GIST: Future Treatment Landscape

Margaret von Mehren, MD: When you think about GIST [gastrointestinal stromal tumor] and the landscape of GIST, I’ve been very fortunate in my career to start out as a very young faculty member with the first trial of imatinib, to now, 20-plus years later, being here with the approval of ripretinib and avapritinib. We’ve gone from having 0 drugs to now having 5 drugs that are approved for use in GIST, which is really exciting for our patients.

There are still some forms of GIST, though, for which we have less to offer. Fortunately, they are much rarer subtypes of GIST, but we still need to sort out what’s the best way to take care of these patients. One of the subtypes consists of patients who, many years ago, we called wild-type, because they didn’t have mutations in KIT or PDGFR-α. But these commonly are tumors of the stomach that have lost expression of the protein called SDHB. That can happen either through a mutation of a family of genes, the SDH family of genes, or sometimes it can happen because of loss of expression of the genes based on abnormal methylation of the promoter of one of the genes, SDHC. That group of tumors is seen more commonly in young patients, or even in what we used to call pediatric GIST. But in general, if you look at patients with that class of tumors, they tend to be much younger.

Treatment of that type of GIST remains a question. We’ve looked at imatinib, but that really doesn’t seem to provide much benefit. Sutent [sunitinib] and regorafenib have shown disease control in studies for which a few patients with this type of GIST have been identified, and we think that’s because it targets the VEGF receptor pathway. But these patients probably need additional forms of therapy, particularly those with tumors that can be quite aggressive. Fortunately, in many patients, these tumors are rather indolent and don’t change much over long periods of time. Many patients live normal lives with their disease and are not limited by it, even when off therapy.

Patients with tumors that are associated with neurofibromatosis changes are also a challenge. Some of these patients will have routine KIT and PDGFR-α mutations and will respond to the standard drugs, and that’s terrific. But many of them do not. To date, we have not found a great way of addressing these tumors. Biologically, there’s some thought that impacting the RAS pathway using MEK inhibitors, for example, might be of benefit. But to date, there is little clinical data to support that, in part just because these patients are rare. Those are the 2 big groups of patients for whom we don’t have much to offer, or we might think about alternative therapies for.

I think the other area that we still seek treatment for is patients who progress on standard therapies. For patients who are initially diagnosed and receive adjuvant therapy, we probably are curing some, but could we cure more patients if we had a different approach? Does that approach mean we should be combining therapies that target more than just the KIT pathway, but maybe alternative pathways? What’s the role for immunotherapy? Certainly, there’s been some interesting preclinical work that suggests that there are certain subtypes of GIST that have more immune infiltration, particularly the PDGFR-α mutant GISTs. There is some information in preclinical models that suggests imatinib may activate parts of the immune system. And so, maybe combining with immunotherapy might be of benefit. I think these are unanswered questions. Are there better ways to deliver effective therapies that we currently are limiting because of adverse effects? So there are still lots of unanswered questions, and this is 1 of the reasons why I still enjoy getting up every morning and thinking about this disease and how to try to manage it and find more effective therapies for patients.

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