Ripretinib Continues to Demonstrate Benefit in Advanced GIST

An updated analysis of the phase III INVICTUS trial showed improved survival in patients with advanced gastrointestinal stromal tumors (GIST) treated with ripretinib (Qinlock) as later-line therapy, a researcher reported.

At 19 months after the primary analysis, median progression-free survival (PFS) with the fourth- or later-line therapy remained stable, at 6.3 months with ripretinib versus 1 month with placebo (HR 0.16, 95% CI 0.10-0.27), according to Robin Jones, MBBS, MD, of the Royal Marsden NHS Foundation Trust and Institute of Cancer Research in London.

However, median overall survival (OS) in the ripretinib arm was 18.2 months compared with 6.3 months in the placebo arm, an improvement compared to the primary analysis (15.1 vs 6.6 months), he said at the Connective Tissue Oncology Society (CTOS) virtual meeting.

Ripretinib is a switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits mutant KIT and PDGFRA kinase signaling. The drug was recently approved based on results of INVICTUS.

“These more mature data continue to support the clinically meaningful benefit in PFS and OS for ripretinib with an acceptable safety profile in patients with advanced GIST previously treated with three or more TKIs,” Jones noted.

In INVICTUS, a total of 129 patients with advanced GIST previously treated with at least imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga) were randomized 2:1 to ripretinib 150 mg once daily or placebo. If disease progressed in the placebo group, patients were given the opportunity to cross over to treatment with ripretinib.

Other findings from the study (previously presented at the European Society for Medical Oncology congress in September) were the following:

• The 6-month PFS rate was 51.0% for patients in the ripretinib group versus 3.2% for those on placebo

• PFS rates at 12 and 18 months were 22.2% and 11.8%, respectively, with ripretinib (not evaluable in the placebo arm)

• The response rate was 11.8% with ripretinib (median duration 14.5 months) compared with 0% with placebo

Landmark OS analyses showed the following for the ripretinib group versus placebo group, respectively:

• 6-month: 84.3% vs 55.9%
• 12 months: 65.1% vs 29.7%
• 18 months: 50.1% vs 29.7%
• 24 months: 42.8% vs 19.8%

Median OS among patients who crossed over to ripretinib was 10.0 months.

Treatment-emergent adverse events “were consistent with the primary analysis of the trial and [confirm] the favorable side effect profile of ripretinib,” Jones reported.

Considering the poor survival rates within the placebo arm, “is it still ethical to use a placebo arm or should we abandon it?” asked CTOS Program Chair Winan van Houdt, MD, PhD, of The Netherlands Cancer Institute in Amsterdam, during a question-and-answer period after the presentation.

“The curve of the placebo arm dramatically dropped in this trial,” commented Javier Martin-Broto, MD, PhD, of Fundacion Jimenez Diaz University Hospital in Madrid, Spain. “So I think, at least in the fourth line, it is not a good idea to offer placebo.”

“Based on these data I would not support another trial with a placebo arm,” Jones said. “One of the comments in the [virtual meeting chat room] was that we need to find better ways to design trials, and I would agree with that.”

Jason Sicklick, MD, of Moores Cancer Center at the University of California San Diego Health, who served as session chair, noted that the treatment algorithm for patients with advanced GIST includes imatinib, sunitinib, and regorafenib as first-, second-, and third-line therapies, as well as ripretinib in the fourth line, raising the question about next steps. “Where do we go from here?”

“I think combination therapy and [personalized] therapy are definitely the way forward,” Jones responded.