Utilizing Newer TKIs to Treat GIST

Margaret von Mehren, MD: Regarding my personal experience with ripretinib, I’ve been fortunate to be able to participate in the phase 1 study, in particular the dose expansion part, where the dose was known and we were trying to check and see what activity was seen. I participated in the phase 3 INVICTUS trial [NCT03353753], and currently I am also participating in the phase 3 trial that is evaluating ripretinib versus sunitinib. The results are not known because the study is not finished. However, in general, as I’ve said, while I’ve listed and talked about adverse effects that the drug can have, I think most patients tolerate the drug very well. I have some patients who are continuing on the drug for more than 2 years and have been able to tolerate it without major adverse effects that limit their ability to do what they want to do. It’s been gratifying to see patients in whom the disease has been controlled and even patients with tumors that have decreased in size. Certainly, from the INVICTUS data and the phase 1 data, the number of patients whose tumors shrank is less than 10%. That is on a par with what we see with Sutent [sunitinib] and regorafenib. I think it’s sort of in that same ballpark.

In terms of tolerability, in general, it is well tolerated, on par with or better than the things that we think about in second- and third-line therapy. The real art of medicine for patients with gastrointestinal stromal tumors [GIST] is working with them to make a dose of therapy, of a drug, work for them. Certainly, studies look at using “X” dose of a drug in a certain way, but with time and experience, I think learning how to start a drug, titrate it up to where patients can tolerate it, are important. In my experience with ripretinib, less of that needs to be done. Patients really can tolerate 150 mg, for the most part. And then, if the disease has progressed and they need to, they can tolerate 150 mg twice a day. So I think it’s been, from my perspective, a very easy drug to use, and I think patients have found it to be very tolerable. One caveat of this drug is hair thinning, which is quite different from many of the other drugs that they’re on.

The patient in the case was treated with ripretinib as fourth-line therapy. That is now available based on the FDA approval from May 2020. I think that’s a very appropriate use of this drug, and I would expect that this will likely be what many physicians will choose for their patients. Avapritinib, as we know, was also recently approved, although the indication for its approval was much more narrow—for patients with the D842V [PDGFR-α]-mutation. Interestingly enough, the drug, when it was developed in the phase 1 setting, was tested not only in patients with that specific mutation, but also in patients with KIT mutations, and there are some patients who benefit.

We know that this drug was tested and there was a recent release in the media of the study comparing it with regorafenib. The end point that was being evaluated was progression-free survival. Investigators looked to see whether avapritinib would be even better than regorafenib. Based on the news release, that was found not to be the case. We haven’t seen that data, so it’s a little bit hard to comment on what this study means and what the implications are. But in my mind, based on data from the phase 1 study, which I participated in, as well as in the phase 3 trial, I have seen some activity with that drug. So I would think that is a drug you may be able to utilize in this group of patients. The toxicities are similar to the kinases, with 1 exception: It does seem to have some toxicities of special interest. Of concern are issues with cognition, memory, which I think will have to be managed and handled carefully in patients. But I think avapritinib is a drug that may have a role for selected patients whose disease is progressing beyond the standard therapies that have been approved for KIT-mutant GIST.

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