Dovitinib Meets Primary Endpoint in Phase II Trial of Advanced GIST

Heikki Joensuu, MD, PhD

Dovitinib, an investigational oral tyrosine kinase inhibitor (TKI), demonstrated a “manageable” safety profile while controlling disease in about half of patients with advanced gastrointestinal stromal tumor (GIST) who had discontinued treatment with imatinib due to disease progression or intolerance, according to Heikki Joensuu, MD, PhD, who presented the data of the single-arm, phase II clinical trial at the 2014 ESMO Congress.

The multicenter, open-label, DOVIGIST (NCT01478373) trial evaluated the safety and efficacy of dovitinib in 39 patients with GIST who were intolerant to or had disease that was no longer responsive to first-line imatinib. Eligible patients had histologically confirmed advanced or metastatic GIST that was refractory to imatinib at >400 mg/day, or did not tolerate this dosage of imatinib, or had recurrent GIST after receiving imatinib in the adjuvant setting. Patients had no prior TKI therapy other than imatinib.

All patients received 500 mg/day of dovitinib on a 28-day cycle (5 days on followed by 2 days off). The primary endpoint was the rate of disease non-progression by Response Evaluation Criteria in Solid Tumors (RECIST) at 12 weeks; success was defined as a disease control rate of ≥45%. This level of disease control was determined to be clinically meaningful based on a prior trial of sunitinib, the current standard in the second-line setting after imatinib, as second-line therapy in GIST, said Joensuu, professor of oncology at the University of Helsinki.

Of the 38 patients who had histologically confirmed GIST, 31 (81.6%) discontinued imatinib because of progressive disease, 5 were intolerant, and 2 were both intolerant to and developed resistance to imatinib.

“The result of this phase II study in a limited number of patients is interpreted as positive,” said Joensuu. “The results in my opinion are fairly good and this could be a second-line option, but I don’t know if this compound will be developed further.”

At data cutoff (April 30, 2014), dovitinib treatment was ongoing in 2 patients and was withdrawn in 36. The primary reason for discontinuation was progressive disease, experienced by 27 patients. Adverse events caused discontinuation in 8 patients and protocol deviation in 1.

The disease control rate at 12 weeks was 52.6%, which met the criterion for success. The median progression-free survival (PFS) was 141 days. At week 12, there was 1 partial response, 19 patients had stable disease, and 5 patients had progressive disease per RECIST; the best overall response was unknown in 13 patients.

At the end of treatment, 2 patients had a partial response, 16 had stable disease, and 5 had progressive disease; the best overall response was again unknown in 13. The 2 patients in whom treatment was ongoing were not scored for best overall response at the end of treatment.

Almost all patients (37 of 39) had an adverse event. According to Joensuu, higher toxicity with dovitinib was expected given its activity on multiple pathways. Dovitinib targets the fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived factor receptor beta, in addition to KIT and other kinases.

“Toxicity was manageable, with the majority being gastrointestinal toxicity that was usually not severe,” he said. “We also saw some hypertension, which is common with agents that inhibit VEGF, ” Joensuu said.

Most of the adverse events were grade 1/2. Diarrhea (71.8%), vomiting (51.3%), and nausea (41%) were the most common adverse events of any grade suspected to be drug-related. There were 5 reports (12.8%) of grade 3 fatigue that were suspected to be drug-related. Grade-2 hypertension occurred in 15.4% of the patients while grade-3 hypertension occurred in 17.9%.

There were 2 grade-3 hematologic abnormalities. The most common grade-3 biochemical abnormalities were an increase in levels of gamma-glutamyltransferase (28.1%) and triglycerides (18.5%).

As second-line therapy for metastatic GIST, dovitinib did not perform as well as sunitinib, said Nicolas Penel, MD, PhD, who was not involved in the study.

In this setting, the 12-week disease control rate was 70% and PFS was 7.8 months with sunitinib, compared with 52% and 4.7 months, respectively, with dovitinib, he noted.

For this reason, “I’m not sure there is room for a phase III trial,” said Penel, medical oncologist at Centre Oscar Lambret in Lille, France.

Joensuu H, Blay J, Comandone A, et al. Phase 2 trial to evaluate the efficacy and safety of dovitinib in patients (pts) with gastrointestinal stromal tumor (GIST) refractory and/or intolerant to imatinib (IM).Presented at: ESMO Congress 2014; September 26-30, 2014; Madrid, Spain. Abstract LBA46.

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