Avapritinib Is a Game Changer for PDGFRA Exon 18-Mutated GIST

Michael C. Heinrich, MD

The recent approval of avapritinib (Ayvakit) for advanced PDGFRA exon 18—mutated gastrointestinal stromal tumor (GIST) offers patients a new treatment option for a disease subtype that has not responded to standard therapy. On January 9, 2020, the FDA approved avapritinib for adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including the PDGFRA D842V alteration, the most common exon 18 mutation. Avapritinib is the first therapy cleared for use in this specific patient population.¹

The approval for the genomically defined subset of GIST was based on efficacy results from the phase I NAVIGATOR trial (NCT02508532), in which the overall response rates (ORRs) were 84% and 89% among 43 patients with a PDGFRA exon 18 mutation and 38 patients with a PDGFRA D842V alteration, respectively.¹

Avapritinib remains under review for fourth-line treatment of GIST, and investigators are eagerly awaiting the FDA’s decision, which is due by May 14, 2020.²

“There is no approved or recognized fourth-line therapy” in GIST, said Michael C. Heinrich, MD, a leading investigator of the drug. In an interview with OncLive, Heinrich discussed avapritinib’s approval and its potential in later lines of GIST.

The agent has shown impressive duration of response for patients with PDGFRA exon 18 mutations. Discontinuations were few, and the toxicity profile is mild, although memory and concentration problems may arise, and providers need to watch for these, said Heinrich, a hematologist/oncologist and a professor of medicine in the Cell and Developmental Biology Graduate Program at Oregon Health & Science University Knight Cancer Institute in Portland.

OncLive: Please provide an overview of the patient population.

Heinrich: The [NAVIGATOR] study comprised 2 main efficacy populations. The findings that led to the agent’s approval were in patients with GIST who also harbor a PDGFRA exon 18 mutation. PDGFRA is one of the 2 targets of the drug. The other is KIT. Both KIT and PDGFRA are receptor tyrosine kinases.

We considered patients with PDGFRA exon 18—mutated GIST a separate population because most of those mutations would be resistant to any drug developed to date, so this was a population with unmet medical need. Whether these patients had been treated with 1 drug or treated with many drugs, none of the drugs would have been expected to work. We knew from preclinical data that avapritinib would be very active against this mutation, and in the dose-escalation part of the study, we saw a durable partial response using the lowest dose of avapritinib ever tested in a patient. We saw responses at all the different drug dose levels that were tested. Once we arrived at the dose that was recommended for phase II testing, we recruited more patients and that group formed the data set that led the FDA to approve avapritinib for these patients.

The other major population was the fourth-line and later group. These patients have tumors that are drug resistant, but it’s not because their primary mutation is resistant. Rather, it’s because tumor cell clones have arisen with secondary mutations that defeat drug activity. For example, imatinib works until a clone arises that prevents imatinib from inhibiting KIT. Right now, for KIT-mutant GIST, which is the most common form of GIST, the current paradigm is first-line imatinib, second-line sunitinib [Sutent], and thirdline regorafenib [Stivarga], but no approved or recognized fourth-line therapy exists.

We often try other kinase inhibitors, but the situation in the later lines is complicated because there are maybe 20 different resistance mutations, and each of them has a different spectrum of drugs that might work, will often work, and would never work against those mutations. The fourth-line population is just more complicated because we’re trying to treat a lot of different clones with different secondary mutations at the same time, so the duration of benefit in that population is less, as would be expected. We still thought that avapritinib’s activity was impressive in the fourth-line setting, and the data for those patients were submitted to the FDA for approval at the same time as the PDGFRA exon 18 data set. The FDA decided to split the approval and look at PDGFRA exon 18 as 1 indication and the fourth line as a different indication. They are considering the fourth-line data to determine whether to approve avapritinib in the fourth-line and later setting.

An ongoing phase III study [VOYAGER, NCT03465722] is also looking at avapritinib in the third line versus the standard third-line therapy, regorafenib.³ Because the data originally submitted to the FDA was from a phase I study with no comparison arm, I think the FDA would like a bigger data set just to see what it looks like, even though it is an earlier line of therapy.

Can you discuss the efficacy data that led to the approval?

For the population with PDGFRA exon 18 mutations, the response rate was very high, around 85%. We don’t know the median duration of activity, but even at 2 years, more than half of the patients are deriving benefit from the drug, so we’ll have to wait longer to determine the progression-free survival. This observation completely transforms the potential health outcomes for patients with PDGFRA exon 18 mutations because previously we wouldn’t have thought we could get any responses or only a couple of months of benefit at most.

For the fourth-line population, we still would like this drug to be approved, so even though it may take a few more months, we still are hopeful that avapritinib will be approved in this later line of treatment.

The investigational KIT inhibitor ripretinib has also been tested in the fourth line and its developer has also filed for FDA approval. Ripretinib’s FDA review has moved almost simultaneously with avapritinib’s, so it’s possible that we may have 2 new drugs approved for patients in the fourth line or later by the summer or midsummer, which would be exciting.

Can you describe the mechanism of action?

KIT and PDGFRA are types of enzymes known as tyrosine kinases. To execute their tyrosine kinase activity, they need a little battery pack called adenosine triphosphate [ATP] to provide the energy for that reaction. Historically, all the drugs—imatinib, sunitinib, regorafenib, and avapritinib—have worked as a sort of decoy and bound where the ATP battery pack is supposed to bind. This deprives the kinase of its energy supply, so it can’t do anything. This is the classic mechanism of action.

What do we know about the agent’s tolerability?

Avapritinib is a well-tolerated drug. Not very many patients, fewer than 10% discontinued the drug because of adverse events, which is a low discontinuation rate. Many of the adverse effects seen with avapritinib—anemia, fluid accumulation, or patients’ hair turning white—would be expected of a strong KIT inhibitor. These events are related to the dose, so if they occur, we can lower the dose and they will attenuate. Most patients have mild gastrointestinal adverse effects that we could easily manage the way that we manage them with other drugs, using, for example, an antiemetic for nausea or an antimotility agent if is diarrhea.

What’s somewhat novel about avapritinib is its potential to cause central nervous system or cognitive adverse effects. These are in the spectrum of short-term memory problems or concentration problems. Patients also have mild word-finding difficulties. Some of these events are quite subtle and I think oncologists need to be aware that they can happen with avapritinib.

We can manage these adverse effects by decreasing the dose or by interrupting the dose, so even a short-term break from therapy in the range of 7 to 14 days can cause patients to reset quite significantly, and most will revert to an acceptable baseline. It will be important for oncologists to consider these strategies when treating patients with avapritinib.

We think intervening early, when symptoms are mild, is better than waiting until patients become much more confused or have many more cognitive problems. Even though these events are reversible, it’s much harder on patients if these effects are not addressed until they’re severe. As oncologists, we’re used to asking people about their bowel movements. Do they have nausea? Are they eating? But we’re not used to asking them about their memory or concentration, so this will be an important educational point to get across to physicians now that this drug is approved and commercially available.

How does the agent fit into the current treatment paradigm?

For the current approval, if a patient has a PDGFRA exon 18 mutation, you would use it in any line of therapy that you recognize the mutation. Results of recent studies have shown that in the United States, only 25% of GIST tumors have mutational profiling, which means that 75% of the patients who potentially could benefit from this drug are not being detected. This is one of the things that we will have to improve, and this is clearly a message that needs to get to physicians.

In these more unusual diseases, often it’s the patients who drive the testing conversation. Patient advocacy groups and patient online educational resources will emphasize the importance of testing, and patients are going to have to go to their physicians and ask, “Well, what about this new drug? Do I have that mutation? Should I be on that drug?” And if the physician says, “I didn’t do the testing,” I think the next point will be completing the testing to help determine what drug the patient should be treated with, but it will take a while for [physicians to adopt this practice]. I think that one of the challenges of using the drug is making sure that we identify all the patients who that could benefit from avapritinib.

What are the next steps for avapritinib?

We have to see what the FDA will say about the data set for fourth-line GIST. As investigators, we feel that it is strong enough considering that no standard treatment exists, so it should be approved, but given that there is another agent being considered in the fourth line, that might complicate the FDA decision making process. However, we are hopeful that avapritinib will be approved in the fourth line based on existing data.

A third-line study is also evaluating avapritinib versus regorafenib, and it’s anticipated that we will know the results of that study sometime this spring. If it is a positive study, there would be an application for the approval of avapritinib as a third-line treatment. If it is not positive but at least shows activity comparable to that seen in the fourth-line patients, that would support the fourth-line approval.

In the past, there has been talk about potentially going into the second line to see whether avapritinib would beat out the standard treatment, but I think that given all the complexity of what’s going on with the fourth-line approval and the third-line study, I think the company is waiting to see how the results come out before making a final decision on that.

Would you like to highlight anything else about the drug?

Philosophically, if we went back 10 or 15 years when we were developing cancer drugs of this type, the theory was to make them inhibit as many cancer targets as possible, because that would potentially make the drug more broadly efficacious. The idea was that we could treat every cancer with 1 drug, but that didn’t pan out in terms of efficacy. These multikinase inhibitors have a lot of adverse effects, and often these side effects result from targets that don’t even apply to the disease that you’re trying to treat.

Avapritinib is an example of trying to be more super-selective with treatment. We knew that we wanted to target only KIT and PDGFRA, and we knew that this decision would restrict avapritinib’s use to just a handful of diseases, but the team that developed avapritinib was looking to design a really potent and specific inhibitor of those targets, and we’re going to try to move the field forward.

All the other approved drugs for the treatment of GIST were developed to treat a different disease—leukemia, kidney cancer, colon cancer, etc—and we took a capability of avapritinib, the ability to inhibit KIT, and made it the role of avapritinib in GIST. The existing drugs really weren’t optimized for inhibiting KIT, and there was really no thought of resistance mechanisms and how to handle them. Avapritinib was designed with knowledge of known resistance mutations to these approved agents and the intent was to inhibit as many of them as possible so we could achieve better outcomes. I think that’s very promising not only for GIST but also for a lot of other diseases. Even when the target is restricted to a certain subset of cancers, we can treat patients more effectively than we have historically if we’re just more deliberate about what we’re doing.

References

1. FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors [news release]. Silver Spring, MD: FDA; January 9, 2020. www.fda.gov/news-events/ press-announcements/fda-approves-first-targeted-therapy-treat-rare-mutation-patients-gastrointestinal- stromal-tumors. Accessed February 24, 2020.
2. Blueprint Medicines announces FDA intent to split avapritinib new drug application into separate submissions for PDGFRA exon 18 mutant GIST and fourth-line GIST [news release]. Cambridge, MA: Blueprint Medicines Corp; October 28, 2019. ir.blueprintmedicines.com/news-releases/news-release-details/ blueprint-medicines-announces-fda-intent-split-avapritinib-new. Accessed February 24, 2020.
3. Blueprint Medicines initiates VOYAGER phase 3 clinical trial of avapritinib in patients with advanced gastrointestinal stromal tumors [news release]. Cambridge, MA: Blueprint Medicines Corp; June 21, 2018. ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-initiates-voyager- phase-3-clinical-trial-0. Accessed February 24, 2020.