A new phase 2 randomized clinical trial has evaluated the efficacy and safety of ripretinib compared to sunitinib as second-line treatment for advanced gastrointestinal stromal tumors (GIST) in Chinese patients. The study, published on November 14, 2023 in the European Journal of Cancer, was designed as a bridging study to the global phase 3 INTRIGUE trial and provides important data on the use of ripretinib in the Chinese population.
The multicenter, open-label study was conducted across multiple sites in China and funded by Zai Lab (Shanghai) Co., Ltd. A total of 108 patients with advanced GIST who had progressed on or were intolerant to first-line imatinib treatment were randomized 1:1 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 primary endpoint was progression-free survival (PFS) as assessed by independent radiological review.
To be eligible for inclusion, patients had to be at least 18 years old with histologically confirmed advanced or metastatic GIST and at least one measurable lesion. They were required to have progressed on or been intolerant to imatinib and to provide molecular test results for KIT/PDGFRA mutation status. Key exclusion criteria included prior therapy beyond imatinib for advanced GIST, imatinib-containing combination therapy in the first-line setting, and known active central nervous system metastases.
The study population had a median age of 59 years (range 25-82) and was predominantly male (63.9%). Most patients (57.5%) had an ECOG performance status of 1 or 2 at baseline. In terms of tumor genotype, 64.8% of patients had a primary KIT exon 11 mutation, 18.5% had a KIT exon 9 mutation, and 16.7% had other mutations. The demographic and baseline characteristics were generally well-balanced between the two treatment arms.
After a median follow-up of 13.8 months in the ripretinib arm and 11.3 months in the sunitinib arm, the study found that ripretinib demonstrated comparable efficacy to sunitinib in the overall population. The median PFS was 10.3 months with ripretinib versus 8.3 months with sunitinib (HR 0.99, 95% CI 0.57-1.69, nominal p=0.92). The objective response rate was numerically higher with ripretinib at 29.6% compared to 20.4% with sunitinib.
Notably, in the subgroup of patients with KIT exon 11 mutations (n=70), ripretinib showed a significant PFS benefit over sunitinib. The median PFS was not reached in the ripretinib arm compared to 4.9 months in the sunitinib arm (HR 0.46, 95% CI 0.23-0.92, nominal p=0.03). This represents a 54% reduction in the risk of progression or death with ripretinib in this important molecular subgroup.
The safety profile of ripretinib was favorable compared to sunitinib. Grade 3-4 treatment-related adverse events occurred in 17% of ripretinib-treated patients versus 56% of sunitinib-treated patients. The most common grade 3-4 treatment-related adverse events with ripretinib were anemia (4%) and diarrhea (4%). In contrast, sunitinib was associated with higher rates of hematologic toxicities, including grade 3-4 neutropenia in 26% of patients.
Treatment-related adverse events led to dose interruptions in 7% of ripretinib patients versus 43% of sunitinib patients. Dose reductions occurred in 20% and 30% of patients, respectively. Only 2% of ripretinib patients discontinued treatment due to adverse events, compared to 7% in the sunitinib arm. No treatment-related deaths occurred with ripretinib, while one treatment-related death (due to thrombocytopenic purpura) was reported with sunitinib.
The study authors concluded that ripretinib demonstrated similar overall efficacy and a more favorable safety profile compared to sunitinib as second-line treatment for advanced GIST in Chinese patients. They highlighted the clinically meaningful benefit observed with ripretinib in patients harboring KIT exon 11 mutations, which aligns with findings from the global INTRIGUE trial.
There are some limitations to consider when interpreting these results. The open-label design could potentially introduce bias, although the use of blinded independent radiological review for the primary endpoint helps mitigate this concern. The sample size was relatively small at 108 patients, which limits the power for subgroup analyses. Additionally, overall survival data were immature at the time of analysis.
Despite these limitations, this study provides important evidence supporting the use of ripretinib in Chinese patients with advanced GIST after imatinib failure. The efficacy results are consistent with those observed in the larger global INTRIGUE trial, while the safety profile appears particularly favorable in this population.
The potential clinical impact of these findings is significant. Ripretinib could offer an alternative second-line treatment option for advanced GIST patients in China, with the possibility of improved outcomes for those with KIT exon 11 mutations. The more tolerable safety profile may allow for longer treatment duration and improved quality of life compared to sunitinib.
Furthermore, the differential efficacy observed based on molecular subtype underscores the importance of genotyping in guiding treatment selection for GIST. The strong benefit seen in KIT exon 11 mutated tumors suggests that ripretinib could become a preferred option in this subgroup, while sunitinib may retain a role in other genotypes such as KIT exon 9 mutations.
The results also highlight the value of conducting bridging studies in specific populations. While the overall findings align with the global INTRIGUE trial, there are some notable differences. For instance, the hazard ratio for PFS in KIT exon 11 mutated tumors was more favorable in this Chinese study (HR 0.46) compared to INTRIGUE (HR 0.88). Such regional variations in treatment effects are important to elucidate to optimize patient care.
It is worth noting that ripretinib has already been incorporated into clinical practice guidelines based on prior evidence. The 2022 Chinese Society of Clinical Oncology (CSCO) guidelines recommend ripretinib as an alternative second-line therapy option for GIST. The current study provides additional support for this recommendation specifically in Chinese patients.
Looking ahead, several questions remain to be addressed in future research. Longer follow-up will be needed to assess the impact on overall survival. Studies with larger sample sizes could help further delineate efficacy in molecular subgroups beyond KIT exon 11. Additionally, investigations into potential biomarkers of response and resistance to ripretinib would be valuable for treatment optimization.
The optimal sequencing of targeted therapies for GIST also warrants further study. While ripretinib has shown efficacy in both second-line and later-line settings, determining the best treatment strategy to maximize long-term outcomes remains a challenge. Comparative studies and real-world evidence will be important to inform clinical decision-making.
In conclusion, this phase 2 trial provides compelling evidence for the efficacy and safety of ripretinib as second-line treatment for advanced GIST in Chinese patients. The results are consistent with global data while offering insights specific to this population. If confirmed in larger studies, these findings could lead to changes in treatment paradigms, particularly for patients with KIT exon 11 mutated tumors. As our understanding of GIST biology continues to evolve, studies such as this one are crucial for refining therapeutic approaches and improving outcomes for patients with this challenging disease.
References
Li J, Zhang J, Zhang Y, et al. Efficacy and safety of ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2, multicenter, randomized, open-label study in China. Eur J Cancer. 2024;196:113439. doi:10.1016/j.ejca.2023.113439
