Alternating Glivec and Stivarga Doesn't Improve Advanced GIST Outcomes

Alternating between treatment of Glivec (imatinib) and Stivarga (regorafenib) did not positively impact survival outcomes, leading to more toxicity and discontinuations among patients with advanced gastrointestinal stromal tumors (GIST), according to research from the phase 2 ALTGIST study, which were published in the journal, Nature.

In total, 76 patients were enrolled onto the study — 36 in Arm A and 40 in Arm B — and all were eligible for evaluation. Following a median follow-up of approximately 46 months, both groups showed similar response rates at nine months. However, 50% of patients in Arm A and 30% in Arm B paused their treatment due to disease progression. No patients in Arm A stopped because of severe side effects, while 30% of patients in Arm B discontinued due to side effects.

Serious side effects, mostly grade 3 (severe), occurred in 33.2% in Arm A and 30.0% in Arm B. Moreover, when researchers looked at progression-free survival and overall survival data at one year, the results were not statistically different.

“Alternation of [Glivec] and Stivarga did not impact on 9 months objective response nor on the secondary objectives of PFS and OS. Patients in the alternating arm experienced more toxicity and protocol discontinuations,” first study author, Dr. Desmond Yip, and colleagues wrote.

Yip works as a senior staff specialist in Medical Oncology, Canberra Health Services, and is a professor at Australian National University (ANU), ANU School of Medicine and Psychology, ANU College of Science and Medicine, in Canberra, ACT, Australia.

“In summary there was no meaningful difference in the primary endpoint of OTR and in PFS between the groups in this final analysis of AGITG ALT-GIST. The difference in the Kaplan-Meier estimate of OS and time to treatment failure at 12 months were also not significant. Post-hoc analyses to the time of last available follow-up found no differences in duration of response or PFS and OS at four years between the study arms,” Yip and colleagues emphasized.

Although the clinical benefit rate is over 80% with current treatment of Glivec for metastatic GIST, most patients eventually experience disease progression. Studies have shown that, on average, the median progression-free survival was approximately two years, although those starting treatment with a smaller amount of tumor may experience longer benefits. Overall, patients now have a median survival of at least five years.

Moreover, researchers have developed tools that can estimate individual risk based on factors such as tumor genetics, size and blood counts at the start of treatment. Despite strong early responses, tumors often develop resistance to Glivec due to new genetic mutations, making long-term cures rare.

Based on the current therapeutic landscape, researchers investigated the benefit of short breaks from treatment to limit the growth of resistant cancer cells and introducing a second targeted therapy, Stivarga. Stivarga works differently than Glivec and targets multiple cancer growth pathways. In clinical trials, it significantly delayed disease progression in patients whose cancer had already stopped responding to previous treatments.

By using a treatment-free period followed by Stivarga, investigators hypothesized that more patients would achieve longer-lasting responses, potentially turning partial tumor responses into complete ones and improving survival rates in advanced GIST.

More Information on the Study

This investigation was a phase 2, randomized, open-label trial and was conducted across 37 centers in 11 countries, including Australia, Finland, France, Italy, Netherlands, Norway, Singapore, Slovakia, Spain, Sweden and the United Kingdom. To enroll, participants had to have been aged 18 years or older, with a confirmed diagnosis of CD-117 positive, unresectable, metastatic GIST, as well as have had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function. Patients had to have had measurable disease and no prior history of taking a TKI for metastatic disease.

Regarding exclusion criteria, patients who had progression of GIST while on adjuvant therapy were not eligible for enrollment. Poorly controlled hypertension or persistent proteinuria; inability to swallow or malabsorption; an arterial or venous thrombotic event within six months prior to randomization; known central nervous system metastases; active hepatitis B or C or HIV infection; and presence of a known mutation all called for exclusion from the trial as well.

Patients who were eligible for enrollment were enrolled to either minimization to continuous Glivec (Arm A) or to alternating Glivec with Stivarga (Arm B). Stratification to these arms were by site, receipt of previous adjuvant therapy (prior vs. none) and receipt of Glivec for metastatic disease for less than or equal to 21 days.

In Arm A, patients received Glivec at a dose of 400 milligrams by mouth once daily without interruption during a 56-day cycle. Treatment continued until the cancer progressed or side effects became too severe. Patients in Arm B took Glivec at 400 milligrams daily for 21 to 25 days, then stopped for 3 to 7 days, followed by Stivarga at 160 milligrams daily for three weeks, and then another seven-day break. Treatment cycles repeated until disease progression or intolerable side effects occurred.

“This alternating schedule does not warrant further study. We conclude that clinicians should continue the current standard of first-line single-agent continuous [Glivec] until disease progression on highest tolerable dose,” the investigators concluded in their research.

Reference:

“Selective internal radiation with Y-90 resin microspheres (SIRT) for liver metastases of gastro-intestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy” by Dr. Peter Hohenberger, et al., Nature.

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