Ripretinib Demonstrates Clinical Benefit in KIT Exon 11, 17/18–Mutated Advanced GIST

Sebastian Bauer, MD

Second-line ripretinib (Qinlock) produced a clinical benefit in patients with advanced gastrointestinal stromal tumor (GIST) harboring KIT exon 11 and 17/18 mutations who progressed on or were intolerant to imatinib (Gleevec), according to a circulating tumor DNA (ctDNA) analysis from the phase 3 INTRIGUE trial (NCT03673501) presented during the 2023 January ASCO Plenary Series.¹

The ctDNA analysis also showed that patients with KIT exon 11 and 17/18 mutations did not derive a clinical benefit from sunitinib (Sutent). Conversely, patients with advanced GIST harboring KIT exon 11 and 13/14 mutations did experience a clinical benefit from sunitinib, but not ripretinib.

Findings showed that patients with KIT exon 11 and 17/18 mutations treated with ripretinib (n = 27) experienced a median progression-free survival (PFS) of 14.2 months (95% CI, 8.1-not estimable [NE]) compared with 1.5 months (95% CI, 1.4-4.2) for those treated with sunitinib (n = 25; HR, 0.22; 95% CI, 0.11-0.44; P < .0001).

However, patients with KIT exon 11 and 13/14 mutations given ripretinib (n = 21) had a median PFS of 4.0 months (95% CI, 1.5-7.1) compared with 15.0 months (95% CI, 5.6-NE) for those administered sunitinib (n = 20; HR, 3.94; 95% CI, 1.71-9.11; P = .0005).

“This is the largest global phase 3 trial in second-line, imatinib-resistant advanced GIST that demonstrates the significance of ctDNA next-generation sequencing–based analysis of the complex landscape of KIT mutations and correlates mutational status with treatment response,” lead study author Sebastian Bauer, MD, of the Department of Medical Oncology and Sarcoma Center/West German Cancer Center of University Hospital Essen in Essen, Germany, said in a presentation of the data.

Previously reported findings from the primary analysis of INTRIGUE showed that ripretinib was not superior to sunitinib regarding PFS in the intent-to-treat (ITT) population of patients with KIT exon 11 mutations or the overall ITT population.²

In the overall ITT population, those treated with ripretinib (n = 226) experienced a median PFS of 8.0 months compared with 8.3 months for those given sunitinib (n = 227; HR, 1.05; 95% CI, 0.82-1.33; nominal P = .72). In the KIT exon 11 mutation ITT population, the median PFS was 8.3 months for patients in the ripretinib arm (n = 163) vs 7.0 months for those in the sunitinib arm (n = 164; HR, 0.88; 95% CI, 0.66-1.16; P = .36).

INTRIGUE enrolled patients who were at least 18 years of age with a confirmed diagnosis of GIST who progressed on or had documented intolerance to imatinib. Patients were enrolled from 122 sites across North America, South America, Europe, Australia, and Asia.

Enrolled patients were randomly assigned in a 1:1 fashion to receive 150 mg of continuous ripretinib once daily or 50 mg of sunitinib once daily on a 4-week-on/2-weeks-off schedule. Stratification factors included KIT/PDGFRα mutation status and imatinib intolerance. Notably, no crossover was permitted between the arms.

PFS by independent radiologic review per mRECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included objective response rate (ORR) by independent radiologic review, safety, and patient-reported outcomes.

ctDNA was analyzed using the Guardant360^® assay. Among the 453 patients randomized during the trial, samples were received from 374 patients, and ctDNA was analyzed in 362 patients. ctDNA was detected in 280 patients. KIT mutations were detected in 213 patients, including 109 in the ripretinib arm and 104 in the sunitinib arm.

Additional data showed that among patients with KIT exon 11 and 17/18 mutations, those treated with ripretinib achieved a median overall survival (OS) that was NE (95% CI, 24.4-NE) compared with 17.5 months (95% CI, 7.9-30.9) for those given sunitinib (HR, 0.34; 95% CI, 0.15-0.76; P = .0061). For patients with KIT exon 11 and 13/14 mutations, ripretinib elicited a median OS of 24.5 months (95% CI, 13.5-NE) vs NE (95% CI, 19.5-NE) for sunitinib (HR, 1.75; 95% CI, 0.72-4.24; P = .2085).

Among patients with KIT exon 11 and 17/18 mutations, ripretinib produced an ORR of 44.4% (95% CI, 23.0%-62.7%) compared with 0% for sunitinib (nominal P = .0001). In patients with KIT exon 11 and 13/14 mutations, the ORR was 9.5% and 15.0% for ripretinib and sunitinib, respectively.

In patients with KIT exon 11 and 13/14 and 17/18 co-mutations, those treated with ripretinib (n = 11) experienced a median PFS of 8.1 months compared with 10.9 months for those treated with sunitinib (n = 11; HR, 1.07; 95% CI, 0.41-2.84). The ORR was 27.3% and 9.1% for ripretinib and sunitinib, respectively, in this population. The median OS was 14.7 months for ripretinib and 20.3 months for sunitinib (HR, 2.61; 95% CI, 0.95-7.19).

In the KIT exon 11 and 17/18 mutation population, 74% of patients in the ripretinib arm received follow-up anticancer therapy, including sunitinib (67%), regorafenib (26%), imatinib (3.7%), and other (11%). Additionally, 64% of those in the sunitinib arm were given follow-up anticancer therapy, including sunitinib (4%), regorafenib (48%), ripretinib (40%), and imatinib (4.0%).

Regarding safety, Bauer noted that ripretinib appeared to have a more favorable safety profile compared with sunitinib.

In the KIT exon 11 and 17/18 mutation population, 33% of patients in the ripretinib arm experienced grade 3/4 treatment-emergent adverse effects (TEAEs) compared with 50% in the sunitinib arm. Drug-related serious TEAEs were reported in 3.7% and 13% of the ripretinib and sunitinib arms, respectively.

Any-grade TEAEs occurring in at least 20% of patients with KIT exon 11 and 17/18 mutations included alopecia (78% vs 8.3% for ripretinib and sunitinib, respectively), constipation (52% vs 33%), fatigue (48% vs 38%), hypertension (33% vs 50%), palmar-plantar erythrodysesthesia syndrome (37% vs 42%), myalgia (44% vs 13%), abdominal pain (26% vs 33%), decreased appetite (26% vs 33%), diarrhea (22% vs 38%), nausea (26% vs 29%), pruritus (26% vs 17%), and muscle spasms (30% vs 8.3%).

The planned phase 3 INSIGHT trial will further evaluate the efficacy and safety of ripretinib compared with sunitinib in patients with advanced GIST harboring KIT exon 11 and 17/18 mutations who received prior treatment with imatinib. Patients will be randomly assigned in a 2:1 fashion to receive ripretinib or sunitinib in the same dosing regimens as INTRIGUE. Notably, patients in the sunitinib arm will be permitted to cross over to the ripretinib arm following disease progression.

In a discussion of the presentation, Breelyn A. Wilky, MD, of the University of Colorado, said that findings from the ctDNA analysis of INTRIGUE produced compelling evidence of the power of ctDNA to identify predictive biomarkers, which could allow for critical findings even in negative trials.

However, Wilky also noted that the sensitivity of ctDNA assays remains limited, and the currently available options could still be missing patients who could potentially benefit from a given treatment based on mutational status.

“In the INTRIGUE study, despite 77% of tested samples detecting ctDNA, KIT mutations were found in only 59%, and exon 11 plus secondary mutations [were found] in only 44% of the KIT-mutant patients. Similar observations were seen in the [phase 3] VOYAGER trial [NCT03465722],” Wilky said. “This suggests that the sensitivity of ctDNA with Guardant360 is still relatively low to detect underlying secondary mutations, and these data, which could be critical for treatment selection, may still be under captured.”

Editor’s note: Dr. Bauer has honoraria with Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKline, and Deciphera; a consulting or advisory role with Blueprint Medicines, Bayer, Lilly, Deciphera, Nanobiotix, Daiihi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, GlaxoSmithKline, Adcendo, and Boehringer Ingelheim; research funding from Blueprint Medicines, Novartis, and Incyte; and travel expenses from Pharmamar.

References

1. Bauer S, Jones RL, George S, et al. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE. J Clin Oncol. 2023;41(suppl 36):397784. doi:10.1200/JCO.2023.41.36_suppl.397784
2. Heinrich MC, Jones RL, Gelderblom H, et al. 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. J Clin Oncol. 2022;40(suppl 36):359881. doi:10.1200/JCO.2022.40.36_suppl.359881