Dr Somaiah on Mutation-Specific Therapy in Gastrointestinal Stromal Tumors

“Before you start a patient on a TKI for [the management of] GIST, you must know their mutational subtype. Even if you start them on imatinib, at least send off, if not the full panel, the primary 

Neeta Somaiah, MD, a professor and chair of the Department of Sarcoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the landscape of mutation-specific therapy for the treatment of patients with a gastrointestinal stromal tumor (GIST).

Before initiating therapy with a TKI such as imatinib (Gleevec), a patient’s mutational subtype must be known, Somaiah began. At least primary 

 mutational testing must be performed, if not a full next-generation sequencing (NGS) panel, she continued.

Mutational status testing is crucial because there are certain subsets of patients with GIST for whom imatinib will not be effective, Somaiah noted. However, a majority of patients will respond to treatment with frontline imatinib, she added.

Mutation-specific therapy is gaining a larger role in the imatinib-resistant setting, Somaiah said. Depending on the primary and secondary mutations of the disease, there may be greater benefit with one agent vs another, she continued. Most of the late-stage clinical trials in the GIST space are focused on developing agents with better outcomes compared with sunitinib (Sutent) in the second-line setting and beyond, she explained. Agents are being developed for patients harboring specific mutations as are those with broader coverage, she said.

The most common secondary mutations in patients with GIST are 

 ATP binding pocket mutations in exons 13 and 14, Somaiah said. Patients with 

 exon 13 and 14 mutations usually experience better disease control with sunitinib, she said. Patients with 

activation loop mutations in exons 17 and 18 should be considered for treatment with regorafenib (Stivarga) or ripretinib (Qinlock), she added.

Knowing a patient’s mutational status in the post-imatinib setting helps to personalize therapy, Somaiah emphasized. Giving an effective drug in this setting can open the possibility for surgery and broader disease control, she added. On the other hand, giving a less effective agent in this setting can lead to increased resistance and disease growth, she concluded.

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Neeta Somaiah, MD, discusses the landscape of mutation-specific therapy for the treatment of patients with a gastrointestinal stromal tumor.

Dr George on the Clinical Relevance of Targetable Mutations in GIST

“Understanding the primary driver [of GIST] is important because it may [affect] the upfront treatment.”

Suzanne George, MD, chief of the Division of Sarcoma and a senior physician at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, discussed the ways that mutational profiles influence treatment decision-making for patients with gastrointestinal stromal tumor (GIST).

The most prevalent subtype of GIST harbors 

 mutations, but the disease can also develop in the absence of a 

-driven GIST comprises a substantially smaller subset than 

-driven disease and are biologically distinct with management strategies that differ as a result, she said.

-mutant GIST, it is well established that secondary mutations arising after imatinib (Gleevec) therapy occur in a nonrandom distribution, George stated. These alterations are typically clustered either within the ATP binding pocket (exons 13 and 14) or within the activation loop (exons 17 and 18), she explained. Data indicate that following imatinib exposure, approximately 50% of patients with GIST develop secondary mutations in the ATP binding pocket, and the remaining patients develop mutations in the activation loop, she noted.

Sunitinib (Sutent), the standard second-line therapeutic agent for patients with GIST, is a highly potent inhibitor of ATP binding pocket mutations and has significant activity against alterations in exons 13 and 14, according to George. Consequently, later-line treatment often reveals a shift in the mutational landscape, with an enrichment of exon 17 activation loop mutations over time, she added.

The therapeutic paradigm has evolved with the development of avapritinib (Ayvakit), a selective kinase inhibitor with potent activity against 

 D842V mutations, which were previously considered undruggable, George reported. In contrast, agents such as imatinib, sunitinib, regorafenib (Stivarga), and ripretinib (Qinlock) exhibit minimal to no efficacy in the setting of 

 D842V mutations, she emphasized. As a result, the presence of this primary mutation has become a critical determinant of first-line treatment selection, she summarized.

Similarly, SDH-deficient GIST is typically excluded from pivotal studies, and management of these tumors may therefore differ from the standard treatment algorithm, she said. Additionally, rare molecular subsets, including 

-driven GIST, warrant individualized therapeutic considerations distinct from conventional approaches, she concluded.

Suzanne George, MD, discusses the evolving development of targeted therapies for patients with gastrointestinal stromal tumor.

As novel agents including NB003 and IDRX-42 look to join established drugs such as imatinib (Gleevec) and ripretinib (Qinlock) for the treatment of patients with gastrointestinal stromal tumor (GIST), the importance of biomarker-informed treatment decisions and communication between academic and community centers is paramount, according to Robin Jones MD, MBBS, MRCP. 

“It’s a very exciting time with a lot of new treatments being developed, [which] highlights the importance of communication between community and referral centers,” Jones, the head of the Sarcoma Unit and a medical oncologist at The Royal Marsden NHS Foundation Trust in London, United Kingdom, said in an interview with 

Jones noted that a significant recent development in the field came when investigators shared updated findings from the phase 3 IMADGIST trial (NCT02260505). Data from the study demonstrated that patients with localized GIST who received maintenance imatinib for 3 years following the standard 3 years of adjuvant therapy (n = 71) achieved a 3-year disease-free survival (DFS) rate of 72% compared with 42% among patients who stopped therapy with imatinib after 3 years (n = 65; HR, 0.40; 95% CI, 0.19-0.80; 

Notably, a DFS benefit was also reported in favor of the investigational arm in patients with a high risk of relapse (HR, 0.08; 95% CI, 0.01-0.61; 

In the interview, Jones discussed recent data updates from clinical trials in the space and ongoing studies, the role of disease mutations in treatment selection, and how patients with GIST can be best treated in the community setting.

What are some notable clinical trials in patients with GIST?

: In terms of the results from clinical trials of adjuvant imatinib, the French Sarcoma Group have recently published the results the multicenter, open-label, randomized phase 3 IMADGIST trial. IMADGIST evaluated maintenance imatinib for 3 additional years after the standard 3 years of [the drug]. There was a 6-year arm which was compared with an arm that stopped treatment at 3 years from the day of random assignment.

At a median follow-up of 55 months [IQR, 46-59] after random assignment, the [median] DFS was significantly superior in the 6-year arm with a HR of 0.40 [95% CI, 0.19-0.80; log-rank 

 = .008]. The follow-up from this trial is still early and we need more mature data.

Another trial that is interesting in terms of adjuvant therapy is the Scandinavian Sarcoma Group phase 3 trial [NCT02413736], which is close to [full] recruitment. This trial randomly assigned patients to receive either 3 or 5 years of adjuvant imatinib, and it recruited patients with very high-risk GIST. We’re still awaiting the results, but it’s an interesting time with 2 randomized trials which will hopefully guide treatment in the future.

In terms of metastatic disease, there are a number of ongoing trials. The [phase 3] INSIGHT trial [NCT05734105] is currently recruiting patients. This trial is randomly assigning patients with advanced or metastatic disease with disease progression on imatinib with circulating tumor DNA [ctDNA]–detected 

 exon 11 and 17/18 mutations to receive ripretinib or sunitinib [Sutent]. The primary end point is progression-free survival [PFS].

INSIGHT is based on an earlier randomized [phase 3] INTRIGUE trial [NCT03673501] in the second-line setting, which [also] randomly assigned patients to receive ripretinib or sunitinib. This trial did not meet its primary end point, but a subgroup analysis indicated the potential benefit of ripretinib in a subgroup of patients with ctDNA-detected 

 exon 11 and 17/18 mutations. This is very much a work in progress and over the next few years we’ll see refinement of treatments for patients with advanced GIST based on ctDNA and mutational profile.

[Additionally], the [phase 3] Peak trial [NCT05208047] has closed recruitment. This is another second-line trial which randomly assigned patients to receive either sunitinib alone or sunitinib plus bezuclastinib, with PFS being the primary end point.

Beyond these trials, there are a number of other exciting drugs being developed for [patients with] metastatic GIST, including NB003, and IDRX-42. IDRX-42 and NB003 will be further evaluated in randomized trials, so hopefully over the next few years we’ll see the approval of more treatments for patients with metastatic GIST.

How do mutations evolve with each subsequent line of therapy and how does this affect disease progression and prognosis?

We know that GIST becomes more complex with each subsequent line of therapy, and this makes these tumors harder to treat and therefore affects prognosis. There tends to be more heterogeneity, but it seems to be within 

. In 2006, [there was a] study that documented the polyclonal evolution of multiple 

 mutations in patients treated with imatinib. These tumors became more complex with subsequent lines of therapy.

[There was also] a study published recently that analyzed patients who experienced [disease progression] on ripretinib, and found that these tumors were enriched for secondary mutations in the ATP binding pocket frequently occurring with preexisting activation loop mutations, resulting in highly resistant genotypes. Notably, these mutations were rarely observed in a cohort [of patients] with disease progression from the pre-ripretinib era. Our understanding of the evolution of these tumors is still a work in progress, and it’s an important thing for us as investigators to focus on.

How has treatment shifted from an all-comers approach to mutation-specific therapy?

We are moving away from all-comer trials to more mutation-specific trials or directed therapy. INSIGHT is the primary example of this, in terms of the random assignment being based on the detection of ctDNA 

 exon 11 and 17/18 mutations. The results of INSIGHT are important in this respect and will probably change the way we practice if the trial is positive. It will also have an effect on the design of future trials. INSIGHT will highlight the importance of future trials in [terms of] incorporating ctDNA analysis into trial design.

How can ctDNA be used to improve patient monitoring and disease management?

The use of ctDNA is still exploratory in the management of GIST. If INSIGHT is positive, it will have a huge effect and will result in the introduction of routine ctDNA monitoring, particularly in the second-line setting. Across the world, ctDNA analysis is not routine. But, over the next few years, this will change, and INSIGHT will have a pivotal role in the routine introduction of ctDNA into clinical practice.

Since treatment has moved into community centers, what is the importance of referral networks in terms of initiating the appropriate therapy?

One of the crucial aspects of referral networks is the importance of communication between the referral and the community center. The treatment of patients with GIST will become more complex and communication will be key in terms of managing patients and giving them the best treatment. Additionally, communication is always useful in terms of the availability of specific clinical trials based on ctDNA or imaging markers, and close communication improves treatment for patients.

What can be done to strengthen patient referral networks?

One of the things that we’ve done in London is to hold educational events regarding clinical trials and research, where community [investigators] can visit our center and even join us in clinic. Sometimes we even go out to the community centers to give presentations regarding clinical trials and research. That clear communication and building the relationship with the community oncology center is key [because it] helps patients.

Blay JY, Schiffler C, Bouché O, et al. A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. 

. 2024;35(12):1157-1168. doi:10.1016/j.annonc.2024.08.2343

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Robin Jones MD, MBBS, MRCP, discusses the treatment landscape of GIST and how patients can be effectively treated in the community.

Additional Treatment Options Underscore the Need for Collaboration and Mutational Testing in GIST

Dr Jones on the Evolving Treatment Landscape in GIST

"The exciting thing here is that [investigational agents such as] NB003 and IDRX-42, will be further evaluated in randomized trials. Hopefully over the next few years, we'll see the approval of even more treatments for patients with metastatic GIST."

Robin Jones, MD, MRCP, a consultant medical oncologist, professor of medical oncology, and head of the Sarcoma Unit at The Royal Marsden NHS Foundation Trust, outlined developments in the evolving treatment landscape for patients with gastrointestinal stromal tumor (GIST), spanning both the adjuvant and metastatic settings.

In the adjuvant setting, Jones highlighted data from the French Sarcoma Group's phase 3 IMADGIST trial (NCT02260505), which randomly assigned patients with high-risk GIST to receive an additional 3 years of imatinib (Gleevec) following completion of the standard 3-year course, compared with patients who discontinued therapy at 3 years. With a median follow-up of 55 months (IQR, 46-59) post randomization, 3 additional years of maintenance imatinib significantly improved disease-free survival, with a HR of 0.40 (95% CI, 0.20-0.69; 

 = .0008) favoring the 6-year arm. However, follow-up remains relatively early, and longer-term data will be needed to fully characterize the benefit, he noted. A complementary phase 3 trial (NCT02413736), led by the Scandinavian Sarcoma Group, has completed accrual and randomly assigned patients with very high-risk GIST to 3 vs 5 years of adjuvant imatinib; results are pending and expected to further inform optimal treatment duration, Jones shared.

In the metastatic setting, Jones emphasized several ongoing and recently completed trials. The phase 3 INSIGHT trial (NCT05734105) is currently enrolling patients with advanced or metastatic GIST and 

 exon 11, 17, or 18 mutations following progression on imatinib. Patients are randomly assigned to receive either ripretinib (Qinlock) or sunitinib (Sutent), with progression-free survival (PFS) as the primary end point. This trial builds on a prior second-line study of ripretinib vs sunitinib, the phase 3 INTRIGUE trial (NCT03673501), which did not meet its primary end point overall but suggested potential benefit in patients with specific 

 mutations based on circulating tumor DNA analyses, Jones explained.

Additionally, the phase 3 PEAK trial (NCT05208047), now closed to recruitment, investigated sunitinib alone vs sunitinib plus the TKI bezuclastinib (CGT9486) in the second-line setting, with PFS as the primary end point. Beyond these, Jones pointed to several promising investigational agents, including NB003 and IDRX-42, which are being explored in early-phase studies and are anticipated to move into randomized trials. These efforts collectively reflect a robust pipeline of therapies aimed at improving outcomes for patients with metastatic GIST, he concluded.

Robin Jones, MD, MRCP, discusses the treatment armamentarium for patients with gastrointestinal stromal tumors. 

Gaining Insight Into Treatment Personalization in GIST | Supplements and Featured Publications

Dr Somaiah on Mutation-Specific Therapy in Gastrointestinal Stromal Tumors

Dr George on the Clinical Relevance of Targetable Mutations in GIST

Additional Treatment Options Underscore the Need for Collaboration and Mutational Testing in GIST

Dr Jones on the Evolving Treatment Landscape in GIST