Cogent Biosciences’ phase 3 PEAK trial marks an advance in the treatment of gastrointestinal stromal tumors.

Cogent Biosciences announced positive results from its PEAK phase 3 trial evaluating bezuclastinib plus Sutent (sunitinib) in patients with imatinib-resistant or intolerant gastrointestinal stromal tumors (GIST). The first positive phase 3 study in the second-line GIST setting in over two decades met its primary and key secondary endpoints with profound clinical and statistical significance. Cogent plans to submit a New Drug Application in 2026.

GISTs are rare tumors of the GI tract, most often driven by mutations in the KIT gene or, less commonly, platelet-derived growth factor receptor A. Over 80% of GISTs are driven by primary activating mutations in the KIT receptor tyrosine kinase, most commonly in exon 11 or exon 9. The first-line therapy, Gleevec (imatinib), targets these mutations. While imatinib revolutionized first-line treatment, resistance inevitably develops, often through secondary mutations in KIT exon 17. Resistance to imatinib is nearly universal, with 60% of patients progressing within two years.

Patients progressing on imatinib typically move to sunitinib, then Stivarga (regorafenib) or Qinlock (ripretinib) in later lines. However, these therapies provide only modest benefits, with median progression-free survival often under a year. For decades, the second-line setting has been defined by limited efficacy and significant toxicity, leaving patients with few durable options.

The current standard of care for imatinib-resistant GIST is sunitinib, a multi-targeted tyrosine kinase inhibitor. While effective in delaying progression, sunitinib is associated with hypertension, fatigue, hand-foot syndrome, and cytopenias. Perhaps more importantly, sunitinib has negligible activity against mutations in exon 17. This gap means that patients whose resistance is driven by exon 17 are mechanistically destined to fail sunitinib therapy. Later agents such as regorafenib and ripretinib extend survival incrementally but rarely induce deep responses.

This treatment landscape demonstrates a gap in care; patients with resistant disease face declining benefit with each line of therapy, and no second-line agent has demonstrated transformative efficacy until now.

Bezuclastinib is a selective KIT inhibitor designed to target resistant mutations, including 17 exon variants. By combining it with sunitinib, the PEAK trial leveraged complementary mechanisms to overcome resistance. The combination achieved a median progression-free survival (mPFS) of 16.5 months, compared to 9.2 months with sunitinib alone, cutting into the risk of progression or death. The objective response rate (ORR) was also significantly higher, 46% vs. 26%, with a safety profile consistent with sunitinib monotherapy.

The safety profile was manageable, with no unexpected toxicities beyond those already known for sunitinib. The primary safety signal associated with adding bezuclastinib was an increase in Grade 3+ ALT/AST (liver enzyme) elevations (10.8% vs. 1.4%). However, these events were described as predominantly transient, manageable, non-serious, reversible, and asymptomatic. The rates of other common Grade 3 or higher adverse events were comparable between the two arms. This balance of efficacy and tolerability is critical for patients who often endure years of sequential therapies.

With regulatory approval anticipated in 2026, bezuclastinib plus sunitinib could soon fill a long-standing therapeutic void. If adopted, this combination may shift the treatment paradigm, offering patients not just incremental benefit but a meaningful extension of disease control. For rare cancer where innovation has been slow, the PEAK trial signals a positive step towards managing GIST.