An open-label phase II trial of regorafenib given continuously at a reduced dose of 100 mg daily to patients with refractory gastrointestinal stromal tumors found that nearly two-thirds of patients achieved disease control lasting for at least 12 weeks.<br />
An open-label phase II trial of regorafenib (Stivarga) given continuously at a reduced dose of 100 mg daily to patients with refractory gastrointestinal stromal tumors (GIST) found that nearly two-thirds of patients achieved disease control lasting for at least 12 weeks. The study, which was conducted at Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, was published recently inThe Oncologist.
The authors, led by Jae-Joon Kim, MD, hypothesized that giving regorafenib continuously might prevent exacerbation during off-treatment periods and that the lower dose might lessen adverse effects. “With regorafenib 100 mg daily continuous dosing, [the] DCR [disease control rate] lasting for at least 12 weeks was 64% (16 of 25 patients), which met the primary endpoint,” they wrote. “Thus, although this trial was an uncontrolled study and had somewhat different patient characteristics from previous studies, DCR of 100 mg of regorafenib continuous administration was comparable to that of the standard dosing schedule (160 mg daily for 3 weeks followed by a 1-week rest).”
The best response was partial response in 2 patients (8.0%), while slightly more than half of the patients had stable disease (SD; n = 14; 56.0%). One-third of patients had progressive disease (PD; n = 8; 32.0%). No patient achieved a complete response.
With a median follow-up of 8.6 months (range, 2.3-14.6), the median progression-free survival (PFS) was 7.3 months (95% CI, 5.9-8.6). The median overall survival (OS) was not reached with a 1-year survival rate of 64.5%. The authors observed no exacerbation of tumor-related symptoms while patients were on the continuous dosing schedule.
Patients in the trial received 100 mg of regorafenib orally each day of a 28-day cycle and continued regorafenib treatment until disease progression, as defined by RECIST version 1.1, or unacceptable toxicity. Following baseline CT imaging, follow-up CT scans were performed every 8 weeks until disease progression or death, while blood draws were performed at the completion of each 4-week cycle. Plasma free circulating tumor DNA was tested every 3 months.
Of the 25 patients, the median age was 60 years (range, 42-74), and a large majority were male (84%). All patients had an ECOG performance status of 1. All patients had been previously treated with imatinib (Gleevec) and sunitinib (Sutent) and were regorafenib-naïve. The imatinib median treatment duration was 25.0 months (range, 1.8-86.3), while the sunitinib median treatment duration was 8.3 months (range, 0.7-37.5). One patient had previously received nilotinib (Tasigna) as well.
The small bowel was the most common primary disease site (n = 15, 60%). The liver and peritoneum were the most common sites of metastasis (n = 19, 76% each). Two-thirds of patients had theKITexon 11 mutation (n = 16, 64%).
Patients completed a median of 6 treatment cycles (range, 2-16). Every patient experienced drug-related adverse events (AEs). Ten patients (40%) developed grade 3 non-hematologic toxicities; the most common were hand-foot skin reaction (16%) and elevation of alanine aminotransferase (ALT; 8%). No grade 4 non-hematological toxicities or treatment-related deaths occurred. No serious hematological toxicities or febrile neutropenias were detected.
The study protocol allowed patients’ doses to be reduced to 80 mg daily and then, if needed, to 60 mg daily. If that dose was still insufficient to control toxicities, the patient would have to discontinue study treatment. Once toxicities resolved, dose re-escalation was permitted. About one-quarter of patients (24%) required dose reduction to 80 mg, mainly due to hand-foot skin reaction; an additional 2 patients (8%) required reduction to 60 mg for hand-foot skin reaction (n = 1) and increased ALT (n = 1).
Of the 13 total patients who experienced PD, 12 continued the study treatment. Seven of these patients progressed further while on regorafenib. Of the 10 patients who continued treatment with the best assessable response, 6 patients had SD. AEs among this study subset were similar to those experienced prior to disease progression.
Kim et al concluded that regorafenib at a lower dose on a continuous schedule can be a treatment option for patients with refractory GIST after treatment failure. “With good efficacy and acceptable safety profiles, regorafenib at a lower, continuously administered dose might be an alternative treatment in patients with GISTs after imatinib and sunitinib,” they wrote. “Further administration of regorafenib after disease progression with regorafenib treatment may slow the disease[’s] progression.”
The authors also investigated the correlation between the mutation or entity of serum free circulating tumor DNA and clinical outcomes as an exploratory endpoint. Those data will be reported in a future paper.
Kim JJ, Ryu MH, Yoo CH, Beck MY, Ma JE, Kang YK. Phase II trial of continuous regorafenib dosing in patients with gastrointestinal stromal tumors after failure of imatinib and sunitinib [published online April 29, 2019].Oncologist. pii: theoncologist.2019-0033. doi: 10.1634/theoncologist.2019-0033.