Phase 2 trial of rogaratinib in SDH-deficient GIST: partial responses in 10 of 24 patients
Background: Targeting growth signals driven by epigenetic changes
In a phase 2 trial involving 24 adults with advanced succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), partial responses were observed in 10 patients after treatment with rogaratinib. The findings point to the potential of blocking growth signals activated by epigenetic changes by inhibiting fibroblast growth factor receptors (FGFRs). However, this was a small trial without a concurrent control group, so it is too early to conclude that the approach is superior to existing treatments.
Most GISTs are driven by activating mutations in KIT or PDGFRA, but SDH-deficient tumors have different biological characteristics. Clinical benefit from KIT-targeted treatments has generally been limited in this subtype. Rare responses and prolonged stable disease with existing drugs have also been reported, so the subtype cannot be considered completely treatment-refractory.
Prior mechanistic studies indicate that succinate accumulation caused by loss of SDH function inhibits DNA demethylases. Excessive methylation disrupts boundary elements between the FGF3 and FGF4 genes and nearby regulatory signals, allowing adjacent enhancers to increase expression of these growth factors. This creates autocrine signaling in which growth factors secreted by cancer cells stimulate their own FGFRs. Rather than reversing methylation itself, this trial evaluated an approach that inhibits the resulting signal.
Key findings: 41.7% response rate; dose reductions in 63% of patients
The team enrolled 24 adults at 11 US centers with unresectable locally advanced or metastatic SDH-deficient GIST. This cohort in the multicenter, open-label phase 2 trial had no concurrent control group. Sixty-seven percent of patients had received prior systemic therapy. Patients received 800 mg of rogaratinib, an FGFR1–4 inhibitor, orally twice daily. The primary endpoint was the objective response rate on imaging, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
As of the August 1, 2024 data cutoff, 10 patients had a partial response, for an objective response rate of 41.7%. Stable disease was the best response in 12 patients, and progressive disease in two. Median progression-free survival (PFS) was 31.0 months, with a 95% confidence interval from 20.2 months to an upper limit that was not reached. The estimated 1-year PFS rate was 77.4% (95% confidence interval, 61.7–97.1%). This should be distinguished from evidence demonstrating improved overall survival.
The treatment also carried a toxicity burden. Every patient experienced at least one adverse event; hyperphosphatemia occurred in 96%, fatigue in 54%, and diarrhea in 50%. There were no grade 4–5 adverse events, but 63% of patients had their dose reduced, and four discontinued treatment because of toxicity. The investigators considered the toxicities generally manageable, but the burden of dose reductions and discontinuations also needs to be considered.
Implications and outlook: Clinical validation of other FGFR inhibitors remains a priority
These findings support the possibility that growth signals activated by epigenetic changes can also provide a rationale for targeted therapy. However, the number of patients and PFS events was small, and the study did not identify specific SDH gene alterations or other molecular markers that predict response. Methylation patterns were not measured directly, so the trial did not demonstrate normalization or reversibility of the epigenetic state. No post-progression biopsies were available, and serial measurements of FGFRs and growth factors and post-progression exome analyses could not be performed; resistance mechanisms remain a subject for future research.
In mouse models implanted with patient-derived tumors, infigratinib and pemigatinib, as well as rogaratinib, inhibited tumor growth. This provides preclinical support for evaluating other FGFR inhibitors, but it is not evidence that they will have the same effect in patients. The paper states that clinical development of rogaratinib is no longer ongoing. Testing the efficacy and safety of other FGFR inhibitors in clinical trials is a key task for further development.
The study design and results are available in the full text of the paper, published in Nature Medicine.
Nature Medicine, Published online: 26 May 2026. DOI: 10.1038/s41591-026-04376-9
Summary: Resolving the intractable therapeutic blind spot within gastrointestinal stromal tumors (GIST), this multicenter phase 2 clinical trial demonstrates the high-fidelity efficacy of the fibroblast growth factor receptor (FGFR) inhibitor rogaratinib against succinate dehydrogenase (SDH)-deficient GIST lineages. Structurally refractory to conventional tyrosine kinase inhibitors (TKIs) targeting KIT or PDGFRA, SDH-deficient oncogenesis operates via metabolite-driven hyper-methylation and epigenetic transactivation cascades. The clinical metadata successfully establishes that this epigenetic mechanism of oncogene activation can be programmatically arrested via strategic downstream tyrosine kinase domain targeting with rogaratinib. The trial delivers encouraging objective response rates across diverse patient cohorts, delineating a scalable computational and interventional baseline for prospective biomarker deployment and subtype-specific multi-agent combination stratification.
This study provides a rationale for considering growth signals produced by epigenetic changes, as well as genetic mutations, as candidate treatment targets. It could inform the design of future FGFR inhibitor trials that identify patients with SDH deficiency using findings such as loss of SDHB protein and assess imaging responses and duration of disease control alongside hyperphosphatemia and the burden of dose reductions. However, confirmation of SDH deficiency has not been established as a companion diagnostic that predicts an individual patient’s response. Given that rogaratinib development has stopped and other drugs still require clinical validation, the applicability of these findings is limited to guiding future clinical development. They do not directly support changing standard treatment or prescribing other FGFR inhibitors.