According to the results of the INTRIGUE trial, ripretinib (Qinlock) as a second-line treatment for advanced gastrointestinal stromal tumors (GIST) was not significantly better than sunitinib (Sutent).
In the phase III study, the median progression-free survival (PFS) with ripretinib was numerically longer than with sunitinib for patients whose tumors harbored CASE exon 11 mutation (8.3 vs 7.0 months), but this difference did not reach statistical significance (HR 0.88, 95% CI 0.66-1.16, P=0.36), reported Michael Heinrich, MD, of Oregon Health & Science University Knight Cancer Institute in Portland.
Ripretinib was also unable to demonstrate superior PFS in the intention-to-treat study population (median 8.0 versus 8.3 months, respectively; HR 1.05, 95% CI 0.82-1.33, P=0.72), he said during a presentation at the virtual plenary session of the American Society of Clinical Oncology (ASCO).
ASCO-designated commentator George Demetri, MD, of the Dana-Farber Cancer Institute in Boston, called the trial an “intriguing failure.”
“Ripretinib is still a very good drug, with excellent tolerability and reasonably good activity against advanced GISTs regardless of the CASE mutation status, and for this reason, this drug will remain on the market as an FDA-cleared end-of-line GIST drug,” Demetri said. “We also know – and learned more from this INTRIGUE study – that sunitinib is still a very good drug with very good activity against advanced GISTs, but with some troublesome, but manageable toxicities.”
“GIST will likely need other agents to make more significant progress in treatment outcomes for patients,” he added. “We will need highly selective, non-cross-resistant agents that can be combined with optimal pharmacology and good long-term tolerance.”
While sunitinib is approved for patients with advanced GIST after failure of imatinib (Gleevec), Heinrich pointed out that ripretinib demonstrated superior in vitro activity to sunitinib against drug-resistant side effects. imatinib. CASE changes. Ripretinib is indicated for the treatment of adults with advanced GIST who have been treated with at least three tyrosine kinase (TKI) inhibitors, including imatinib. In a phase I study, the broad-spectrum control TKI of KIT and platelet-derived growth factor receptor alpha (PDGFRA) generated a median PFS of 10.7 months for patients who received it as treatment second line.
In the INTRIGUE study, 453 patients who progressed or were intolerant to first-line imatinib were randomized 1:1 to receive either ripretinib or sunitinib. The median age of patients was 60 years, while most were Caucasian (66.2%) and male (62.0%). Of these patients, 72% presented with disease with CASE exon 11 mutation.
Secondary endpoints included overall response rate (ORR) and overall survival (OS). Hierarchical tests were performed for the primary and secondary endpoints in a predefined sequence, starting with patients with a CASE primary mutation of exon 11, followed by the entire study population.
ORRs tended to be higher for ripretinib compared to sunitinib, respectively:
- CASE exon 11 subgroup: 23.9% vs 14.6%
- Total population: 21.7% versus 17.6%
“Notably, both arms yielded higher objective response rates than previously reported in studies of second-line treatment, including second-line treatment with sunitinib,” Heinrich observed.
The median duration of response was 16.7 months for ripretinib and 20.1 months for sunitinib for both study groups. The operating system data was “very immature”, he said.
Fewer patients in the ripretinib arm experienced Grade 3/4 adverse reactions (AEs) compared to sunitinib (41.3% versus 65.6%), including Grade 3/4 hypertension (8.5% versus 26.7%), palmar-plantar erythrodysaesthesia (1.3% versus 10.0%), neutropenia (0% versus 6.3%) and decreased neutrophil count (0% versus 7.2%). There was one AE-related death in the sunitinib arm.
Heinrich noted that patients receiving ripretinib were less likely to need a dose modification compared to those receiving sunitinib (38.1% versus 63.3%).
Session moderator Vicki Keedy, MD, MSc, of Vanderbilt University Medical Center in Nashville, asked Heinrich about the possibility of using ripretinib rather than sunitinib, given the toxicity profiles of both drugs.
Heinrich said ideally he would discuss this option with patients to see what their preferences were. But “we are subject to regulators and third-party payers,” he said.
“And one of the reasons for choosing the superiority of a new drug over a generic drug is that you always have to consider the cost and the value of a new drug,” he added. . “We chose a fairly aggressive 50% improvement in PFS because we thought that was the clinical game-changer for patients and should move regulators. We didn’t get there.”
However, “no one should walk away from this thought that ripretinib is not active against GISTs,” Heinrich pointed out. “He’s definitely fourth line. He’s definitely second line. At the moment he’s only approved for fourth line. We want to post our full results and ask ESMO [European Society for Medical Oncology] and NCCN [National Comprehensive Cancer Network] look at all of this and let the professional societies decide on the value of drugs in different lines of therapy. But I think we’re kind of stuck in the fact that it wasn’t a successful study of our design from a superiority perspective.”
The study was funded by Deciphera Pharmaceuticals.
Heinrich disclosed relationships with Novartis, Blueprint Medicines, Deciphera, and Theseus Pharmaceuticals, as well as patients on Novartis-licensed (institutional) GIST treatment.
Demetri disclosed his relationships with Blueprint Medicines, Bayer, Pfizer, Novartis, Roche/Genentech, GlaxoSmithKline, Janssen, PharmaMar, Daiichi-Sankyo, EMD-Serono/Merck KGaA, Medscape, Mirati, Synlogic, WCG/Arsenal Capital, MJ Hennessy/ OncLive, C4 Therapeutics, McCann Health and Rain Therapeutics, as well as a royalty from Novartis to Dana-Farber for the “use patent” of imatinib in GIST.