Ripretinib Safer Than Sunitinib for Advanced GIST, but Fails to Improve PFS

Sharon Worcester

January 27, 2022

The multitargeted tyrosine kinase inhibitor ripretinib (Qinlock) showed comparable efficacy and less toxicity compared with sunitinib (Sutent), but failed to improve progression-free survival (PFS), a phase 3 trial of adults with advanced gastrointestinal stromal tumors (GIST) suggests.

In the randomized open-label study, researchers found PFS was virtually the same for all patients receiving ripretinib (8.0 months) vs sunitinib (8.3 months). On the toxicity front, however, the ripretinib group fared notably better overall, experiencing fewer grade 3 or 4 treatment-emergent adverse events compared with those in the sunitinib arm (41.3% vs 65.6%, respectively).

"While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib," patients treated with ripretinib after imatinib failure did experience less toxicity, according to lead author Michael C. Heinrich, MD, Oregon Health & Science University, who presented the results of the INTRIGUE trial January 25 at the American Society of Clinical Oncology Plenary Series. The study was simultaneously published in the Journal of Clinical Oncology.

So, "what should we conclude from the INTRIGUE study?" asked invited discussant George D. Demetri, MD, director of the Sarcoma Center at Dana-Farber Cancer Institute, Boston. "Well, I conclude that ripretinib is still a very good drug with excellent tolerability and reasonably good activity against advanced GIST, regardless of KIT mutational status."

The study also demonstrates that sunitinib remains "a very good drug with very good activity against advanced GIST" as well, despite "some annoying yet manageable" toxicities, added Demetri, also senior VP for experimental therapeutics at Dana-Farber and a professor at Harvard Medical School. However, he added, given the limited PFS benefits, patients can still benefit from the development of other drugs.

An "Intriguing Failure"?

Despite progress in treating GIST, "some patients don’t respond to treatment and their tumors continue to progress," according to a 2020 FDA press release announcing the approval of ripretinib as a fourth-line treatment.

For instance, most patients with advanced GIST who receive imatinib (Gleevec) will eventually experience tumor progression, Heinrich said.

Given encouraging PFS findings associated with ripretinib, Heinrich and colleagues wanted to see how ripretinib would stand up to sunitinib in a head-to-head comparison.

The study included 453 adults with advanced GIST randomized 1:1 to receive 150 mg of ripretinib daily (n = 226) or 50 mg of sunitinib daily (n = 227) on a 4 weeks on/2 weeks off schedule. A subgroup with KIT exon 11 mutations included 163 patients in the ripretinib arm and 164 in the sunitinib arm, and another subgroup with KIT exon 9 mutations included 31 patients in the ripretinib arm and 29 in the sunitinib arm.

The researchers found that, ultimately, ripretinib failed to meet the primary endpoint of superior PFS compared with sunitinib. PFS was 8.0 months in the ripretinib group and 8.3 months in the sunitinib arm (hazard ratio [HR], 1.05;
P = .72).

In the subgroup analyses of patients with KIT aberrations, those with exon 11 mutations who received ripretinib had a slightly longer PFS (8.3 vs 7.0 months, respectively) but the results were not significant (HR, 0.88; P = .36). However, those with exon 9 primary mutations who received sunitinib had a notably better PFS (13.8 vs 5.5 months, respectively; HR, 2.85)

The overall objective response rate was similar in both groups (21.7% for ripretinib vs 17.6% for sunitinib; P = .27), but higher for ripretinib in the intention-to-treat KIT exon 11 patient subgroup (23.9% vs 14.6%; P = .03). The overall median duration of response was slightly higher in the sunitinib arm (20.1 vs 16.7 months).

Median overall survival was not reached in either group.

Ripretinib was generally well tolerated, and the safety profile was consistent with existing prescribing information, Heinrich said.

Dose modifications occurred in 38% of patients in the ripretinib arm vs 63% in the sunitinib group, and dose reductions occurred in about 20% of the ripretinib group vs 50% for those on sunitinib.

Almost all patients in both treatment arms experienced at least one treatment-emergent adverse event (TEAE), but those receiving ripretinib had fewer grade 3/4 TEAEs (41.3% vs 65.6%), and also experienced fewer grade 3/4
drug-related TEAEs with ripretinib (26.5% vs. 55.2%).

The most common adverse events in the ripretinib arm were alopecia and fatigue, occurring in 64.1% and 37.7% of patients, respectively. In the sunitinib arm, the most common adverse events were palmar-plantar erythrodysesthesia and diarrhea, occurring in 51.1% and 48% of patients, respectively.

Patients receiving ripretinib were three times less likely to experience grade 3/4 hypertension (8.5% vs 26.7%), and nearly 8 times less likely to experience grade 3/4 palmar-plantar erythrodysesthesia (1.3% vs 10.0%).

Demetri called the INTRIGUE trial an "intriguing failure" — a "very well-designed, expertly conducted clinical trial" that also underscores the need for more effective agents that can move the needle on survival endpoints.

"We will need non–cross-resistant, highly selective agents that can be combined together with optimal pharmacology and good long-term tolerability," Demetri said.

The INTRIGUE trial is funded by Deciphera Pharmaceuticals, LLC. Heinrich reported honoraria from Novartis and consulting or advisory roles for Blueprint Medicines, Deciphera, Novartis, and Theseus Pharmaceuticals. Demetri is a member of the board of directors and scientific advisory board for Blueprint Medicines, and has minor equity holdings in the company, which developed a treatment (avapritinib) for GIST. He is also a consultant and advisory board member for several other pharmaceutical companies and organizations, including Medscape.

ASCO Plenary Series: January 2022 Session: Abstract 359881.
Presented January 25, 2022. 
J Clin Oncol. Published online January 25, 2022. Abstract

Sharon Worcester is an award-winning medical journalist at MDedge News, part of the Medscape Professional Network.

For more from Medscape Oncology, join us on Twitter and Facebook


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.