An ‘Intriguing Failure’ in Advanced, Pre-Treated GIST

Ripretinib (Qinlock) as second-line therapy for advanced gastrointestinal stromal tumors (GIST) was not significantly better than sunitinib (Sutent), according to results from the INTRIGUE trial.

In the phase III study, median progression-free survival (PFS) with ripretinib was numerically longer than with sunitinib for patients whose tumors harbored primary KIT exon 11 mutation (8.3 vs 7.0 months), but this difference failed to reach statistical significance (HR 0.88, 95% CI 0.66-1.16, P=0.36), reported Michael Heinrich, MD, of the Oregon Health & Science University Knight Cancer Institute in Portland.

Ripretinib also was unable to demonstrate superior PFS in the study’s intent-to-treat population (median 8.0 vs 8.3 months, respectively; HR 1.05, 95% CI 0.82-1.33, P=0.72), he said in a presentation at the American Society of Clinical Oncology (ASCO) Virtual Plenary session.

ASCO-designated discussant 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 GIST, regardless of KIT mutational status, and for that reason this drug will stay on the market as a late-line GIST drug approved by the FDA,” Demetri said. “We also know — and we’ve learned more from this INTRIGUE study — that sunitinib is still a very good drug with very good activity against advanced GIST, but with some annoying, yet manageable toxicities.”

“GIST will likely need other agents to make more significant advances in treatment outcomes for patients,” he added. “We will need non-cross-resistant, highly selective agents that can be combined together with optimal pharmacology and good, long-term tolerability.”

While sunitinib is approved for patients with advanced GIST after the failure of imatinib (Gleevec), Heinrich pointed out that ripretinib has demonstrated superior in vitro activity to sunitinib against imatinib-resistant secondary KIT mutations. Ripretinib is indicated for the treatment of adults with advanced GIST who have been treated with three or more tyrosine kinase inhibitors (TKIs), including imatinib. In a phase I study, the broad-spectrum KIT and platelet-derived growth factor receptor alpha (PDGFRA) switch-control TKI turned in a median PFS of 10.7 months for patients who received it as second-line therapy.

In INTRIGUE, 453 patients who either progressed on or were intolerant to first-line imatinib were randomized 1:1 to either ripretinib or sunitinib. The median age of the patients was 60, while most were white (66.2%), and male (62.0%). Of these patients, 72% harbored disease with a primary KIT exon 11 mutation.

Secondary endpoints included overall response rate (ORR) and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence, beginning with patients with a KIT exon 11 primary mutation, followed by the entire study population.

ORRs trended higher for ripretinib versus sunitinib, respectively:

• KIT exon 11 subgroup: 23.9% vs 14.6%
• Total population: 21.7% vs 17.6%

“Notably, both arms yielded higher objective response rates than had previously been reported in studies of second-line treatment, including second-line sunitinib treatment,” Heinrich observed.

The median duration of response was 16.7 months for ripretinib and 20.1 months for sunitinib for both study groups. OS data was “highly immature,” he stated.

Fewer patients in the ripretinib arm experienced grade 3/4 adverse events (AEs) versus sunitinib (41.3% vs 65.6%), including grade 3/4 hypertension (8.5% vs 26.7%), palmar-plantar erythrodysesthesia (1.3% vs 10.0%), neutropenia (0% vs 6.3%), and decreased neutrophil counts (0% vs 7.2%). There was one AE-related death in the sunitinib arm.

Heinrich noted that patients receiving ripretinib were less likely to need any dose modification compared with those receiving sunitinib (38.1% vs 63.3%).

Session moderator Vicki Keedy, MD, MSc, of Vanderbilt University Medical Center in Nashville, asked Heinrich about the prospect of using ripretinib, rather than sunitinib, considering the toxicity profiles of the two drugs.

Heinrich said that ideally he would discuss that 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 to choose superiority for a new drug over a drug that is going generic, is that you always have to consider cost and what is the value of a new drug,” he added. “We chose a pretty aggressive 50% improvement in PFS because we thought that was what would be clinically a game changer for patients and should move the regulators. We did not achieve that.”

However, “no one should come away from this thinking that ripretinib is not active against GIST,” Heinrich emphasized. “It definitely is in the fourth line. It definitely is in the second line. Right now it is only approved for the fourth line. We want to publish our full results and have ESMO [European Society for Medical Oncology] and NCCN [National Comprehensive Cancer Network] look at all of this, and let professional societies opine on the value of the drugs in the different lines of therapy. But I think we are a little bit stuck in that it was not a successful study from our superiority standpoint design.”