Reference No: Author(s) NICaN Drugs and Therapeutics Committee. Approval date: 12/05/16. January Operational Date: Review:

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1 Reference No: Title: Author(s) Systemic Anti-Cancer Therapy (SACT) Guidelines for Gastro- Intestinal Stromal Tumours Dr Martin Eatock, Consultant Medical Oncologist & on behalf of the GI Oncologists Group, Cancer Centre Belfast City Hospital Ownership: Approval by: Operational Date: NICaN NICaN Drugs and Therapeutics Committee June 2016 Version No. 2.0 Supercedes 1.0 Links to other policies Version control for drafts: Approval date: Next Review: 12/05/16 NICaN Gastro-intestinal tumours(gist) SACT protocols January 2018 Date Version Author Comments December 2013 January Dr M Eatock Initial Draft 2.0 Dr M Eatock 4.0 Patients should be tested for HBV infection before initiating treatment with imatinib. 4.3 Third and subsequent line therapy updated to reflect SMC guidance on regorafenib SACT for GIST version2.0 Page 1 of 9

2 SACT for GIST version2.0 Page 2 of 9

3 1.0 INTRODUCTION / PURPOSE OF POLICY 1.1 Background Systemic anti-cancer therapy (SACT) is an important modality in the management of patients with a diagnosis of Gastro-intestinal Stromal Tumours (GIST). This guideline describes the agreed management for patients GIST. 1.2 Purpose To ensure consistent use of SACT for patients with GIST. 2.0 SCOPE OF THE POLICY This document is aimed at all clinical staff involved in the management of patients receiving SACT for GIST. 3.0 ROLES/RESPONSIBILITIES It is the responsibility of all clinical staff involved in the management of patients receiving SACT for GIST to familiarise themselves with these guidelines. 4.0 KEY POLICY PRINCIPLES Adjuvant Therapy following resection of GIST Background GIST are uncommon tumours with an annual incidence of round 16/ population per annum. The primary treatment for patients with a suspected GIST which is localised is surgery. Following surgical resection, however, the risk of disease recurrence is determined by the site of the tumour within the GI tract, the size of the primary tumour and the mitotic index of the disease as assessed by a pathologist with an interest in this disease. The combination of these features are assessed using an algorithm described by Miettinen and Lassota (1) and those patients who have a high risk of disease recurrence should be offered adjuvant therapy with imatinib for 3 years. The evidence for this comes from two multicentre randomised clinical trials. The first of these conducted by the American College of Surgeons Z9000 trial where patients were randomised to receive postoperative imatinib for one year following surgery or to observation. This trial demonstrated no improvement in overall survival for those treated with imatinib but did demonstrate an improvement in disease free survival, particularly marked for those patients defined as having a high risk of recurrence (2). The second trial conducted by the Scandinavian Sarcoma Group randomised patients with a high risk of disease recurrence to either on year or three years of treatment with imatinib. This trial demonstrated a significant improvement in both 5 year disease free survival (from 48% to 66%) and 5 year overall survival (from 82% to 92%) (3). SACT for GIST version2.0 Page 3 of 9

4 Patient selection Consider Adjuvant Therapy for Post-operative patients with: Tumours defined as having a risk of recurrence of >35% using the Modified Miettinen and Lassota Criteria ECOG Patient performance status of 0-2 Patient has adequate hepatic and bone marrow function Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with imatinib. Imatinib 400mg daily for 36 months Follow up Monitoring of LFT weekly for first 4 weeks of imatinib therapy. Clinical review after first 4 week period of imatinib treatment and 12 weekly thereafter during imatinib therapy CT scan 6 monthly for 3 years (during imatinib therapy). Following completion of imatinib therapy clinical review should be every 6 months with no further repeat CT scanning unless clinically indicated for investigation of new symptoms or signs Neo-adjuvant treatment of GIST Patients may be offered neo-adjuvant treatment with imatinib in the following circumstances: 1) Locally advanced disease in the absence of distant metastases which is not thought to be resectable, but which may become resectable with a response to treatment with imatinib or 2) Localised disease which is resectable, but where resection would involve major resection but which may involve a less morbid surgical procedure if there is a response to treatment with imatinib (for example where resection of duodenal GIST would involve a whipples procedure and a reduction in the size of the disease would enable a local duodenal resection) (4,5). Surgery would normally be performed at the time of maximal response to imatinib. Patient Selection ECOG Performance status ECOG 0-2 Good, hepatic and bone marrow function Disease which has been assessed at MDT as meeting the above criteria SACT for GIST version2.0 Page 4 of 9

5 Staging If patients are being considered for radical therapy they require: CT Scan of Chest and Abdomen Imatinib 400mg daily to be continued until disease is assessed by MDT to be resectable. Follow Up Monitoring of LFT weekly for first 4 weeks of imatinib therapy CT scanning every 12 weeks on treatment Clinical review after the first 4 weeks of imatinib treatment and every 12 weeks thereafter. Following surgical resection patients deemed to be at high risk of recurrence using the modified Miettinen and Lassota criteria should be offered adjuvant treatment with imatinib for 3 years and followed up as previously described in section Advanced (Metastatic) Disease Background Palliative treatment of GIST with imatinib is associated with radiological evidence of response (using the Choi criteria (6) ) in approximately 90% of patients. The median duration of response is approximately 2 years, however a proportion of patients will have long term control of their disease beyond 5 years. The chance of response to imatinib is dependent on the mutation status for either c-kit or PDGFR in the tumour and this should be routinely examined in all patients with a diagnosis of GIST (7-11). Duration of Treatment Patients receiving treatment with imatinib for advanced unresectable or metastatic GIST should continue on imatinib therapy until there is radiological evidence of disease progression. NICE Guidance NICE TA86 approves imatinib for the treatment of advanced GIST. SACT for GIST version2.0 Page 5 of 9

6 4.2.1 First Line Therapy Patient selection Patients with locally advanced unresectable or metastatic disease should be considered for systemic therapy providing they demonstrate: ECOG Performance status of 0-3 Adequate liver and bone marrow function Staging CT of Chest Abdomen and Pelvis Imatinib 400mg/day orally Initial cycle for 28 days Further cycles of 84 days duration Continue until progression or intolerable toxicity Management CT Scan of chest and abdomen and pelvis at baseline & 12 weekly thereafter Second Line Therapy Patients who have either progressed after initial response to imatinib or who have failed to respond to imatinib may be offered second line therapy with sunitinib (12) NICE Guidance NICE TA179 recommends sunitinib as a treatment option for people with unresectable and/or metastatic GIST if: Imatinib treatment has failed because of resistance or intolerance The cost of sunitinib for the first treatment cycle will be met by the maufacturer Patient selection Adequate performance status (ECOG PS 0-2) Sunitinib 50mg orally once daily on days 1 to 28 followed by 14 days without treatment. Treatment can continue until disease progression or until intolerable toxicity. Management CT of chest and abdomen and pelvis at baseline and 12 weekly thereafter until disease progression. SACT for GIST version2.0 Page 6 of 9

7 4.3. Third and Subsequent Line Therapy The only licensed third line therapy for advanced GIST is with Regorafenib. This has not been assessed by NICE, however is approved for use within the NHS in Scotland for this indication by the Scottish Medicines Consortium. Its use in Northern Ireland for individual patients is dependant on application for funding using Cost per Case criteria being successful. Regorafenib has been shown to result in a significant improvement in progression free survival compared to placebo (4.8 months Vs 0.9 months, HR 0.27, p<0.0001) 13. SMC Guidance (13/4/2015) Regorafenib (Stivarga ) is accepted for use within NHS Scotland. Indication under review: Treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib. Patient selection Adequate performance status (ECOG PS 0-2) Regorafenib 160mg orally once daily on days 1-21 followed by 7 days without treatment. Treatment can continue until disease progression or until intolerable toxicity. Management CT of chest and abdomen and pelvis at baseline and 12 weekly thereafter until disease progression. 5.0 IMPLEMENTATION OF POLICY 5.1 Dissemination This policy will be agreed by all consultant oncologists treating patients with SACT for tupper GI malignancies. The guideline will form the basis for development of the SACT regimen specific protocols. It will be available on the intranet for use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and delivery in patients with GIST. 6.0 MONITORING Use of these guidelines will be monitored using audit. SACT for GIST version2.0 Page 7 of 9

8 7.0 EVIDENCE BASE / REFERENCES 1) Miettinen M, Lasota J. Gastrointestinal stromal tumours: review on morphology, molecular pathology, prognosis and differential diagnosis. Arch Pathol Lab Med 2006; 130: ) Dematteo RP, Ballman KV, Antonescu CR et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, douible blind, placebo controlled trial. Lancet 2009; 373: ) Joensuu H, Erikson M, Sundby Hall K et al. One Vs three years of adjuvant imatinib for operable gastrointestinal stromal tumour: a randomized trial. JAMA 2012; 307: ) Eisenberg BL, Harris J, Blanke CD et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumour (GIST): early results of RTOG 0132/ACRIN J Surg Oncol; 99: ) Fiore M, Palassini E, Fumagali E et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumours (GIST). Eur J Surg Oncol 2009; 35: ) Choi h, Macapinlac H, Burgess M et al. Correlation of computed tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate: Proposal of a new computed tomography response criteria. J Clin Oncol 2007; 25: ) Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: ) Blanke CD, Demetri GD, von Mehren M et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26: ) Blanke CD, Rankin C, Demetri GD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; 26: ) Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumors with high-dose imatininb: randomized trial. Lancet 2004; 364: ) Zalcberg JR, Verveij J, Casali PG et al. Outcome of patients with advanced gastro-intestinal stromal tumors crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005; 41: ) Demetri GD, van Oosterom AT, Garrett CR et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib: a randomised controlled trial. Lancet 2006; 368: ) Demetri GD, Reichart P, Kang YY, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013; 381: SACT for GIST version2.0 Page 8 of 9

9 8.0 CONSULTATION PROCESS GI oncologists group EQUALITY STATEMENT In line with duties under the equality legislation (Section 75 of the Northern Ireland Act 1998), Targeting Social Need Initiative, Disability discrimination and the Human Rights Act 1998, an initial screening exercise to ascertain if this policy should be subject to a full impact assessment has been carried out. The outcome of the Equality screening for this policy is: Major impact Minor impact No impact. SACT for GIST version2.0 Page 9 of 9