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

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

ctDNA analysis also showed that patients with KIT exon 11 and 17/18 mutations did not result in clinical benefit from sunitinib (Sutent). On the other hand, patients with advanced GIST harboring KIT exon 11 and 13/14 mutations showed a clinical benefit from sunitinib but not from ripretinib.

The results 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 administered with 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 with sunitinib (n = 20; HR, 3.94; 95% CI, 1.71-9.11; P = 0.0005).

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

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

In the general ITT population, those treated with ripretinib (n = 226) had a median PFS of 8.0 months compared with 8.3 months for those receiving sunitinib (n = 227; HR, 1.05; 95% CI, 0.82-1.33; nominal value P = 0.72). At the KIT exon 11 mutation ITT population, the median PFS was 8.3 months for patients in the ripretinib arm (n = 163) versus 7.0 months for those in the sunitinib arm (n = 164; HR, 0.88; 95% CI, 0.66-1.16; P = 0.36).

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

Enrolled patients were randomized in a 1:1 ratio to receive continuous ripretinib 150 mg once daily or sunitinib 50 mg once daily on a 4-week on/2-week off schedule. Stratification factors included KIT/PDGFRα mutation status and intolerance to imatinib. Notably, no crosses were allowed between the arms.

PFS by independent radiology review according to mRECIST v1.1 criteria served as the study’s primary endpoint. Secondary endpoints included objective response rate (ORR) by independent radiology review, safety, and patient-reported outcomes.

The ctDNA was analyzed using Guardant360® test. Among the 453 patients randomized during the study, 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 receiving sunitinib (HR, 0.34, 95% CI, 0.15-0.76; P = 0.0061). For patients with KIT exon 11 and 13/14 mutations, ripretinib caused 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 = 0.2085).

Among patients with KIT exon 11 and 17/18 mutations, ripretinib produced an ORR of 44.4% (95% CI, 23.0%-62.7%) compared to 0% for sunitinib (nominal P = 0.0001). In patients with KIT exon 11 and 13/14, 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 switches, 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).

At 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 others (11%). In addition, 64% of people in the sunitinib arm received follow-up antineoplastic treatment, 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 to sunitinib.

At 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 to 50% in the sunitinib arm. Serious drug-related TEAEs were reported in 3.7% and 13% of the ripretinib and sunitinib arms, respectively.

TEAEs of any grade 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 erythrodysaesthesia 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%), itching (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 to sunitinib in patients with advanced GIST KIT exon 11 and 17/18 mutations who received prior treatment with imatinib. Patients will be randomly assigned in a 2:1 ratio to receive either ripretinib or sunitinib on the same INTRIGUE dosing regimens. Notably, patients on the sunitinib arm will be able to move to the ripretinib arm after disease progression.

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

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

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

Editor’s Note: The Doctor. Bauer has fees from Novartis, Pfizer, Bayer, Pharmamar, GlaxoSmithKline and Deciphera; a consulting or advisory role at 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 Pharmamar travel expenses.

References

  1. Bauer S, Jones RL, George S, et al. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib versus sunitinib in patients with gastrointestinal stromal tumor: INTRIGUE ctDNA analysis. 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 randomized, open-label, phase III 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
Ripretinib Shows Clinical Benefit in Exon 11, 17/18 – Mutated Advanced GIST KIT

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