Regorafenib Prescribing in Advanced GIST Deviates From Guidelines

About 1 in 4 patients with advanced gastrointestinal stromal tumor (GIST) who were prescribed regorafenib (Stivarga; Bayer) started the drug after a single prior therapy or an atypical prior treatment, a pattern that deviates from the guideline-recommended 2-drug sequence, according to a real-world claims analysis published in PLOS One.¹ At least 45% received the full standard sequence beforehand.

The findings suggest that prescribing patterns for the multikinase inhibitor diverge from its guideline-recommended third-line placement for a notable share of patients, raising questions about what is driving earlier use in everyday practice.

GIST is the most common gastrointestinal soft tissue sarcoma, with an estimated 4000 to 6000 new cases diagnosed annually in the US. Tyrosine kinase inhibitors (TKIs) are the standard of care for advanced disease, typically starting with imatinib (Gleevec; Novartis) and moving to sunitinib (Sutent; Pfizer) once resistance develops. Regorafenib is guideline-recommended as the preferred third-line option for patients who have progressed on both drugs.

“Despite guideline recommendations as an established third-line therapy, anecdotal reports suggest regorafenib may be used in earlier lines of therapy in the real world,” the authors explained.

How Regorafenib Was Being Used in Practice

Using the Merative MarketScan Research Databases, researchers identified 166 patients with a documented GIST diagnosis who received at least 1 regorafenib prescription between October 2015 and May 2023. Contrary to guideline-recommended sequencing, 12.0% of patients had received only imatinib or only sunitinib before starting regorafenib, while 45.2% had received both drugs following guidelines. Smaller shares had received prior pazopanib (Votrient; Novartis) alone (9.0%) or ripretinib (Qinlock; Deciphera Pharmaceuticals) alone (1.8%).

Dosing also diverged from the approved label. Regorafenib's standard dose (RSD) is an average daily dose of 160 mg for 21 days of a 28-day cycle, yet more than a quarter of patients (26.5%) were started on a lower dose (LD).

Despite these variations in prescribing, treatment duration was broadly similar across dosing groups. After a median follow-up of about 7 months (221.5 days), the median duration of therapy (DOT) was 95 days, and 20.5% of patients switched to a new therapy, with a median time to next treatment (TTNT) of 142 days. Patients on LD and RSD had comparable median DOT (103 days vs 94.5 days) and TTNT (143 days vs 141 days).

One difference did emerge based on prior treatment history: patients who had received only imatinib or only sunitinib before starting regorafenib remained on the drug numerically longer (median DOT, 142.5 days) than those who had received both drugs beforehand (95 days). However, the study authors cautioned that differences in DOT likely reflect prescribing patterns, patient selection, and other confounding factors, such as underlying disease aggressiveness or treatment tolerance, rather than a direct effect of sequencing on drug effectiveness.

What Might Be Driving Earlier Use of Regorafenib?

The researchers pointed to several possible explanations that claims data cannot capture directly, including physician preference, specific tumor mutation profiles, and the declining accessibility of sunitinib now that it has lost patent protection and lacks financial assistance programs. The arrival of newer GIST therapies such as ripretinib, which was approved as a fourth-line option for patients who have already received 3 or more kinase inhibitors, has continued to reshape how clinicians sequence treatment for this rare cancer.²

The authors acknowledged several limitations common to claims-based research, including the inability to capture treatments received through clinical trials or patient assistance programs and the fact that dosing cohorts were defined by pills dispensed rather than confirmed adherence.¹ The analysis was also limited to commercially insured and Medicare populations, leaving uninsured and Medicaid patients unrepresented.

“While acknowledging the limitations of a claims-based analysis, this real-world study reveals that the utilization patterns of regorafenib may not always align with guideline recommendations, potentially reflecting use in earlier lines of therapy for a small subset and different dosing,” the authors concluded.

References

1. Denu RA, Appukkuttan S, Hocum B, et al. Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States. PLoS One. 2026;21(7):e0353357. doi:10.1371/journal.pone.0353357
2. Melillo G. FDA approves Qinlock (ripretinib) for gastrointestinal stromal tumors. AJMC^®. May 18, 2020. Accessed September 18, 2026. https://www.ajmc.com/view/fda-approves-qinlock-ripretinib-for-gastrointestinal-stromal-tumors