# The Evolving Role of Second- and Third-Generation Tyrosine Kinase Inhibitors in Gastrointestinal Malignancies: Advances in Targeted Therapy with Sunitinib, Regorafenib, and Avapritinib

## TL;DR

This paper reviews how newer tyrosine kinase inhibitors like sunitinib, regorafenib, and avapritinib are improving treatment for gastrointestinal stromal tumors by targeting specific mutations and extending survival.

## Contribution

The paper highlights the role of second- and third-generation tyrosine kinase inhibitors in mutation-specific therapy for gastrointestinal stromal tumors.

## Key findings

- Sunitinib, regorafenib, and avapritinib offer improved disease control for imatinib-resistant gastrointestinal stromal tumors.
- Avapritinib specifically targets PDGFRA D842V and KIT exon 17 mutations, addressing a previously untreatable subgroup.
- Therapeutic sequencing and biomarker-driven decisions are transforming personalized treatment for advanced gastrointestinal stromal tumors.

## Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. While imatinib revolutionized first-line therapy, resistance and specific mutation profiles necessitate subsequent generations of tyrosine kinase inhibitors (TKIs). Sunitinib, regorafenib, and avapritinib represent second-line, third-line, and mutation-specific therapies, respectively, offering improved precision and disease control. This review summarizes clinical trial evidence, real-world data, and translational studies evaluating the efficacy, safety, and mechanistic basis of second- and third-generation TKIs in GIST. Emphasis is placed on therapeutic sequencing, resistance mechanisms, and molecularly guided treatment selection. Sunitinib, a multitargeted TKI inhibiting KIT, PDGFR, and VEGFR, provides effective disease control in imatinib-resistant or intolerant patients. Regorafenib, a broad-spectrum multikinase inhibitor, improves progression-free survival in refractory GIST and targets additional angiogenic and oncogenic pathways. Avapritinib, a next-generation TKI, selectively inhibits PDGFRA D842V and KIT exon 17 mutations, addressing a previously untreatable, mutation-driven subgroup. Integration of these agents into treatment algorithms exemplifies a shift toward personalized therapy, with outcomes guided by mutation profiling and biomarker-driven decisions. Second- and third-generation TKIs have transformed the management of advanced GIST, extending survival and offering mutation-specific precision therapy. Ongoing research into resistance mechanisms, combination strategies, and novel inhibitors promises further optimization of patient-centered care.