Lining Up New Options for GIST

On a summer Sunday in 2011, Lee Keenan competed in the Pleasant Prairie Triathlon in Wisconsin. At 42 years old and having completed numerous triathlons, he was in fighting shape. This time around, he decided not to focus on speed and instead just to have a good time. And that he did.

Back at home that afternoon, just over the state line in Illinois, he had energy left to man the grill at a cookout.

“It was a great day. I enjoyed the race and had a lot of fun,” says Keenan, now 54.

But Monday morning, he woke up with such intense abdominal pain that he thought he had torn something in the race. Over the next couple of hours, the pain only got worse. He got in to see his doctor that day. After an ultrasound, the doctor sent Keenan to the hospital for a CT scan. That was when they found a mass.

Doctors took a biopsy, told Keenan it was benign and scheduled a surgery to take it out. As he lay in the hospital recovering from the removal of the mass, an oncologist came into the room and introduced himself.

“At this point in my life, I didn’t even know what an oncologist was. My wife and I looked up the word ‘oncologist’ on our phones. When he came back into the room, I asked him, ‘Do I have cancer?’”

He did. Keenan had a gastrointestinal stromal tumor, or GIST, but the doctor explained that his prognosis was great. This cancer typically did not metastasize. Keenan would take medication, go in for annual scans to ensure the cancer hadn’t returned and live a long life, the doctor told him.

The next three years on Gleevec (imatinib), the treatment doctors typically prescribe first for GIST, were uneventful, Keenan says. He had no side effects from the drug and his routine scans were clear – until a scan revealed a new tumor.

After another surgery to remove the tumor, he remained on Gleevec for a few more years, until he had to have another tumor removed. Keenan’s doctor, Dr. Mark Agulnik, section chief of sarcoma medical oncology at City of Hope in Duarte, California, then put him on Sutent (sunitinib), which he remained on until a new growth required another procedure. From there, he qualified for a clinical trial that compared Ayvakit (avapritinib) to Stivarga (regorafenib). He started on Stivarga then moved on to Ayvakit. After progressing on Ayvakit, Keenan started taking Qinlock (ripretinib).

“A lot of the medicines I’ve taken weren’t even available when I first got GIST. The last three didn’t even exist at that time,” Keenan says.

The many options that have been available to Keenan reflect the dramatic advances that have taken place in GIST treatment over the last decade. This progress has been possible, in large part, because the role that driver mutations play in GIST is among the most well understood of solid tumors and one of the first that was amenable to a dramatic anti-cancer treatment effect from drugs designed to specifically target the mutations.

Over the last 10 years, five options have been added to the treatment arsenal, including new drugs and additional indications for existing drugs. This decade of progress culminated with two new drug approvals in 2020. Qinlock earned approval from the Food and Drug Administration (FDA) for inoperable or metastatic GIST after progression on the three existing GIST drugs Gleevec, Sutent and Stivarga. Ayvakit also got the nod from the FDA, which made it the first therapy for patients with the multidrug-resistant PDGFRA D842 mutation.

“Each additional option we have for treatment of these cancers adds time that we are able to control the growth and spread of these tumors, which buys people more time,” says Dr. Andrew Brohl, a medical oncologist who treats patients with GIST at Moffitt Cancer Center in Tampa, Florida.

Tyrosine Kinases — the Key to GIST Treatment

Targeting tyrosine kinase has long been the approach to treating GIST. First-line therapies Gleevec, Sutent and Stivarga are kinase inhibitors.

Tyrosine kinases are chemical messengers that control how cells grow and divide. Doctors often liken them to an on-off switch for the process of cell growth and division. When they are on, the cell divides and produces another cell.

“Normally, in GIST, the kinase is mutated. That is, it’s always turned on,” says Dr. Margaret von Mehren, chief of sarcoma medical oncology at Fox Chase Cancer Center in Philadelphia and an investigator on the INVICTUS trial, which led to FDA approval of Qinlock.

A metabolite called ATP (adenosine triphosphate) flips the switch on by attaching — or “binding” — to the kinase. The three kinase inhibitors for GIST bind to the kinase where ATP is supposed to latch on. In effect, the drug molecules take ATP’s spot and prevent it from flipping the switch on.

Doctors typically start patients on Gleevec, switch them to Sutent if needed and then Stivarga.

When Tumors Find a Workaround

These first- through third-line kinase inhibitors work for a time, but eventually cancer cells come up with a way to outsmart them.

“Once people progress on Gleevec, Sutent or Stivarga, we find they have developed additional, secondary mutations that alter the structure of the kinase and prevent these other drugs from binding,” von Mehren says.

These secondary mutations – that is, new mutations that develop in the tumor as it becomes resistant to a drug – are typically in the KIT or PDGFRA genes located on what’s called the activation loop of the kinase. Simply put, the activation loop allows the kinase to put itself in the on position.

Qinlock and Ayvakit have a different structure that allow the drug to target the altered kinases encoded by gene mutations that make the tumors resistant to first-line drugs. By acting on the activation loop, these drugs prevent the cancer-promoting kinases from getting into the position that would allow the kinase to switch to on.

Qinlock Targets Two Common Resistance Mutations

Qinlock targets both KIT and PDGFRA mutations. Based on the results of the INVICTUS trial, the drug earned FDA approval for people who had progressed on three or more prior kinase inhibitors.

In the trial, the drug extended progression-free survival (the time during and after treatment when a patient lives with the disease without worsening) by a median 6.3 months compared with one month on placebo. The overall response rate (the percentage of patients with a partial or complete response to treatment) was 9% and overall survival (the time from treatment until death of any cause) was just over 15 months compared with about six months in the placebo group.

“Ripretinib is a very good drug for many types of GIST tumors as it affects a broad spectrum of mutations,” von Mehren says.

Qinlock seems able to block some mutations that other drugs do not: KIT mutations in two distinct locations on the gene – exons 17 and 18.

After progressing on numerous other drugs, Keenan has been taking Qinlock for almost 16 months. “I feel very lucky,” Keenan says. “It’s been effective at reducing the size of the growths. It’s been very good.”

He’s scheduled for another scan in June to ensure that the drug continues to do its job. In the meantime, the former triathlete continues to live an active life. “Like a lot of people in my group of friends, I put the running shoes away around age 47 and biking is now my main way to exercise.”

Ayvakit Beats a Tough Mutation

While Keenan has always had another drug to move on to, for one particular group of patients, no drug seemed to work.

“A primary PDGFRA mutation known as D842V was resistant to all the drugs from the get-go,” says Dr. Michael Heinrich, a professor of medicine at Oregon Health & Science University Knight Cancer Institute in Portland. “We tried different things but none of them ever worked, so we had to go back to the test tube.”

In the development of Ayvakit, intended to be a KIT inhibitor, researchers learned that it seemed to block this less common mutation as well. Expanding the search for trial participants to sites around the world, the NAVIGATOR trial, which included Heinrich as an investigator, began to enroll patients with the D842V mutation.

In the clinical trial, most patients with a PDGFRA mutation on exon 18 responded to the drug. The highest response rate was among people with a D842V mutation.

Shortly after 53-year-old Brian Gilhooly received a diagnosis of GIST in October 2021, he learned he had this once-drug-resistant mutation. His doctor at Loyola Medicine in Maywood, Illinois, told him he wouldn’t respond to first-line Gleevec and that he would be taking Ayvakit instead.

But Gilhooly didn’t like the sound of this new drug.

“They say it can affect your brain — your memory and cognition,” Gilhooly says.

Gilhooly traveled to Portland to get a second opinion from Heinrich, who agreed that Ayvakit was the best option.

“The key to managing these neurocognitive side effects is early recognition of them, modifying the dose, and doing dose interruptions,” Heinrich says.

It was decided. Gilhooly would take the drug until it shrank his tumor enough for surgery. In the end, he never had to worry about cognitive problems. After eight months on the drug, he was ready for surgery.

But Gilhooly did still get his fair share of side effects. The whites of his eyes turned yellow because of elevated bilirubin, a yellow substance the body produces during the breakdown of old red blood cells. His red blood cell count plummeted, too.

“The drug was harsh, but it killed off the tumor,” he said. “When they removed it, they said it was 90% necrotic, only 10% viable.”

The surgeon managed to remove the entire tumor and Gilhooly was up and walking the same day. Now, more than 18 months later, his first two post-surgery scans showed no evidence of disease. He’ll continue to get scans every four months. His next one is scheduled for July.

The Way Forward

As the treatment arsenal for GIST expands, researchers are learning the nuances of each. Not only do the current drugs target specific gene mutations, but each seems to be more effective against mutations at different locations in the tumor’s DNA.

Sutent, for example, works especially well in patients whose tumors develop resistance mutations in KIT on exons 13 and 14. Qinlock, on the other hand, does its best work in people who have primary mutations at exon 11 and secondary ones at 17 and 18.

This knowledge may drive changes in how doctors make treatment recommendations.

“We are moving toward being able to choose which option we use for a patient based on the genetics of their tumor as some drugs are more or less effective depending on the genetic characteristics of the tumor,” Brohl says.

The deeper understanding of these molecular differences is driving further research, too.

Deciphera, the maker of Qinlock, is planning a trial for patients who have developed resistance to Gleevec. They will be treated with Qinlock or Sutent based on their tumor’s DNA.

“This is the first biomarker-driven study we’ve ever done in GIST,” Heinrich says. “I expect patients would be very interested in this.” At the same time, he adds, “Another approach is to try to be more holistic by inhibiting mutations in either 13/14 or 17/18. Currently our drugs can inhibit one class but not the other – for example, 13/14 but not 17/18 or the other way around.”

Cogent Biosciences is sponsoring the phase 3 PEAK trial for patients who are resistant to Gleevec. It will compare second-line Sutent, which blocks mutations on exons 13 and 14, with and without a new drug called bezuclastinib, which is expected to inhibit mutations at 17

and 18. The trial’s crossover design will eventually allow all patients access to the combination therapy if it gets positive results.

As most patients with GIST eventually become resistant to their treatment, the newest drugs available and in the pipeline will have a significant impact. They offer patients yet another option after resistance develops. But the persistent problem of resistance shines a light on the need for additional treatment approaches.

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“There’s still resistance to these drugs because they are all tyrosine kinase inhibitors that partially overlap in their mechanism of action and primarily affect the same pathways within the cell,” Brohl says. “Alternate ways to enhance treatments or avoid those shared resistance pathways are still very much needed.”