Resistance to TKI Therapies in GIST

Margaret von Mehren, MD: Regarding the secondary mutations, there is lots of discussion about how and why these occur. Clearly, when we look at the tumor cells, we find they all exist within 1 individual cell, although they may differ between different cells. Many have suggested that this is something that was always present—that they were always there—and just with the selection pressure of effective therapy they now become more present and more prominent in a tumor mass because they’re not being controlled by therapy.

In terms of thinking about why I would change therapy, most of the tyrosine kinase inhibitors that we use have a very similar mechanism of action. They’re really trying to inhibit the ATP activation of the kinase. Imatinib, Sutent [sunitinib], and regorafenib do that, as does avapritinib.

One drug that is different and unique in terms of mechanism of action is ripretinib. It essentially works by binding the KIT and PDGFR-α molecule and blocking it in a state where it cannot become activated. These kinases tend to switch from an active to an inactive conformation of the protein, and they do that in part by a loop that flips into the activation site. Ripretinib essentially binds the molecule in 2 spots, preventing that loop from being able to get into the activation site. So that is a different mechanism of action and may be helpful when we’re thinking about resistance, because, at this point, we believe that ripretinib is somewhat agnostic—it doesn’t care what the mutation is. I think with time we’re going to learn more and more about how the drug works clinically, and we will better understand whether that’s a completely true statement or not. Certainly, it is likely that, like other drugs, the tumor cells are going to figure out a resistance mechanism, which we will be learning about as we continue to use that drug.

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