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

Supplements and Featured Publications, Gaining Insight Into Treatment Personalization in GIST, Volume 1, Issue 1

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

Robin Jones MD, MBBS, MRCP

Robin Jones MD, MBBS, MRCP

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 OncLive®.

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; P = .008).1 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; P = .0016).

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.

OncLive: What are some notable clinical trials in patients with GIST?

Jones: 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 P = .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 KIT 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 KIT 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 KIT. In 2006, [there was a] study that documented the polyclonal evolution of multiple KIT 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 KIT 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.

Reference

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


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