oncol 2011

B2222: Imatinib Treatment of Patients with Advanced GISTs is Highly Effective Are these long-term survivors cured? No!

BFR14 – Study Design R A N D O M I S A T I O N PD Imatinib 400 mg STOP Advanced/ metastatic GIST CR PR SD Imatinib 400 mg Surgery possible if resectable Imatinib 400 mg Follow-up 1 / 3 / 5 years Courtesy Dr. Axel Le Cesne

BFR14: Progression-Free Survival (After Responding) 1, 3 and 5 Years After Stopping Imatinib 1.0 1 year 0.9 0.8 3 years 0.7 5 years 0.6 Survival probability 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Months after randomisation to stopping Blay et al, J Clin Oncol 2007; Le Cesne et al, Lancet Oncol 2010; Ray-Coquard et al, PASCO 2010

1.0 0.9 0.8 0.7 0.6 Survival probability 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 Months from 5-year point BFR14: PFS for Continuous Group

1.0 0.9 0.8 0.7 0.6 Survival probability 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 Months from 5-year point BFR14: PFS for Continuous Group 5 years not enough to control patients with advanced GIST in complete remission… Would findings be the same in adjuvant use? Adapted Le Cesne

Disease-Specific Survival After Surgery Alone for GIST Fraction Surviving DeMatteo et al., Ann Surg 2000

Phase III Z9001 ACOSOG Adjuvant Trial Primary GIST > 3 cm Complete Gross Resection Tumor KIT + Placebo x 1 yr Imatinib x 1 yr Double-blind cross-over if recur Recurrence/Survival (6/2002 – 4/2007) Courtesy Corless and DeMatteo

ACOSOG Z9001: Recurrence-Free Survival Imatinib Placebo Adapted DeMatteo et al., Lancet 373:1097, 2009

Recurrence-Free Survival Curve on Z9001 Suggests Lack of Cure

Z9001: Overall Survival No overall survival benefit was observed with adjuvant therapy

SSGXVIII: 12 versus 36 Months of Adjuvant Imatinib in GIST • Background on treatment of GISTs • Adjuvant • Metastatic disease • SSGXVIII methodology and validity of conclusions • Questions raised by SSGXVIII • Adjuvant treatment of other tumours • Conclusions and issues outstanding

SSGXVIII Study Snapshot • Key eligibility factors: • Resected KIT+ GIST • High risk for recurrence by 2002 Modified Consensus Criteria • Recurrence-free survival hazard ratio aimed for: 0.44 • Hazard ratios found: RFS = 0.46; OS = 0.45 • Authors concluded 3 years of imatinib improve RFS and OS

SSGXVIII: Methodology and Validity of Conclusions Goals were reasonable Methodologies for primary and secondary objectives were sound Conclusion regarding recurrence-free survival is valid Conclusion regarding overall survival is valid, with some limitations

SSGXVIII Question 1: Can we administer imatinib for a prolonged period in the adjuvant setting?

SSGXVIII: Completion of Therapy Category 12 Months 36 Months n = 181 n = 177 On treatment at data cut-off (%) 0 11 Early discontinuation (%) 16 36 - GIST recurred on treatment 2 7 - Adverse event 8 15 - Other reason 6 14 Adapted Joensuu

Issues Related to Administering Imatinib for a Prolonged Period in the Adjuvant Setting • Grade 3/4 toxicities similar in frequency on both arms • Twice as many dropped out on 3-year arm related to an adverse event; same for “other” reasons • Were low-grade side effects challenging to tolerate long-term? • Is it too difficult to take a pill for years with no disease evident?

Difficulties on the 3-year arm of SSGXVIII may bode poorly for therapy lasting even longer

SSGXVIII Question 2: Who should receive adjuvant therapy after resection of GIST?

Who Should Receive Post-Operative Imatinib? • SSGXVIII eligibility included being at “high risk” for recurrence • “High risk” patients have recurrence probablilities ranging from ~34% to nearly 100% • Can assign an actual number to individual patients using clinical factors and Gold nomogram1 1Gold et al., Lancet Oncol 2009

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

Risk-Reduction with 3 Years of Adjuvant Imatinib (cont.) • Within categories, higher and lower risk patients enjoy the same benefits from longer therapy • We can thus apply SSGXVIII’s results to patients at roughly a 1 in 3 or greater chance or recurrence

Risk-Reduction with 3 Years of Adjuvant Imatinib (cont.) • Within categories, higher and lower risk patients enjoy the same benefits from longer therapy • We can thus apply SSGXVIII’s results to patients at roughly a 1 in 3 or greater chance or recurrence • But should we?

Who Should Receive Adjuvant Therapy after Resection of GIST? • In current practice, adjuvant imatinib often administered to patients with >25% chance of recurrence • Therapy routinely continued for >1 year, especially in highest-risk patients • Is 25% to ~35% reasonable, given the possibility we may need to treat very long term? • Possible strategy: Give imatinib for 3 years to lower risk patients and >3 years for higher risk • Not recommended

SSGXVIII Question 3: What is the ideal duration for adjuvant GIST treatment with imatinib?

SSGXVIII: Recurrence-Free Survival 100 88.1% % 36 months 80 67.4% 12 months 60 62.1% 50.3% 40 Hazard ratio 0.46 (95% CI, 0.31-0.68) P <0.0001 20 0 0 1 2 3 4 5 6 7 Years since randomization

SSGXVIII: Recurrence-Free Survival 100 % 36 months 80 12 months 60 40 20 0 0 1 2 3 4 5 6 7 Years since randomization

Recurrence-Free Survival Assuming Patients on Both Arms Stop Therapy at the Same Time 100 % 36 months 80 12 months 60 40 20 0 0 1 2 3 4 5 6 7 Years

Is a 3-year treatment duration (versus one year) delaying recurrence 2 years longer without increasing cure rates?

SSGXVIII: Overall Survival 96.3% 92.0% 100 94.0% % 80 81.7% 60 36 months Hazard ratio 0.45 (95% CI, 0.22-0.89) P = .019 12 months 40 20 0 0 1 2 3 4 5 6 7 Years since randomization

SSXVIII: What Does the Overall Survival Difference Mean? • Improved long-term overall survival usually equates with increased cure rate • Do not know if overall survival difference will hold up • Period by period hazard rate assessment necessary to prove better overall survival from increased cure rate • Cure = finite drug administration; Prolonged remission = lifelong treatment

What is the Ideal Duration for Imatinib in the Adjuvant Setting? • 3 years, as per the experimental arm on SSGXVIII? • 5 to 10 years, still aiming for cure? • Indefinite, abandoning goal of cure? • Combination: Finite for some, lifelong for others?

Heinrich et al., J Clin Oncol. 2006 GIST Practice: Can We Use the Lab to Guide Us? GIST H and E Adapted Corless Day 0 Day 7 Duensing et al., Oncogene 2004

Adjuvant Treatment of Other Solid Tumours 1breast cancer 2prostate cancer 3colon cancer

X Adjuvant Treatment of Other Solid Tumours 1breast cancer 2prostate cancer 3colon cancer

Identifying the Ideal Adjuvant Duration for Imatinib in GIST and for Other Biologics • As of June 5th, 2011, we do not know how long to administer adjuvant imatinib in GIST • We still need to test multiple possible durations • Economic and patient availability limit feasibility of doing so • Little enthusiasm for 5 year v. 10 year v. lifelong study

Post-Resection Evaluation of Recurrence-Free Survival for Gastro-Intestinal Stromal Tumors Treated with Adjuvant Imatinib: PERSIST-5 Resected GIST >2 cm and mitotic rate >5 or Non-gastric primary >5 cm Imatinib 400 mg/d x 5 years Register Phase II N = 85 patients Primary objective: Recurrence-free survival Adapted DeMatteo

My Conclusions from SSGXVIII • In GIST, 3 years of adjuvant imatinib are better than one in terms of recurrence-free and overall survival • 3 years of post-operative imatinib treatment represent the new gold standard for patients with resected “high-risk” GISTs • The overall survival advantage demonstrated means we cannot try to “catch-up” later, in advanced disease setting

Issues Remaining from SSGXVIII • Should we treat post-operative patients longer than 3 years? • Should we treat lifelong? • Whom should we treat with adjuvant imatinib? • I will use a “50% chance of recurrence” threshold

Issues Remaining (cont.) • How do we best study adjuvant therapy for GISTs? • Probably will not truly be able to figure out how long to treat or • Will not matter, if GISTs are incurable in any setting • Thus, need to identify biomarkers to tell us whomto treat

Charles D. Blanke, M.D., F.A.C.P., F.R.C.P.C.