The INVICTUS Trial in GIST

Margaret von Mehren, MD: The INVICTUS trial [NCT03353753] was the study that led to the approval of ripretinib for advanced GIST [gastrointestinal stromal tumor]. This was a placebo-controlled trial of patients who had progressed on at least 3 lines of prior therapy. The majority of patients were receiving ripretinib in the fourth line, but there were some patients who had also received additional lines of therapy.

Patients, as is typical in most studies, had to have appropriate blood counts, kidney function, liver function, and had to have measurable disease. They were treated with the medication as dosed at 150 mg daily versus placebo in the first portion of the trial, which was the blinded portion. In this portion, the physician did not know what the patient was receiving. Patients were initially assessed for their disease status every 6 weeks, and then out further.

When a patient was suspected to have progression, it was reviewed centrally, so an individual physician with bias couldn’t lead to the decision. Rather, it was done by central review. On finding progression, patients were unblinded. At the time of unblinding, if a patient was on placebo they were offered the opportunity to receive ripretinib.

They did have to meet criteria of being well enough—blood counts, performance status, etc—to be able to receive the therapy. Patients who were on ripretinib were allowed to increase their dose from 150 mg daily to twice daily, and that was based on the phase 1 trial of this study where the maximum tolerated dose was really not defined.

In general, as I said, the drug is pretty well tolerated. The decision on the dose to use really was based on biologic markers of disease control. So because of some work from phase 1, where clearly the drug was safe and, in that cohort of patients, some patients did seem to benefit from a higher dose, that was offered. For those patients who were initially on placebo who then went on to ripretinib dosed at 150 mg, they did, too, also get the opportunity to increase to twice daily, if they needed, with progression.

I think one of the most important points from this study that we observed was the large number of patients who started on placebo and were not able to get to ripretinib. This just speaks to the disease at this time frame. Patients who have had multiple prior therapies tend to have disease that is going to grow, and will probably grow quickly off any therapy. And many of these patients had larger volumes of tumor. This study demonstrated, again, the importance of continuing on some form of kinase inhibitor therapy until you have an appropriate alternative to try to control the disease.

Transcript edited for clarity.

Case: A 68-Year-Old Man With Gastrointestinal Stromal Tumor

Initial presentation

• A 68-year-old man complains of a 5-month history early satiety and vague abdominal pain
• PMH: hypertension, medically controlled; colonoscopy at age 55 unremarkable; no family history of cancer
• PE: diffuse abdominal pain on palpation; otherwise unremarkable
  
  

Clinical workup

• Labs: Hb 10.1 g/dL, plt 100 x 109/L; other lab values WNL
• Endoscopy: showeda submucosal ~ 5 cm mass with ulceration
• EUS-FNA biopsy: irregular borders on extraluminal surfaces of the stomach with evidence of heterogeneous echogenicity
• Biopsy showed gastrointestinal tumor with mitotic activity showed >5 mitoses/50 HPFs
• Abdominal/pelvic CT confirmed a 5.4 cm lesion in the body of the stomach
• MRI showed evidence of peritoneal metastases
• IHC and genetic mutational analysis: KIT exon 11 mutation
• ECOG 0
  
  

Treatment

• He was started on imatinib 400 mg PO qDay, continued for 26 months until he complained of increased abdominal pain and decreased appetite
  • ECOG 1; Imatinib was discontinued due to progressive disease
• Treatment with sunitinib 50 mg PO qDay for 4 weeks, with a 2-week drug-free interval was started
  • Treatment was well tolerated for 9 cycles when he developed an altered sense of taste, occasional vomiting and diarrhea; sunitinib was discontinued
• Regorafenib 160 mg (four 40 mg tablets) PO qDay for the first 21 days of each 28-day cycle was started and tolerated except for hand-foot syndrome
  • Regorafenib was discontinued on progression of disease
• The patient was started on ripretinib 150 mg PO qDay