In the field of targeted therapies for malignant tumors, the advent of ripretinib (QINLOCK) has brought renewed hope to patients with gastrointestinal stromal tumors (GIST). In particular, it provides a critical treatment option for patients whose disease continues to progress after multiple lines of therapy.

As a broad-spectrum kinase inhibitor with a novel and innovative mechanism of action, ripretinib has established a new milestone in the treatment of GIST through its unique design concept, robust clinical efficacy, and manageable safety profile. Leveraging years of deep expertise in the pharmaceutical industry, DengyueMed provides a comprehensive analysis of this important targeted therapy, covering its mechanism of action, target patient population, clinical evidence, and future development prospects.

Precisely Blocking Resistance Mutations to Overcome Treatment Barriers

The initiation and progression of GIST are primarily driven by mutations in the KIT and PDGFRA genes. Approximately 80% of cases are associated with KIT mutations, while 5–10% are driven by PDGFRA mutations. Although conventional tyrosine kinase inhibitors (TKIs) can effectively target certain primary mutations, tumors often develop secondary resistance mutations over time, ultimately leading to treatment failure.

The core advantage of ripretinib lies in its unique “switch-control” mechanism. Specifically designed as a broad-spectrum inhibitor targeting both KIT and PDGFRA, ripretinib can precisely inhibit the full spectrum of mutations driving GIST progression, including both primary and secondary resistance-associated mutations.

Ripretinib effectively inhibits mutations across KIT exons 9, 11, 13, 14, 17, and 18, which are key contributors to drug resistance and disease progression in GIST. In addition, it suppresses PDGFRA exon 12, 14, and 18 mutations, including the exon 18 D842V mutation, which is known to be resistant to several other therapies. This broad inhibitory profile enables ripretinib to overcome the limitations of traditional targeted agents and offers a new therapeutic direction for patients with drug-resistant disease. Furthermore, ripretinib can inhibit amplification of wild-type PDGFRA, further expanding its antitumor activity.

Addressing the Unmet Needs of Patients After Multiple Lines of Therapy

GIST is the most common type of sarcoma of the gastrointestinal tract. In the United States, approximately 4,000–6,000 new cases are diagnosed annually, with a similar incidence rate observed in Europe. Five-year survival rates range from 52% to 94%, depending on disease stage at diagnosis.

Prior to the approval of ripretinib, targeted agents such as imatinib, sunitinib, and regorafenib were available for GIST treatment. However, a subset of patients eventually develops resistance to these therapies or experiences continuous disease progression after multiple lines of treatment, leaving them with limited or no effective therapeutic options.

Based on pivotal data from the phase III INVICTUS trial, ripretinib was first approved by the U.S. FDA for the treatment of adult patients with advanced GIST who had previously received three or more kinase inhibitors, including imatinib. Subsequently, ripretinib received regulatory approval in multiple regions, including Australia, Canada, China, and the European Union, becoming the first globally approved fourth-line treatment for GIST and filling a critical gap in the post-multiline treatment landscape. With further clinical investigation, the potential role of ripretinib in second-line therapy is also being explored, offering an alternative option for patients who are intolerant to standard second-line treatments.

Significant Efficacy with Meaningful Survival Benefits

The approval of ripretinib was primarily supported by the positive results of the INVICTUS trial, a randomized, double-blind, placebo-controlled phase III study that enrolled 129 patients with advanced GIST previously treated with imatinib, sunitinib, regorafenib, and other therapies. Patients were randomized in a 2:1 ratio to receive either ripretinib (150 mg once daily) or placebo.

Results demonstrated a median progression-free survival (PFS) of 6.3 months in the ripretinib group, compared with only 1.0 month in the placebo group, representing an 85% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.15; 95% CI: 0.09–0.25).

Ripretinib also showed a clear advantage in overall survival (OS). Median OS reached 15.1 months in the ripretinib group, significantly longer than 6.6 months in the placebo group, corresponding to a 64% reduction in the risk of death (HR = 0.36; nominal p = 0.0004). Notably, patients in the placebo group were allowed to cross over to ripretinib upon disease progression; these patients achieved a median PFS of 4.6 months and a median OS of 11.6 months, further confirming the clinical benefit of ripretinib. The objective response rate (ORR) was 9.4% in the ripretinib group, compared with 0% in the placebo group, demonstrating clear tumor control.

Beyond the fourth-line setting, the final analysis of the phase III INTRIGUE trial showed that ripretinib, when used as second-line therapy in patients with advanced GIST after imatinib failure, provided long-term survival outcomes comparable to sunitinib (median OS: 35.5 months vs. 31.5 months), while offering a more favorable safety profile. The incidence of grade 3/4 treatment-related adverse events was significantly lower with ripretinib (27% vs. 58%). Importantly, the study introduced the concept of “second progression-free survival (second PFS)”, demonstrating that second-line use of ripretinib does not compromise the efficacy of subsequent third-line therapies, thereby supporting more flexible and optimized treatment sequencing.

Future Outlook: Expanding Indications and Treatment Scenarios

As a major breakthrough in GIST treatment, clinical exploration of ripretinib continues beyond fourth- and second-line settings. Ongoing studies are evaluating its efficacy in specific molecular subtypes of GIST. For example, the phase III INSIGHT trial focuses on patients with KIT exon 11 plus exon 17/18 mutations, aiming to deliver more precise treatment strategies for this distinct population.

In addition, the mechanism of action of ripretinib suggests potential applicability in other KIT- or PDGFRA-driven malignancies, such as systemic mastocytosis (SM), with related clinical studies currently underway.

From an accessibility standpoint, ripretinib has been approved and launched in multiple countries and regions worldwide, including China, providing new treatment opportunities for patients with advanced GIST. As reimbursement policies continue to improve and clinical adoption expands, a growing number of patients are expected to benefit from this breakthrough therapy.

Conclusion

As a broad-spectrum KIT and PDGFRA kinase inhibitor, ripretinib overcomes the resistance limitations of traditional targeted therapies through its innovative switch-control design, delivering meaningful survival benefits for patients with advanced GIST who have failed multiple lines of treatment. Robust clinical evidence confirms its significant advantages in both progression-free survival and overall survival, while its manageable safety profile ensures reliable and effective treatment.

With ongoing clinical research and expanding therapeutic applications, ripretinib is poised to benefit a broader patient population and play an increasingly important role in the era of precision oncology.