Guidance on Treating GIST in the Second-Line and Beyond

Alexander Helfand, MD

With a well-understood molecular landscape and more research underway, oncologists who treat gastrointestinal stromal tumors (GIST) currently have good tools for aiding therapeutic selection.

Beyond the first-line treatment of GIST, there are some questions around which tyrosine kinase inhibitor (TKIs) offer the best treatment outcomes, and what to do for patients who have failed multiple lines of therapy.1 According to, Alexander Helfand, MD, molecular testing, prognostication, and watching for disease progression are key.

“The first thing is making sure that sequencing is done and that we have accurately prognosticated the patient and are doing the most individualized therapy,” Helfand, medical oncologist at Allegheny Health Network and assistant professor of Medicine at Drexel University College of Medicine told Targeted Oncology™, in an interview. “The other aspect of it is that we need to be careful in terms of deciding that the patient is progressing. We know that the Choi criteria, which reflect either a 10% decrease in size of these tumors or 15% decrease in the density on CT scan, are much better at predicting the response to treatment and survival outcomes than RECIST criteria.”

In the interview, Helfand discussed the treatment of GIST in the second-line setting, as well as later lines, including the available options, guideline recommendations, and ongoing research.

TARGETED ONCOLOGY: What are the treatment options for second-line GIST?

Helfand: The advent of the imatinib [Gleevec] in the first line has very much changed the landscape of GIST over the past 20 years. The question of what to do next remains an important one in the second-line. What we know is that it's important when the patient is coming in with assumed progression that we do a few things. Number 1, it's important that we have done molecular profiling and identified whether that patient is a cKIT exon 9 variant carrier, whether the patient may have a PDGFRA D842V mutation, or whether this may be a wild-type patient. It's important to identify that because we don't want to have a patient who could benefit from raising the dose of imatinib, who has an exon 9 mutation, or alternatively, continuing a patient longer than necessary on imatinib, when we know that imatinib is not likely to be successful if they have a canonical PDGFRA D842V mutation. The first thing is making sure that sequencing is done and that we have accurately prognosticated the patient and are doing the most individualized therapy.

The other aspect of it is that we need to be careful in terms of deciding that the patient is progressing. We know that the Choi criteria, which reflect either a 10% decrease in size of these tumors or 15% decrease in the density on CT scan, are much better at predicting the response to treatment and survival outcomes than RECIST criteria. The stable disease does not indicate a need to change treatment and it is important to interpret the imaging appropriately. In addition, the theory in terms of GIST management is that you develop resistant clones over time and so, some of these clones may arise in a single area or in an oligometastatic pattern or oligo progressive pattern in which case, if you have excellent widespread control with the use of imatinib, targeted radiation, or even resection of a newly growing lesion, [which] may be effective and provide durable response, at least for some period of time. It will also allow you to continue in that niche because we know that unfortunately, people tend to get progressively shorter responses with the use of subsequent lines of therapy.

In terms of second-line therapy, sunitinib [Sutent] is the standard of care for a second-line nowadays. There are 2 populations of patients. One is population with primary resistance to imatinib, and they tend to progress within about 2 to 3 months of treatment. We also have patients who develop acquired resistance over time, and we know that in terms of sunitinib, patients tend to have decent clinical benefit of about 58%. This includes stable disease, and partial and complete responses, although very few people have complete responses. But we also know that patients who have KIT exon 11 mutations do not tend to do as well on sunitinib. In terms of the choice of sunitinib vs regorafenib, the data are more robust for the use of sunitinib. In the second-line, there has been a trial called the INTRIGUE trial [NCT03673501] which compared the use of sunitinib [with] ripretinib [Qinlock] in the second-line after progression on imatinib, and this included a population of patients who have cKIT exon 11 mutations. There was much better tolerance of the ripretinib in terms of grade 2 or greater toxicity, and essentially, there was no difference in progression-free survival [PFS]. As a rule, ripretinib is not favored in the second-line, and we would favor sunitinib. That said, I think that we should always make sure that imaging and molecular profiling have been interpreted appropriately before moving on to second-line therapy.

You explained that INTRIGUE supports the use of sunitinib for second-line GIST. What data support the use of ripretinib?

Ripretinib is another tyrosine kinase inhibitor that targets KIT as well as PDGFRA. It targets a number of the acquired resistance mutations and thus it is thought to undergird its efficacy in the fourth-line. It was compared [with] placebo in a trial of 129 patients and found that with the primary outcome of PFS of 6.3 vs 1 month of benefit. That said, there was no difference in overall response rate. For the most part, we were talking about maintaining stable disease. The trial was not powered to detect the difference in overall survival, but the median overall survival was 15 vs 6 months, which is certainly promising.

Of note, while there was the difference in response and PFS in the trials using sunitinib and regorafenib [Stivarga], even in earlier lines of therapy, ripretinib, did show this survival benefit albeit as a secondary outcome that was not statistically significant. However, we should not assume that ripretinib should replace it in the second-line. The result of the INTRIGUE trial was that ripretinib was not superior to sunitinib in that setting.

The other issue with ripretinib is that while efficacy rates are certainly promising, especially in a later-line setting, there is notable toxicity in terms of skin toxicity, cardiac toxicity, as well as the need to avoid cytochrome p45 3A inducers, which can reduce the efficacy of ripretinib. I think this is a good option in the fourth-line, but again, with some caution in terms of toxicity and need for careful managing of drug-drug interactions.

Can you discuss other third- and fourth-line options for the treatment of GIST?

In the third-line, we rely on evidence from the GRID trial [NCT01271712] to guide us. That study used regorafenib, another tyrosine kinase inhibitor, and essentially examined it vs placebo and identified a 4.80- vs 0.09-month progression-free survival benefit in the phase 3 trial with 199 patients. This is the best evidence that we have in the third-line. That is what I would typically recommend in the third-line. Then in the fourth-line, I would recommend ripretinib for patients who are eligible.

The NCCN also recommends alternative therapies for later-line GIST. Can you discuss those other therapies and in which cases they would be appropriate?

The first thing that comes to mind is the use of avapritinib [Ayvakit], which should be used when we identify a PDGFRA D842V mutation. In addition, in patients who do not have the canonical PDGFRA mutation, if they have progressed on imatinib and sunitinib, then it's certainly reasonable to put them on avapritinib. The truth is that we don't necessarily know whether these patients would be better served by ripretinib them versus avapritinib, but it is likely that ripretinib would be more efficacious, at least in the fourth-line, based on the survival data that we do have and what we know about the efficacy of avapritinib in the wild-type population. In terms of other options, there are a number of other TKIs. For example, nilotinib [Tasigna] is being studied in GIST. It is approved for the use of chronic myeloid leukemia. This may be another option in the fourth- or fifth-line for patients if they're not able to tolerate ripretinib. We know that compared [with] imatinib, it was not superior in the first-line. But again, we do know that there are reports of responses to nilotinib in later-line settings. Another thing we do know about nilotinib is that it's not effective in exon 9 mutations. In a patient with an exon 9 mutation, I would, and in general, favor the use of ripretinib in the fourth-line. But in the fifth-line, there is not a lot of data to guide whether to use a nilotinib, ripretinib, or something like sorafenib.

There’s a thought that it may result in faster toxicities because of a its shorter half-life. It may be possible to do dose adjustments more quickly in this patient population. But again, this is more theoretical than what has been confirmed in randomized trials. There aren't too many patients in whom I would use sorafenib, nor is there any data to support its use instead of regorafenib, nor is it likely to work in patients who have progressed on regorafenib. But if there were a patient who had a need for fifth-line therapy, or even a need for sixth-line therapy after progression on fifth-line avapritinib, I think it would be reasonable to try it.

There is data on pazopanib [Votrient], as well. With pazopanib, there's some speculation that it may be better in wild-type GIST. There was a phase 2 trial, the PAZOGIST trial [NCT01323400], which basically looked at this population and identified a small but significant progression-free survival benefit of a difference of about 1 month improvement in a later-line GIST population. Most of these were patients with stable disease, minimal partial response. I would say the data to support its use in earlier than the fifth-line in patients who still have good performance status, and are still eager to continue treatments in later lines of therapy. I think that with careful shared decision-making, use of some of these agents, which are not FDA-approved for GIST, could be considered in the right setting.

What ongoing GIST research do you find interesting?

The use of immunotherapy in GIST will be an exciting opportunity to make progress. At this point, I think that enrollment in these early phase trials is important, and that patients will be well served by doing so. Also, through identifying novel ways to try to both target the known mutations in this disease and making use of the incredible progress that we've made in treating this disease, not only in the first-line, but also in the second- third-, fourth-, and even fifth-line, which is unique to GIST since we really don't have such late line options. In terms of progress, finding ways to generate new tumor antigens and target them using immunotherapy will be the wave of the future. Time will tell whether this is effective.

_REFERENCE:

_{Kelly CM, Sainz LG, and Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021;5;14(1):2. doi:10.1186/s13045-020-01026-6.}