Ripretinib extends survival when all else fails in advanced GIST

Last Updated: 2020-07-03

By Reuters Staff

NEW YORK (Reuters Health) - Treatment with oral ripretinib significantly prolonged survival in patients with advanced gastrointestinal stromal tumors (GIST) who did not respond or were intolerant to three other tyrosine-kinase inhibitors in the INVICTUS study.

The phase-3 study led the U.S. Food and Drug Administration (FDA) to approve ripretinib in May as fourth-line treatment for advanced GIST. Deciphera Pharmaceuticals, which markets ripretinib as Qinlock, funded the research.

The multicenter, randomized, double-blind, placebo-controlled trial enrolled 129 patients with advanced GIST whose disease progressed on at least imatinib, sunitinib and regorafenib or who were in tolerant to any of these drugs despite dose modifications.

Eighty-five patients received ripretinib (150 mg) and 44 received placebo once a day in 28-day cycles until disease progression or intolerable toxicity.

Median progression-free survival, the primary endpoint, was longer in the ripretinib arm than in the placebo group (6.3 months vs. 1.0 month; hazard ratio 0.15; P<0.0001). At the data cutoff date of May 31, 2019, 51 (60%) patients receiving ripretinib and 37 (84%) patients receiving placebo had disease progression or had died.

Eight (9.4%) patients in the ripretinib arm had a confirmed objective response (all partial) versus none of the patients in the placebo arm, although the difference failed to reach statistical significance.

Median overall survival was 15.1 months with ripretinib versus 6.6 months with placebo. "To our knowledge, ripretinib is the first agent to show an improvement in progression-free survival of such magnitude and a median overall survival above 15 months in this patient population," write Dr. Jean-Yves Blay of Centre Leon Berard, in Lyon, France, and colleagues in The Lancet Oncology.

"Notably, 29 (66%) of 44 patients in the placebo group crossed over to ripretinib at time of progression, and thus the improvement in overall survival could potentially be underestimated," they say.

Ripretinib was "generally well tolerated and associated with acceptable safety profile," they report.

The most common adverse events (>=20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome and vomiting.

The authors of an accompanying comment point out that ripretinib in the fourth-line shows "similar or better safety compared with other TKIs with a similar mode of action, has similar oncological activities to sunitinib in the second-line, and appears to be better than regorafenib in the third-line in terms of progression-free survival and objective response rate."

They also note that most patients who responded had durable responses. "These results might suggest that ripretinib could have greater and longer-lasting responses compared with other TKIs and, consequently, might be more effective in earlier treatment lines, which should be further investigated," write Dr. Toshirou Nishida of the National Cancer Center Hospital, in Tokyo, and Dr. Toshihiko Doi of the National Cancer Center Hospital East, in Chiba.

Finally, they say it will be critical to explore biomarkers to pinpoint which patients might benefit from ripretinib. "Active monitoring of biomarkers (e.g., by liquid biopsy) could help to identify the right medicine for the right patient at the right time and might improve the prognosis of patients with gastrointestinal stromal tumors."

Several of the INVICTUS study authors disclosed financial relationships with Deciphera Pharmaceuticals.

SOURCE: https://bit.ly/3fEPjxU and https://bit.ly/2YKN3P7 Lancet Oncology, online June 5, 2020.