Sunitinib Therapy at Progression of Metastatic GIST

Jonathan Trent, MD, PhD: This patient had a CT scan of the abdomen-pelvis performed after 2 years on imatinib therapy, and was determined to have peritoneal implants and a new liver lesion. At this point in time, the patient still had a reasonable quality of life and was able to perform his activities of daily living, other than really strenuous activity. The determination was made to initiate the patient on sunitinib, 37.5-mg continuous daily dosing.

This patient was initiated on 37.5 mg of sunitinib orally, continuous daily dosing after progression on imatinib. Although the initial studies of sunitinib and metastatic gastrointestinal stromal tumor involved the 50-mg dose of sunitinib—4 weeks on, 2 weeks off—subsequent studies support the use of 37.5 mg daily. This is better tolerated in patients and pharmacokinetically appears to be similar to the 50-mg dose. Additionally, patients do not have that 2-weeks off schedule, where the patients are drug-free and the tumors can flare.

This patient, after initiation of sunitinib, should be monitored by CT scan of the abdomen-pelvis, chest X-ray, and laboratory testing to include a CBC, a chemistry, and a magnesium. Additionally, we perform a thyroid-stimulating hormone test, generally every 3 months, to detect hypothyroidism at an early stage. Patients with GIST often have anemia. Patients with GIST take kinase inhibitors like sunitinib, and these can all cause severe fatigue. And so, we try to address the fatigue by managing the hypothyroidism that might be due to sunitinib, as well as managing the anemia with a thorough workup of etiology including iron deficiency, B12 deficiency, folate deficiency, and supplementation of any of these if they are low. If this patient continues to have fatigue, we may refer the patient to our fatigue clinic.

When a patient’s tumor becomes resistant to imatinib therapy, this may be due to a situation called secondary resistance. This situation is due to the selection of a resistant clone that has a mutation in a different site from the initialKITmutation. The initialKITmutation might beexon 9,exon 11,exon 13, but then after selection on imatinib this resistant clone emerges due to a new mutation, typically anexon 13or anexon 17of the same KIT allele. This is an important mechanism of resistance because these secondary mutations are at sites where imatinib binds. In the presence of this mutation, imatinib is not able to bind effectively to the KIT protein and inhibit it, thus the patient becomes resistant to imatinib.

Some of these mutations, for instance,exon 13secondary mutations, seem to be more sensitive to sunitinib. So, in this case using sunitinib, 37.5 mg, continuous daily dosing is a reasonable second-line therapy and would be recommended.

Transcript edited for clarity.

September 2014

• A 64-year old Caucasian male presented with abdominal pain and 3-month history of fatigue
  • PMH was remarkable for hypertension well-controlled with a beta-blocker
  • No family history of cancer
  • He could perform all activities independently
• Abdominal CT findings:
  • 12-cm mass arising from the stomach and involving the cardia, fundus, and body of the stomach
  • 7-cm solitary mass in the left lobe of the liver
• Biopsy results:
  • Gastric GIST with liver metastases
  • IHC positive for CD117 (c-KIT), molecular analysis showed exon 9 deletion
  • Mitotic activity, high with >5 mitoses/50 HPFs
• Treatment was initiated with neoadjuvant imatinib 600 mg daily for 5 months
  • The primary tumor was stable during this time, the liver mass size decreased from 7 cm to 4 cm
• The patient was referred to a surgeon and underwent hepatectomy for the liver metastasis
  • Following surgery, R0 resection with clear margins
• Treatment was initiated with imatinib 800 mg daily

August 2016

• Abdominal CT imaging findings:
  • Multiple peritoneal implants
  • A new small nodule (<1 cm) in the liver
• The patient could perform all activities independently with small occasional breaks, but could not perform physically strenuous activities
• He was switched to sunitinib 37.5 mg daily

February 2017

• At his 6-month follow-up, the patient was still able to perform most non-strenuous activities independently; however, the frequency of being able to do so had declined significantly
• Abdominal CT scan showed progression in multiple peritoneal implants; the liver nodule increased in size to 2 cm
• He was referred to an academic center
  • His treatment was switched to regorafenib 160 mg, 3 weeks on, 1 week off
• The patient appeared to tolerate therapy well, after initial dose modification due to diarrhea experienced during the second week of therapy
• At the 6-month follow-up:
  • Abdominal CT scan showed slight reduction in the peritoneal implants
  • The liver nodule was no longer visible