Approach to Patients With Metastatic Gastrointestinal Stromal Tumors Who Are Progressing on Standard Therapy
In the current paradigm, non–wild-type metastatic gastrointestinal stromal tumors (GIST) are generally treated in a sequential fashion with imatinib in the first line, sunitinib in the second line, regorafenib in the third line, and ripretinib in the fourth line. In the future, advances in molecular profiling may allow for a more tailored approach.
How do you approach advanced GIST that are currently progressing on tyrosine kinase inhibitor (TKI) therapy, and will molecularly selected therapy have a greater role in the future?
Professor of Medicine
“One new strategy that is being explored in late-line therapy is the use of circulating tumor DNA to determine whether a patient may have a resistance mutation in a specific region that might help predict the most appropriate agent to use next.”
Until recently, there were only 3 drugs that were approved by the US Food and Drug Administration for patients with unresectable or metastatic GIST: imatinib, sunitinib, and regorafenib. More recently, ripretinib was shown to have a 6.3-month median progression-free survival (PFS) in the fourth-line setting or beyond. In addition, avapritinib had a median PFS of 4.2 months and was shown to be highly active against GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. So, for patients with these mutations, avapritinib is first-line therapy, and there is no known second-line treatment. Dose escalation for progressive GIST may have a role in some settings, and there are some recent data that support ripretinib.
After these standard available agents are found to be noneffective, perhaps the most important option to emphasize to patients is the importance of participating in a clinical trial. If that is not possible, there are other strategies that can be considered, including the use of agents that might target specific mutations. There are several TKIs that have shown some activity in tumors with select identified genomic alterations. In addition to targeted therapy, localized therapy (eg, surgery, hepatic arterial embolization, radiation therapy, and microwave or radiofrequency ablation) may be an option in certain patients with isolated progression.
One new strategy that is being explored in late-line therapy is the use of circulating tumor DNA to determine whether a patient may have a resistance mutation in a specific region that might help predict the most appropriate agent to use next. For example, for patients with KIT exon 13–resistant mutations, a rechallenge with sunitinib could be considered since it is the most active agent against these mutations. In contrast, for patients with KIT exon 17–resistant mutations, which are resistant to sunitinib, it may be reasonable to consider ponatinib, as it is active against KIT exon 17–resistant mutations.
Clinical Research Director, Sarcoma Center
“We are always eager to evaluate novel compounds and approaches. And there are a number of new broad-spectrum kinase inhibitors that are currently in trials aiming to continue building upon the standard approaches that we already have.”
For patients who have progressed on first-line therapy with imatinib, sunitinib remains the standard of care for second-line therapy. This was reinforced in the INTRIGUE trial, which found that, although ripretinib was better tolerated, overall, the PFS was similar between the 2 agents.
Regarding molecular profiling, I think that we are still learning. After imatinib treatment, tumors can become quite complex and heterogenous, with mutations that can cluster in both the activation loop and the ATP-binding pocket region of the KIT gene, and this is a significant challenge. Preclinical data suggest that some of the TKIs may be preferentially beneficial for treating GIST with resistance mutations at particular sites, but there is still more to learn.
After patents have been treated with all of the available lines of therapy, this is an area of unmet need, highlighting the importance of clinical trials. We are interested in the identification of new targets, the use of KIT-directed therapy in combination with novel agents, and the use of other investigational protocols. DS-6157a, for example, is an antibody against a novel GIST protein called GPR20 that is conjugated with a potent topoisomerase I inhibitor payload. It has been shown to have activity in patients with advanced GIST, including response in those with succinate dehydrogenase–deficient GIST with both SDHB and NF1 mutations. Such investigational efforts highlight the fact that there may be novel ways to approach the treatment of GIST using targets other than KIT and PDGFRA.
Agents with different mechanisms of action have the potential to improve upon the response rates that we see with KIT inhibitors, which typically produce disease stability. The challenge with regard to incorporating newer therapies will be to develop appropriate tools to define the molecular profiles of progressive tumors and then to match a therapy to that profile to optimize outcomes. We are always eager to evaluate novel compounds and approaches. And there are a number of new broad-spectrum kinase inhibitors that are currently in trials aiming to continue building upon the standard approaches that we already have. So, clinical trials are always an important tool.
Associate Professor of Medicine With Tenure
“I think that the future is bright for GIST, and there is a lot of enthusiasm in the community regarding the use of novel therapeutic approaches that have the ability to target a wide range of both primary and secondary mutations.”
For patients who progress on frontline standard-dose imatinib, I will routinely consider imatinib dose escalation to 400 mg twice daily before moving to sunitinib in the second-line setting. The INTRIGUE trial showed no statistically significant improvement in PFS for ripretinib over sunitinib in the second-line setting, despite improved tolerability for ripretinib, as Dr George mentioned. As a result, I continue to follow the US Food and Drug Administration–approved sequence of TKI-based therapy for KIT and PDGFRA (non-D842V) mutant–positive GIST (ie, imatinib, sunitinib, regorafenib, and then ripretinib).
We continue to learn about the heterogeneity of GIST and about the range of secondary resistance mutations that can develop in response to TKI exposure. There are emerging data to suggest that a specific TKI may provide a preferential response over another in the context of specific secondary mutations. As a result, we may be able to tailor our therapies in subsequent lines based on the molecular profile of the tumor. In my opinion, these questions are best answered in the setting of a clinical trial, and I would not be surprised if we are tailoring therapies based on molecular subtypes in the coming years.
Given the GIST treatment landscape over the past 20 years, I am very excited about agents with new mechanisms of action. I find the idea of novel approaches, such as the anti-GPR20 antibody-drug conjugate, particularly appealing. I think that the future is bright for GIST, and there is a lot of enthusiasm in the community regarding the use of novel therapeutic approaches that have the ability to target a wide range of both primary and secondary mutations.
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George S, Heinrich MC, Somaiah N, et al. A phase 1, multicenter, open-label, first-in-human study of DS-6157a in patients (pts) with advanced gastrointestinal stromal tumor (GIST) [abstract 11512]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.
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