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Masitinib superior to sunitinib in advanced GIST
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Patients with inoperable, advanced imatinib-resistant gastrointestinal stromal tumor who underwent treatment with masitinib demonstrated significantly longer survival than those treated with sunitinib, according to results of a prospective, multicenter, randomized open-label trial.
Masitinib also appeared more tolerable.
“Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit–risk ratio,” Antoine Adenis, MD, of the department of gastrointestinal oncology at Centre Oscar Lambret in Lille, France, and colleagues wrote. “Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.”
The analysis included 44 patients with inoperable, advanced GIST who were intolerant to or experienced failure after treatment with imatinib (Gleevec, Novartis).
Adenis and colleagues randomly assigned 23 patients to 12 mg/kg daily masitinib (AB Science). The other 21 patients received 50 mg/kg daily sunitinib (Sutent, Pfizer). Treatment was administered in a 4-weeks-on, 2-weeks-off regimen until progression, intolerance or patient refusal.
Upon study termination, patients who had been assigned masitinib had the option to switch to sunitinib treatment. Crossover from sunitinib to masitinib was not allowed.
Median treatment exposure was 4.7 months in the masitinib arm and 3.8 months in the sunitinib arm.
Median follow-up was 14 months. Results showed patients assigned masitinib demonstrated significantly longer median OS. Median OS was not reached in the masitinib arm (estimated >21.2 months) but was 15.2 months (95% CI, 9.4-21.7) in the sunitinib arm, translating to an HR of 0.27 (95% CI, 0.09-0.85).
Researchers conducted a subsequent analysis at 26 months follow-up to assess whether the OS benefit was sustained long term.
Results showed median OS was 29.8 months (95% CI, 17.8-not reached) in the masitinib arm vs. 17.4 months (95% CI, 9.4-28.6) in the sunitinib arm (HR=0.4; 95% CI, 0.16-0.96).
Median PFS was similar between the masitinib arm (3.7 months; 95% CI, 1.9-6) and the sunitinib arm (1.9 months; 95% CI, 1.8-4.4), equating to an HR of 1.1 (95% CI, 0.6-2.2). However, patients assigned sunitinib experienced significantly higher rates of serious adverse events (91% vs. 52%; P=.008), nonhematological grade 3 and any grade 4-related adverse events (76% vs. 48%); nonfatal serious adverse events (33% vs. 13%) and adverse events leading to dose reductions (38% vs. 22%).
Dysgeusia, hypertension, thrombocytopenia, mucosal inflammation, palmar-plantar erythrodysesthesia syndrome and abdominal pain occurred at a significantly higher frequency in the sunitinib arm. Nausea and vomiting occurred at a significantly higher rate in the masitinib arm.
“An international phase 3 trial of masitinib in imatinib-resistant/intolerant patients with advanced GIST is in progress, the objectives of which are to reaffirm that masitinib has a superior safety profile to that of sunitinib in this population and also to confirm the observed survival benefits of administering masitinib in the second-line setting,” Adenis and colleagues wrote.
Disclosure: The study was sponsored by AB Science. The researchers report consultant or advisory roles with, research funding or honoraria from, expert testimony for and other remuneration from AB Science, Bayer, GlaxoSmithKline, Novartis, Pharmamar and Pfizer.
Perspective
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Charles D. Blanke, MD, FACP, FASCO
Imatinib has “ruled the roost” in front-line treatment of GIST since its first use in March 2000. Sunitinib, approved in 2006 for salvage treatment and in patients intolerant of imatinib, also has had a relatively privileged position, with few real challengers. Adenis and colleagues recently published a small, open-label, randomized phase 2 trial of masitinib — a highly selective tyrosine kinase inhibitor — vs. sunitinib in imatinib-resistant patients. The “noncomparative” primary analysis showed modest PFS for masitinib (3.71 months), with a nonsurprising OS benefit for those given masitinib followed by sunitinib vs. those randomly assigned sunitinib and who were not allowed by protocol to then get masitinib. Also not surprising, masitinib was better tolerated than sunitinib, the latter being given on its more toxic high-dose interrupted schedule.
Three drugs are commonly used in patients with advanced GIST — imatinib, sunitinib and regorafenib (Stivarga, Bayer). It is gratifying to see more candidates emerge. Although the current study does not prove masitinib should ascend to second-line status, it does show activity for that agent, with use in a variety of potential settings currently being analyzed.
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