A new Phase III clinical trial called INSIGHT is evaluating the efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) previously treated with imatinib. The study specifically targets patients whose tumors harbor KIT exon 11 mutations along with co-occurring mutations exclusively in KIT exons 17 and/or 18, as identified by circulating tumor DNA (ctDNA) analysis.
The INSIGHT trial is an international, randomized, multicenter, open-label study sponsored by Deciphera Pharmaceuticals. The study design and protocol were published online in Future Oncology on September 4, 2024. This trial builds on exploratory analyses from the earlier Phase III INTRIGUE study, which suggested differential efficacy of ripretinib versus sunitinib based on specific KIT mutation profiles.
The primary purpose of INSIGHT is to prospectively evaluate progression-free survival (PFS) with ripretinib compared to sunitinib in this molecularly-defined subgroup of advanced GIST patients. Key secondary endpoints include objective response rate (ORR) and overall survival (OS).
Approximately 54 patients will be enrolled and randomized in a 2:1 ratio to receive either ripretinib 150 mg once daily continuously or sunitinib 50 mg once daily on a 4 weeks on/2 weeks off schedule. The study is being conducted at sites across the United States, Canada, Europe, Taiwan, Brazil, Chile, Korea and Australia.
To be eligible for inclusion, patients must have a histologic diagnosis of advanced GIST with radiologic progression on prior imatinib treatment. Central laboratory ctDNA analysis must confirm the presence of a KIT exon 11 mutation along with co-occurring mutations restricted to KIT exons 17 and/or 18, without additional mutations in KIT exons 9, 13 or 14. Patients must have at least one measurable lesion by modified RECIST v1.1 criteria and an ECOG performance status of 0-2.
Key exclusion criteria include any history of KIT exon 9 mutations, known active CNS metastases, major surgery within 4 weeks of starting study treatment, and use of strong CYP3A inhibitors or inducers. Patients with certain cardiovascular conditions or gastrointestinal abnormalities affecting oral drug absorption are also excluded.
The sample size of 54 patients was chosen to provide sufficient statistical power to detect differences between the treatment arms for the primary and key secondary endpoints. Demographic data on enrolled patients has not yet been reported, as the trial is still ongoing and recruiting participants as of July 2024.
Patients will receive study treatment until disease progression (as assessed by blinded independent radiologic review), unacceptable toxicity, or withdrawal of consent. Upon progression, patients in the sunitinib arm will be allowed to cross over to receive ripretinib. The primary analysis will be conducted after the pre-specified number of PFS events have occurred.
The rationale for INSIGHT stems from exploratory ctDNA analyses of the earlier INTRIGUE trial, which evaluated ripretinib versus sunitinib as second-line therapy in a broader advanced GIST population. Those analyses, published in Nature Medicine in 2024, found that patients with KIT exon 11 + 17/18 mutations had significantly improved outcomes with ripretinib compared to sunitinib.
Specifically, in the KIT exon 11 + 17/18 subgroup from INTRIGUE, median PFS was 14.2 months with ripretinib versus 1.5 months with sunitinib (nominal p<0.0001). ORR was 44.4% versus 0% (p=0.0001) and median OS was not reached versus 17.5 months (p=0.0061) for ripretinib and sunitinib, respectively.
In contrast, patients with KIT exon 11 + 13/14 mutations appeared to derive greater benefit from sunitinib. This aligns with preclinical data showing differential activity of these TKIs against various secondary KIT resistance mutations. Ripretinib demonstrated more potent activity against activation loop (exon 17/18) mutations, while sunitinib was more active against ATP-binding pocket (exon 13/14) mutations.
The INSIGHT trial aims to prospectively validate these findings in a more homogeneous, biomarker-selected patient population. By restricting enrollment to patients with KIT exon 11 + 17/18 mutations, the study can more definitively assess the efficacy of ripretinib in this molecular subgroup.
A key aspect of INSIGHT is the use of ctDNA analysis for patient selection and biomarker assessment. This non-invasive "liquid biopsy" approach offers potential advantages over traditional tumor tissue biopsies, particularly in capturing the genomic heterogeneity that can develop in advanced GIST. However, the investigators acknowledge potential limitations of ctDNA, such as variable tumor shedding rates that may impact detection sensitivity.
Safety monitoring will be an important component of the trial. In INTRIGUE, ripretinib demonstrated a more favorable overall safety profile compared to sunitinib. The INSIGHT protocol includes regular adverse event assessments, physical exams, laboratory tests and ECG monitoring. An independent data monitoring committee will periodically review safety data.
Some limitations of the INSIGHT study design should be noted. The open-label nature of the trial could potentially introduce bias in patient-reported outcomes or adverse event reporting. The relatively small sample size, while appropriate for this molecularly-defined subgroup, may limit the ability to detect more subtle differences between treatments or perform extensive subgroup analyses.
Additionally, as a pharma-sponsored registration trial, there may be concerns about potential bias in study design or data interpretation. However, the use of blinded independent radiologic review for the primary endpoint helps mitigate some of these concerns.
The trial investigators conclude that INSIGHT represents an important step towards more personalized treatment approaches in GIST. By prospectively evaluating treatment efficacy based on specific molecular profiles, the study may help optimize sequencing of targeted therapies and improve outcomes for patients with advanced disease.
If positive, the results of INSIGHT could have significant clinical implications. Demonstrating superior efficacy of ripretinib in KIT exon 11 + 17/18 mutated GIST could support its use as a preferred second-line option for this subgroup. This would represent a more tailored approach compared to current practice, where sunitinib is the standard second-line therapy for most advanced GIST patients progressing on imatinib.
The study may also help validate ctDNA analysis as a predictive biomarker to guide treatment selection in GIST. If successful, this could pave the way for broader adoption of liquid biopsy approaches in clinical practice. The ability to non-invasively characterize tumor genomics and track clonal evolution over time could be particularly valuable in managing a heterogeneous disease like advanced GIST.
More broadly, INSIGHT exemplifies the growing trend towards biomarker-driven precision medicine in oncology. By matching specific molecular alterations to targeted therapies, this approach aims to maximize clinical benefit while minimizing exposure to less effective treatments.
However, it's important to note that even if positive, the results of INSIGHT would be applicable only to a subset of GIST patients - those with KIT exon 11 + 17/18 mutations. In the exploratory INTRIGUE analysis, this group represented about 24% of patients with detectable KIT mutations. Further research would still be needed to optimize treatment for patients with other molecular profiles.
Additionally, questions may remain about the optimal sequencing of targeted therapies in GIST. While INSIGHT could support use of ripretinib in the second-line setting for this subgroup, its current regulatory approval is for fourth-line and beyond treatment. Studies evaluating earlier use of ripretinib or other next-generation TKIs may be warranted.
The cost-effectiveness of this precision medicine approach will also need to be evaluated. While biomarker-guided treatment has the potential to improve outcomes, the added costs of molecular testing and potentially more expensive targeted therapies must be weighed against clinical benefits.
In conclusion, the INSIGHT trial represents an important step in advancing personalized medicine for GIST. By prospectively evaluating a biomarker-selected treatment approach, it has the potential to optimize outcomes for a subset of patients with this rare but challenging cancer. Results are eagerly anticipated by the sarcoma oncology community and could help shape future treatment paradigms in GIST.
References
George S, Blay JY, Chi P, et al. The INSIGHT study: a randomized, Phase III study of ripretinib versus sunitinib for advanced gastrointestinal stromal tumor with KIT exon 11 + 17/18 mutations. Future Oncol. 2024;20(27):1973-1982. doi:10.1080/14796694.2024.2376521
