Ripretinib Shows Antitumor Activity in Fourth-Line KIT/PDGFRA-Mutated Advanced GIST

Ripretinib (Qinlock) demonstrated clinically meaningful activity in patients with fourth-line or later advanced gastrointestinal stromal tumor (GIST) and several, heterogeneous genetic subsets of KIT/PDGFRA mutations, according to results from an exploratory analysis of the phase 3 INVICTUS trial (NCT03353753) presented during the 2020 Connective Tissue Oncology Society (CTOS) Virtual Meeting.¹

Results showed that the investigational broad-spectrum KIT and PDGFRα inhibitor improved progression-free survival (PFS) in all primary mutation subgroups analyzed versus placebo. Among the patients whose tumors harbored KIT exon 11 mutations, 55.3% received ripretinib and 63.6% with placebo; the hazard ratio [HR] for PFS was (0.15; 95% CI, 0.08-0.29). In those who harbored KIT exon 9 mutations, 16.5% received ripretinib and 13.6% received placebo; in this subgroup, the HR for PFS was 0.22 (95% CI, 0.07-0.69).

Moreover, in the subgroup of patients whose baseline primary mutation information was not available, 14.1% of patients were given ripretinib and 11.4% received placebo; here, the HR for PFS was 0.13 (95% CI, 0.02-0.66). Lastly, among those with other mutations, 14.1% and 11.4% of patients received ripretinib and placebo, respectively, and the HR for PFS was 0.38 (95% CI, 0.11-1.37).

“These results demonstrate that ripretinib can inhibit a broad spectrum of KIT/PDGFRA mutations in patients with advanced GIST who have received prior treatment with 3 or more kinas inhibitors, including imatinib,” Patrick Schöffski, MD, MPH, of Catholic University Leuven, and colleagues, wrote in a poster highlighting the data.

Ripretinib, a switch-control TKI that was developed to inhibit mutant KIT/PDGFRA kinases, was approved by the FDA in May 2020 for use as a fourth-line treatment in patients with advanced GIST; it was specifically indicated for adult patients who received prior treatment with 3 or more kinase inhibitor therapies, including imatinib (Gleevec).

The regulatory decision was based on data from INVICTUS, where the agent resulted in an 85% reduction in the risk of disease progression or death versus placebo in heavily pretreated patients with advanced GIST.2The median PFS with ripretinib was 6.3 months versus 1.0 months with placebo (HR, 0.15; 95% CI, 0.09-0.25; P <.0001). Ripretinib also demonstrated a substantial improvement in overall survival (OS) compared with placebo, at 15.1 months versus 6.6 months, respectively (HR, 0.36; 95% CI, 0.20-0.63; P =.0004).

In the double-blind, placebo-controlled phase 3 INVICTUS trial, participants were randomized 2:1 to receive either ripretinib at 150 mg once daily (n = 85) or placebo (n = 44) after having received treatment with imatinib, sunitinib (Sutent), or regorafenib (Stivarga). Stratification factors included previous treatments (3 vs 4 or more lines) and ECOG performance status (0 vs 1 or 2). Patients received treatment until progressive disease per blinded independent central review (BICR).

In the open-label period, patients in the investigational arm went on to dose escalate ripretinib to 150 mg twice daily, to continue ripretinib at 150 mg once daily, or to discontinue treatment. Those in the control arm would either cross over to ripretinib and receive 150 mg once daily or to discontinue treatment. They continued this until they experienced progressive disease. At that point, they either dose escalated ripretinib to 150 mg twice daily, continued to receive ripretinib at 150 mg once daily, or discontinued treatment.

Among the 85 patients in the ripretinib arm, 55.3% (n = 47) had tumors that harbored KIT exon 11 mutations, 16.5% (n = 14) harbored KIT exon 9 mutations, 14.1% (n =12), did not have any information available, and 14.1% (n = 12) had other mutations, such as KIT/PDGFRA wild-type (n = 7), PDGFRA (n = 3), and KIT other exon (n = 2).

Among the 44 patients in the placebo arm, 63.6% (n = 38) had tumors that harbored KIT exon 11 mutations, 13.6% (n = 6) had KIT exon 9 mutations, 11.4% (n = 5) did not have this information available, and 11.4% (n = 5) had other mutations like KIT/PDGFRA wild-type (n = 3) or KIT other exon (n = 2).

The primary end point of the trial was PFS per modified RECIST criteria based on BICR, while key secondary end points comprised objective response rate (ORR) per BICR and OS.

Tumor biopsies were collected after patients received their last anticancer treatment before study entry. These biopsies were sequenced using a next-generation sequencing panel from FoundationOne. Moreover, plasma circulating tumor DNA were collected before the dose administered on day 1 of cycle 1; this was profiled using the Guardant360 next-generation sequencing liquid biopsy assay.

Investigators identified primary mutation subgroups and KIT/PDGFRA wild-type status via the tumor biopsies. Secondary mutation subgroups were identified by combining information from the tumor and liquid biopsies. Associations between KIT/PDGFRA mutation status and outcomes from the trial were also evaluated. Notably, the retrospective analysis was not part of the trial protocol. The data cutoff for the analysis presented during the meeting was March 9, 2020.

Additional results showed that the median PFS was 5.7 months with ripretinib in patients with KIT/PDFGRAwild-type disease versus 2.1 months with placebo.

In the KIT mutation analysis by combined tumor and liquid biopsy, participants were put into 4 subsets: any KIT exon 9, any KIT exon 11, any KIT exon 13, and any KIT exon 17 mutation. If they had mutations in 2 or more exons, they were included in several groups. A patient with a primary mutation in exon 11 and a secondary mutation in exon 17 would fall into the any KIT exon 11 subset and the any KIT exon 17 subset. Results from this analysis revealed that patients who received ripretinib experienced a PFS benefit compared with placebo in all subgroups evaluated.

When looking at secondary mutations in patients, investigators noted that among 86 patients whose tumors harbored KIT exon 11 mutations, 39.5% (n = 34) also had exon 17 mutations, 29.1% (n = 25) also had exon 13 and 17 mutations, 15.1% (n = 13) also had exon 13 only mutations, and 16.3% (n = 14) had other mutations. In the subgroup of 23 patients with KIT exon 9 mutations, 47.8% (n = 11) also had exon 17 mutations and 52.2% (n = 12) also had exon 9 only mutations.

When investigators combined tumor and liquid biopsies, several secondary resistance mutations were detected versus conventional tumor-based mutational analysis. The combined analysis permitted the identification of resistance mutations in 73% of patients. Specifically, these resistance alterations were identified in up to 4 exons within a single patient.

Results showed that the HRs of PFS within the mutation subsets were all reported to favor ripretinib.

“These results support the proposed broad mechanism of action of ripretinib with its specific receptor binding properties,” the authors concluded.

References

1. Schöffski P, Bauer S, Heinrich M, et al. Ripretinib demonstrated activity across all KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: analysis from the phase 3 INVICTUS study. Presented at: 2020 CTOS Virtual Meeting; November 18-21, 2020; Virtual. https://bit.ly/3fmC1Y6.
2. van Mehren M, Serrano C, Bauer S, et al. INVICTUS: a phase 3, international, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as >4th line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol. 2019;30(suppl 5):LBA87. doi:10.1093/annonc/mdz394.087