Third-Line Therapy for GIST

Jonathan Trent, MD, PhD: At his 6-month follow-up on sunitinib therapy, the patient was evaluated in clinic. He was found to have a slight decrease in his ability to perform his activities of daily living. Additionally, a CT scan of the abdomen and pelvis was performed and revealed an increase in size of the multiple peritoneal implants, as well as a 2-cm increase in size of the liver lesions.

The patient was then referred to a GIST specialty center, where his therapy was changed from sunitinib to regorafenib—160 mg per day, 3 weeks on, 1 week off. The patient was then followed up again after an additional 6 months with a new CT scan of the abdomen and pelvis, that revealed a slight regression of the peritoneal implants and disappearance of the liver lesion.

The appropriate treatment option for a patient with metastatic GIST at the time of progression on sunitinib is regorafenib 160 mg per day, 3 weeks on and 1 week off. Regorafenib was superior to placebo in patients who participated with metastatic GIST on the GRID study.

In the GRID study, patients with metastatic GIST progressing on sunitinib were randomized to either regorafenib—160 mg a day, 3 weeks on, 1 week off—or placebo in the 2:1 fashion. The patients that were randomized to regorafenib experienced a progression-free survival of 4.8 months on median, while the patients treated with placebo only had a 0.9-month median progression-free survival. Additionally, side effect profiles that were found to be due to regorafenib, rather than placebo, included hypertension, hand-foot syndrome, and diarrhea.

Other than treatment with regorafenib, the patient could have been retreated with imatinib. However, this might not make sense because the patient may have one of the secondary mutations that would still render imatinib resistance to the tumor. Additionally, data from the CROSSOVER study of increasing imatinib from 400 mg to 800 mg really only resulted in an approximate 3-month progression-free survival, which is inferior to regorafenib.

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