Selection between sunitinib and ripretinib using mutation analysis for gastrointestinal stromal tumor patients progressing on imatinib

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with an annual incidence of 10 to 15 cases per million (1). The malignancy potential of GISTs varies widely from virtually indolent tumors to aggressive cancers that frequently give rise to metastases that are typically located in the liver or at other intra-abdominal sites. Most (75–80%) GISTs are driven by an activating mutation in the KIT oncogene (encodes the KIT receptor tyrosine kinase) or less commonly in PDGFRA (encodes platelet-derived growth factor receptor-alpha; 10–15%). In KIT, the mutation is usually located either in exon 11 (about 90%) or exon 9 (about 10%). In the remaining about 10% of GISTs no mutation is found in either KIT or PDGFRA, but molecular aberrations may be found in other genes such as the genes encoding the succinate dehydrogenase (SDH) subunits, NF1, BRAF, or the tumor harbors a fusion gene (2,3).

An oral tyrosine kinase inhibitor (TKI) imatinib has been the standard first-line treatment for patients with advanced GIST for over 20 years (4). Imatinib has remained almost unchallenged as the preferred first-line treatment, since it inhibits effectively most mutated KIT and PDGFRA kinases often leading to a durable response, and imatinib is generally well tolerated. The only exceptions are infrequent patients with PDGFRA exon 18 D842V mutation who do not respond to imatinib but usually respond to another TKI, avapritinib (5), and the rare patients with NTRK fusion gene, SDH-deficient GIST, and patients with BRAF V600E mutation who may benefit more from other systemic agents than imatinib (6).

In the first randomized trials that evaluated efficacy of first-line imatinib in patients with advanced GIST the median time to progression was approximately 2 years (7,8), but in about 10% of the patients GIST did not progress during the first ten years after starting imatinib (8). The main reason for imatinib failure is second mutations in KIT exons 13, 14, 17, or 18 that lead to reduced binding of imatinib to the kinase adenosine triphosphate (ATP) binding pocket (9). KIT exons 13 and 14 encode the ATP binding pocket of the KIT kinase where also imatinib binds to, and exons 17 and 18 encode the kinase activation loop that regulates the KIT activity. Mutations in KIT exons 13, 14, 17, and 18 are rare in untreated GISTs (2) but occur in the majority of GISTs that progress on imatinib (9,10).

The approved second-line systemic treatment after imatinib failure is sunitinib, another ATP-mimetic TKI. The recommendation to administer sunitinib as the second-line agent is based on a randomized trial, where 312 GIST patients resistant to or intolerant of previous treatment with imatinib were allocated to receive either sunitinib (50 mg/day; 4 weeks on, 2 weeks off) or placebo orally. In this trial, the median time to GIST progression was about 6 months among patients allocated to sunitinib and 1.5 months among those who received placebo [hazard ratio (HR) 0.33, 95% confidence interval (CI): 0.23–0.47], and the patients who received sunitinib also lived longer (11).

Recently, the selection of sunitinib as the second-line agent after imatinib failure was challenged in the randomized INTRIGUE trial (NCT03673501) with 453 participants, where sunitinib administered at the approved dose (50 mg 4 weeks on, 2 weeks off) was compared head-to-head with ripretinib (150 mg/day orally) (12). While both imatinib and sunitinib bind to the ATP-binding pocket of the target kinase, ripretinib is a switch-control TKI that binds to the kinase switch pocket that is located close to the ATP-binding pocket forcing the activation loop into an inactive conformation (13). In the INTRIGUE trial patients allocated to ripretinib had similar progression-free survival (PFS; the primary endpoint) as those who received sunitinib in the trial intention-to-treat population (8.0 vs. 8.3 months, respectively; HR 1.05; 95% CI: 0.82–1.33; nominal P=0.72).

In the INTRIGUE trial ripretinib was associated with less grade 3 or 4 adverse events (12), and a quality-of-life analysis generally favored ripretinib over sunitinib (14). The approved sunitinib dosing is only moderately well tolerated and, therefore, other sunitinib dosing schemes, such as 37.5 mg once daily administered continuously, were evaluated in non-randomized series and were found to ameliorate sunitinib toxicity in the treatment of advanced GIST (15,16). Yet, the continuous dosing of sunitinib at the daily dose of 37.5 mg was neither more effective nor better tolerated compared with the standard 4 weeks on/2 weeks off dosing in a randomized study in a patient population with advanced renal cell cancer (17).

At present, ripretinib is not approved for second-line treatment of GIST, but the National Comprehensive Cancer Network (NCCN) of the U.S. now recommends considering ripretinib for those patients who do not tolerate second-line sunitinib (6). Ripretinib has been approved for treatment of adult patients with advanced GIST who have received prior treatment with three or more kinase inhibitors, including imatinib. The fourth-line approval was largely based on demonstrated ripretinib safety and efficacy in the placebo-controlled INVICTUS trial (18).

While the efficacy of ripretinib and sunitinib was similar in the overall population of the INTRIGUE trial, this may not to be so for all subgroups of patients. When Heinrich and his co-workers carried out an exploratory mutation analysis study from circulating tumor DNA (ctDNA) samples collected during the INTRUGUE trial, it turned out that patients allocated to ripretinib had longer median PFS than those allocated to sunitinib when GIST harbored a KIT exon 11 mutation and a second mutation in KIT exon 17 or 18 (14.2 vs. 1.5 months, respectively; HR, 0.22; 95% CI: 0.11–0.44; nominal P<0.0001) (19). On the other hand, when the second mutation was found in the KIT exon 13 or 14, treatment with sunitinib was associated with longer PFS (15.0 vs. 4.0 months; HR, 3.94; 95% CI: 1.71–9.11; nominal P=0.0005). The interaction between the mutational subgroup and treatment was highly significant (P<0.0001). Patients with KIT exon 9 mutation benefitted more from sunitinib (Table 1). In the subset of patients with KIT exon 11 plus exon 17/18 population, patients treated with ripretinib had also longer overall survival (HR, 0.34; 95% CI: 0.15–0.76; nominal P=0.0061).

Some prior evidence supports the observation that the second KIT mutation site predicts for drug efficacy. In a study based on a phase I/II trial of sunitinib in patients with advanced imatinib-resistant or intolerant GIST, PFS and overall survival were longer on sunitinib for patients with secondary KIT exon 13 or 14 mutation compared to patients with exon 17 or 18 mutation (20), and some laboratory data also supports sunitinib efficacy for secondary KIT exon 13 or 14 mutations (21). On the other hand, the observed efficacy of ripretinib for GISTs with KIT exon 17 or 18 mutation is compatible with a preclinical study where ripretinib was found to inhibit all known KIT/PDGFRA activation loop mutations (13).

The association between the second KIT mutation site and the relative efficacy of sunitinib and ripretinib was strong in the INTRUGUE trial, but confirmation of this observation is desirable as exploratory subgroup analyses need to be interpreted with caution. Confirmation is now being attempted in the ongoing INSIGHT trial (NCT05734105). INSIGHT is a small randomized open-label multicenter phase 3 trial with a target to recruit 54 patients with advanced GIST who have progressed on prior imatinib and who have KIT exon 11 mutation plus a mutation in KIT exon 17 or 18. Patients with KIT exon 11 mutation plus a mutation in KIT exon 13 or 14 are excluded from INSIGHT, as are patients with KIT exon 9 mutation. In INSIGHT, the study participants are randomly assigned to receive either ripretinib or sunitinib. The planned sample size of only 54 patients is expected to yield sufficient power to detect a significant difference in PFS judging from the INTRIGUE data. To facilitate patient recruitment, cross-over from sunitinib to ripretinib is allowed upon GIST progression.

Plasma ctDNA has some potential advantages as the starting material compared with tumor tissue when a mutation analysis is planned to be performed from a patient with advanced GIST. GIST metastases cannot always be safely accessed for a needle biopsy. Metastatic GISTs frequently harbor more than one resistance mutation (10), and ctDNA may better reflect the overall tumor mutational status compared with the limited tissue volume obtained with a needle biopsy. ctDNA is also better suited for repeat sampling and monitoring of the mutational status. In the INTRIGUE study, where plasma ctDNA was analyzed with a Guardant360 next generation sequencing assay, ctDNA was detected in 280 (77.3%) out of the 362 plasma samples analyzed and KIT or PDGFRA mutation was found in 221 (61.0%) indicating that GIST mutation analysis is often successful from the plasma of patients with advanced GIST.

Mutation analysis from GIST tissue is highly recommended for patients planned to undergo systemic treatment, since this information is needed for the selection of the agent to be administered and the imatinib dose (22). The strong association detected between KIT mutational status and drug efficacy in the INTRIGUE trial suggests that mutation analysis from ctDNA may also be needed for the selection of the most efficacious second-line agent after imatinib failure. Yet, it remains challenging to estimate how often mutation analysis from plasma ctDNA would be carried out in the real-world setting should the observations now done be confirmed in the ongoing INSIGHT trial potentially leading to regulatory approval of ripretinib in the second-line setting. In one study only 27% of U.S. GIST patients had tumor mutation analysis carried out despite the benefits (23). In the INTRIGUE trial 18.6% of the patients with plasma ctDNA detected had KIT exon 11 plus exon 17/18 mutation (Table 1).

In sum, the exploratory mutation analyses carried out from plasma ctDNA samples collected during the INTRIGUE trial suggest strongly that patients with advanced GIST whose tumor has progressed during first-line imatinib benefit from second-line ripretinib when the mutation analysis reveals a KIT exon 11 mutation plus a second mutation in KIT exon 17 or 18. On the other hand, the patients whose second mutation is located in KIT exon 13 or 14 or who have KIT exon 9 mutation may benefit more from sunitinib. The hypothesis that patients with a KIT exon 11 plus exon 17 or 18 mutation benefit more from ripretinib than sunitinib is now under robust evaluation and validation in the randomized INSIGHT trial with an estimated primary completion date in February 2026 (24). Meanwhile, sunitinib remains the standard second-line treatment after imatinib failure for most patients. Mutation analysis of GIST needs to be carried out to achieve optimal patient care, and the findings from the INTRIGUE trial lend further support to this strategy.

Acknowledgments

Funding: The study was supported financially in part by Sigrid Juselius Foundation and Louise and Henrik Kuningas Foundation.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-32/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-32/coif). The author is the Chair of the Scientific Advisory Board at Orion Pharma, Neutron Therapeutics, and Maud Kuistila Foundation; holds stock of Orion Pharma and Sartar Therapeutics and intellectual property in Sartar Therapeutics; and has received an institutional research grant from Defence Therapeutics and Mersana Therapeutics and consulting fees from Orion Pharma and Maud Kuistila Foundation. The author has no other conflicts of interest to declare.

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