Ripretinib fails to improve PFS in advanced gastrointestinal stromal tumor
Click Here to Manage Email Alerts
Ripretinib did not extend PFS compared with sunitinib for patients with advanced gastrointestinal stromal tumor who previously received imatinib, according to randomized phase 3 study results presented during the ASCO Plenary Series.
The two agents conferred comparable median PFS; however, researchers reported a higher overall response rate with ripretinib (Qinrock, Deciphera Pharmaceuticals) among patients with KIT exon 11 primary mutations.
Ripretinib also exhibited a more favorable safety profile, according to researcher Michael C. Heinrich, MD, professor of medicine at Oregon Health & Science University.
“[Consequently], ripretinib may provide meaningful clinical benefit to patients with advanced [gastrointestinal stromal tumor] previously treated with imatinib,” Heinrich said.
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Most patients have activating mutations in KIT (70% to 85%) or platelet-derived growth factor receptor alpha (PDGFRA; 5% to 10%) that drive tumor growth, according to study background.
Most patients with advanced GIST who receive imatinib — a KIT/PDGFRA tyrosine kinase inhibitor — achieve objective response or maintain stable disease, with median PFS of approximately 18 months to 20 months.
“However, over time, most imatinib-treated patients will experience tumor progression due to the development of secondary kinase domain mutations,” Heinrich said during his presentation.
Sunitinib malate (Sutent, Pfizer) —a multitargeted TKI that inhibits KIT, PDGFRA and VEGFR — is approved in the United States for treatment of patients with advanced GIST who failed imatinib, leading to median PFS of about 5.6 months.
Ripretinib is a broad-spectrum KIT and PDGFRA switch-control TKI that demonstrated superior activity to sunitinib in vitro against imatinib-resistant secondary KIT mutations. The agent is approved in the United States for treatment of adults with advanced GIST who underwent prior treatment with at least three TKIs, including imatinib.
Heinrich and colleagues conducted the open-label INTRIGUE study to compare ripretinib with sunitinib for treatment of adults with advanced GIST who experienced disease progression on or had documented intolerance to imatinib.
Researchers enrolled 453 patients from 122 sites in North America, Europe, Asia, Australia and South America.
Researchers randomly assigned 226 patients to ripretinib dosed at 150 mg daily on a continuous schedule. The other 227 patients received sunitinib 50 mg daily in a 4-weeks-on, 2-weeks-off schedule. Study design did not allow for crossover.
Treatment groups appeared well-balanced for age (median, 59.5 years vs. 60 years), sex (male, 61.5% vs. 62.6%), race (white, 65.5% vs. 67%), ECOG performance status (1 or 2, 98.7% vs. 99.6%) and presence of KIT exon 11 mutations (72.1% vs. 72.2%).
PFS in the KIT exon 11 mutation-positive subgroup and in the entire study population served as the primary endpoint. Secondary endpoints included ORR and OS, time to tumor response, quality of life, disease control rate and safety.
At data cutoff, 117 patients (ripretinib, n = 65; sunitinib (n = 52) remained on treatment.
The most common reasons for treatment discontinuation included progressive disease by independent radiologic review or investigator assessment, clinical progression and withdrawal of consent.
Analysis of PFS by independent radiologic review showed no significant differences between ripretinib and sunitinib among patients with KIT exon 11 mutations (8.3 months vs. 7 months; HR = 0.88; 95% CI, 0.66-1.16) or in the intention-to-treat (ITT) population (8 months vs. 8.3 months; HR = 1.05; 95% CI, 0.82-1.33).
Due to the study’s hierarchal statistical testing plan, because ripretinib did not confer a statistically significant PFS benefit compared with sunitinib in the KIT exon 11 ITT population, no further statistical testing could be performed.
Subgroup analysis of PFS by independent radiologic review showed no clear difference between treatment groups with the exception of KIT exon 9-mutated GIST, for whom sunitinib appeared to confer a PFS benefit (median, 5.5 months for ripretinib vs. 13.8 months for sunitinib; HR = 2.85; 95% CI, 1.48-5.48).
Results showed a significantly higher ORR with ripretinib in the KIT exon 11 mutation-positive group (23.9% vs. 14.6%; difference, 9.3%; 95% CI, 0.7-17.8) but not in the entire patient population (21.7% vs. 17.6%; difference, 4.2%; 95% CI, –3.2 to 11.5%).
Sunitinib-treated patients achieved longer median duration of response (20.1 months vs. 16.7 months).
Patients assigned sunitinib more often required dose reduction (50.2% vs. 19.7%) or dose interruption (38% vs. 27.8%).
Almost all patients experienced a treatment-emergent adverse event (99.1% for both ripretinib and sunitinib). However, more patients assigned sunitinib experienced grade 3 or grade 4 treatment-emergent adverse events (65.6% vs. 41.3%) or grade 3/grade 4 drug-related treatment-emergent adverse events (55.2% vs. 26.5%).
The safety profile of ripretinib appeared consistent with its prescribing information, Heinrich said. The most common any-grade treatment-emergent adverse events in this group included alopecia (64.1%) and fatigue (37.7%). The most common any-grade treatment-emergent adverse event in the sunitinib group included palmar-plantar erythrodysesthesia syndrome (51.1%) and hypertension (47.1%).
Incidence of nearly all grade 3/grade 4 treatment-emergent adverse events were lower with ripretinib than sunitinib. Patients assigned sunitinib appeared nearly three times more likely than those assigned ripretinib to develop grade 3 hypertension and nearly seven times more likely to develop grade 3 palmar-plantar erythrodysesthesia syndrome.
Perspective
Back to Top
George D. Demetri, MD, FACP, FASCO
Patients with metastatic GIST benefit greatly from current TKI therapies, but we should aim to improve outcomes further. Our patients need better treatments to prevent the emergence of resistance to TKI therapy. There is still a strong rationale to treat earlier in the course of GIST to prevent new mutational variants from arising or proliferating. We understand the molecular biology of this disease quite well, and GIST — even in its very advanced state — retains a very strong dependence upon abnormal KIT signaling.
INTRIGUE was an aspirational, very well-designed and expertly conducted clinical trial. It points out that drug development is hard, even when a cancer is as well-understood and relatively simplistic as GIST. It is difficult to show superiority over an existing approved therapy with any targeted therapy.
INTRIGUE failed to show that ripretinib was superior to sunitinib for control of metastatic GIST after imatinib failed. We essentially see the same control of disease, with very similar PFS with both drugs. Researchers reported less toxicity with ripretinib than sunitinib. For patients, that is very good, but toxicity was not the primary endpoint of the trial so, at the end of the day, this trial was an “intriguing” failure.
This trial also raises an important question: Why do precision cancer medicines so often fail to live up to expectations? Why do they fail to cure?
There are several reasons. We know resistant cancers — even those driven by a dominant driver of mutant oncogenes — will develop other mutational variants over time to avoid control of the selection pressure by the TKI. Also, our trials often overestimate drug activity from very limited signals in preclinical assays and, more importantly, in early phase 1 trial experience. We know the patient population at academic centers in early phase 1 trials simply is not reflective of the broader population that enters phase 3 trials or those we see in routine clinical practice. We also know single drugs may not be able to overcome genomic instability and the heterogeneity that we see in the evolution of even the most simple cancers.
So what should we conclude from INTRIGUE?
Ripretinib is still a very good drug with excellent tolerability and reasonably good activity against advanced GIST, regardless of KIT mutational status.
We also learned that sunitinib is still a very good drug, with very good activity against advanced GIST, but with some annoying yet manageable toxicities, even when used via an outdated dose schedule from 2006 that was used in the INTRIGUE trial for regulatory reasons but is not commonly used for patients with GIST. We usually use the lower dose with continuous dosing schedule. Patients tolerate it better and it controls the kinase perfectly well.
We also know GIST likely will need other agents to make more significant advances in treatment outcomes for patients. We’ll need noncross-resistant, highly selective agents that can be combined with optimal pharmacology and long-term tolerability. Finally, we need to use all of our available agents as rationally as possible to care for patients with GIST.
This trial adds significantly to our evidence base of both ripretinib and sunitinib, and the investigators, participants and study sponsor should be thanked for contributing to knowledge in this way, even though technically it was a failed study. It has given us a lot on which to build evidence to help treat our patients. Discussions with patients can now include thoughtful discussions of this trial and the data and the pros and cons and the tolerability issues. Future research initiatives will benefit from this work to make more progress. This was not a failure to move our field forward.
Harvard Medical School
Collapse
Heinrich, MC. INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib. Presented at: ASCO Plenary Series; Jan. 25, 2022.
Click Here to Manage Email Alerts