From Sequential TKIs to Combination Therapy in Advanced GIST: Current Standards, PEAK Phase 3 Data, and Practical Guidance for the Community Oncologist
Dr. Jason Sicklick from UC San Diego moderated a comprehensive discussion with sarcoma experts on evolving GIST treatment strategies, marking the first major shift in 6 years since ripretinib's approval. The panel explored the established 4-line sequence: imatinib first-line, sunitinib second-line, regorafenib third-line, and ripretinib fourth-line post-3 TKI progression. Key highlights included PEAK Phase 3 trial results demonstrating bezuclastinib plus sunitinib combination therapy's superiority over sunitinib monotherapy, with median progression-free survival extending from 9.2 to 16.5 months (HR 0.50, P < 0.0001). The combination doubled objective response rates from 26% to 46% while maintaining manageable toxicity profiles. The discussion emphasized mutation-guided therapy selection using ctDNA analysis, particularly for patients with KIT exon 11 plus secondary mutations in exons 13/14 versus 17/18. Panelists addressed practical community oncology challenges including molecular testing accessibility, toxicity management across treatment lines, and avoiding treatment gaps that can accelerate disease progression. Future directions include first-line combination strategies and resistance mechanism understanding to optimize sequencing decisions.
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From Sequential TKIs to Combination Therapy in Advanced GIST: Current Standards, PEAK Phase 3 Data, and Practical Guidance for the Community Oncologist
Dr. Jason Sicklick from UC San Diego introduces this OncLive Peer Exchange program addressing the evolving post-third-line GIST landscape, joined by sarcoma experts Dr. Mark Agulnik, Dr. Neeta Somaiah, Dr. Michael Heinrich, Dr. Seth Pollack, and Dr. Brian Schulte. The discussion focuses on the first positive Phase 3 second-line trial in over two decades currently under FDA review.
Dr. Somaiah outlines the current FDA-approved sequence for advanced KIT-mutant GIST, emphasizing that community oncologists may encounter only handful of patients annually. First-line therapy uses imatinib 400mg daily, escalating to 400mg twice daily for KIT exon 9 mutations based on superior activity data.
Dr. Agulnik analyzes the INTRIGUE trial's landmark contributions to GIST management, representing the first head-to-head Phase 3 comparison rather than placebo-controlled study.
Dr. Pollack characterizes ripretinib as an outstanding fourth-line agent that filled a critical unmet need in post-third-TKI progression settings. Before ripretinib's availability, patients lacked effective treatment options after exhausting the first three lines of therapy.
Dr. Schulte identifies significant knowledge gaps among community oncologists managing GIST, acknowledging that even experienced community practitioners may encounter only 2 to 3 patients annually. This limited exposure creates challenges in maintaining expertise with nuanced treatment decisions and sequencing strategies.
Dr. Heinrich explains the scientific foundation for combining bezuclastinib with sunitinib, addressing the fundamental problem of polyclonal resistance emerging after imatinib progression.
Dr. Agulnik outlines bezuclastinib's regulatory trajectory, noting Breakthrough Therapy Designation granted in March 2026 based on PEAK topline results. This designation indicates the drug addresses unmet medical need with substantial improvement over available therapy. The New Drug Application was accepted under Real-Time Oncology Review with submission completed in April 2026.
Dr. Pollack addresses clinicians' desire for mutation-specific response data before adopting combination therapy, emphasizing the transformative insights from the INTRIGUE trial's ctDNA analysis. The INTRIGUE study demonstrated dramatic differences in patients with KIT exon 11 mutations based on secondary resistance patterns: those with exon 13/14 secondary mutations achieved over 12 months progression-free survival with sunitinib versus only months with ripretinib, while the reverse pattern held for exon 17/18 secondary mutations.
Dr. Schulte addresses the critical question of combination tolerability compared to sunitinib monotherapy, noting that community oncologists' primary concern involves adding a second agent to an already challenging treatment regimen. The PEAK Part 1 safety data provided reassuring evidence that combination therapy doesn't substantially increase toxicity burden.
Dr. Somaiah addresses the critical question of treatment sequencing after combination second-line therapy, acknowledging that all currently approved agents were studied as sequential monotherapies without prospective data on their performance following combination treatment. This represents uncharted territory requiring clinical experience and real-world data collection.
Dr. Pollack emphasizes tissue-based next-generation sequencing as the gold standard for initial diagnosis and primary driver mutation identification. This testing remains absolutely essential at diagnosis to distinguish KIT-mutant from PDGFRA-mutant GIST and identify rare entities like SDH-deficient or NTRK-fusion tumors requiring different treatment approaches.
Dr. Schulte outlines toxicity management strategies across the GIST treatment sequence, emphasizing proactive patient education and monitoring. Imatinib's 25-year track record provides community comfort with characteristic side effects including edema, myalgias, and gastrointestinal irritation, managed with full stomach dosing and symptomatic measures.
The panel discusses exciting future developments including expanded interest in first-line combination strategies and targeting multiple resistance mechanisms simultaneously. Companies are increasingly developing agents specifically for GIST rather than repurposing drugs designed for other malignancies.
