Third-Line Therapy for Metastatic GIST

Jonathan Strosberg, MD:In March 2017, 6 months after starting sunitinib, the patient had further increase in abdominal pain, evidence of progression on CT scan with new liver metastases, and decline in performance status to ECOG PS of 2. Sunitinib was stopped and she was started on regorafenib, 160 mg days 1 through 21 every 28 days. She had side effects with the regorafenib, including palmar-plantar erythrodysesthesia—in other words, pain in the palms and the soles—and also increase in fatigue.

So, regorafenib is a standard third-line treatment. The treatment sequence generally is imatinib, followed by sunitinib, and followed by regorafenib. Regorafenib was studied in the third-line setting after progression or intolerance to imatinib and sunitinib, and showed significant improvement in progression-free survival. Now, this was a pretty advanced aggressive population of patients, so the median PFS on placebo was only 1 month versus roughly 5 months with regorafenib.

Most physicians have a bit more experience with regorafenib in colorectal cancer. But with patients who often tend to have a fairly good performance status and are fairly healthy even in the third-line setting, the drug tends to be fairly well-tolerated, although there are important side effects to consider. One of the more important side effects is hand-foot syndrome. This is something that we tend to have to reduce the dose for in many cases, although there are other strategies that patients can use to manage hand-foot syndrome, including daily moisturizing, wearing comfortable socks and shoes, and trying to avoid calluses. Liver toxicity is an important side effect to be aware of, and patients need to have their LFTs monitored closely, similar with blood pressure. We often encourage patients to get a home blood pressure machine so they can self-monitor and notify us if their blood pressure becomes quite high. Tiredness is another challenging side effect. But usually, these side effects can be overcome with education and with dose reductions in some cases.

We’ve seen several patients who have progressed relatively quickly on second-line sunitinib who have actually had very prolonged durations of stable disease on regorafenib. So, despite the similarity between the drugs, there are probably some biological differences that explain why some patients do better on regorafenib.

Some of the side effects from regorafenib are very acute. Liver toxicity tends to occur early. Hypertension tends to be a very early side effect. Hand-foot syndrome often occurs within the first cycle, although it can progress with subsequent cycles. Tiredness is sometimes something that develops slowly over time.

It’s important for patients to recognize and report their side effects before they become too severe. Using hand-foot syndrome as an example, you don’t want to wait for the condition to evolve into a grade 3 and to the inability to walk, with major blisters and calluses. Patients should report their side effects before they become that severe so they can take a break, probably resume at a lower dose.

The standard starting dose of regorafenib is 160 mg on days 1 through 21 every 28 days. Because of the toxicity profile, we sometimes start at a lower dose. In fact, in some cases, we start at 120 mg, especially in patients who are older, more frail, and have a poor performance status. And in patients who are started on the standard dose, we often reduce the dose for toxicity. In patients who experience excess toxicity on the 160-mg dose, we often reduce to 120 mg. In many cases, we reduce down to 80 mg. And we have some patients who have done very well for a long period of time on even 50% of the standard dose.

Transcript edited for clarity.

August 2014

• A 59—year-old Caucasian female presented with acute onset abdominal pain
• Past medical history was remarkable for hyperlipidemia
  • Her performance status was ECOG 1
• Abdominal CT findings showed an 11-cm mass in the jejunum and a 3-cm lesion in the liver
  • Biopsy confirmed primary gastrointestinal stromal tumor (GIST) in the jejunum
  • The tumor was determined to be unresectable at the time because of its size and location
• IHC was positive for CD117 (c-KIT); molecular analysis demonstrated an exon 11 mutation
• Mitotic activity was high with >5 mitoses/50 high-power fields
• Treatment was initiated with imatinib 400 mg once daily
• No further disease progression was noted

​October 2016

• During routine follow-up, the patient complained of recurring abdominal pain
• Abdominal CT scan showed a slight increase in the primary tumor size and a new small metastatic tumor in the liver
  • Her ECOG performance status was 1
• The patient was switched to sunitinib 37.5 mg and showed stable disease on follow-up imaging at 3 months

March 2017

• At her 6-month follow-up, abdominal CT scan revealed additional metastases in the liver
• ECOG performance status had changed to 2
• The patient was subsequently referred to an academic center for treatment and was switched to regorafenib 160 mg on days 1-21 of every 28-day cycle
• Three weeks after initiating treatment with regorafenib, she complained of increased fatigue
• She presented with hand-foot skin reaction, which presented as tingling, burning sensations on her palms and a decreased tolerance for touching hot objects