Ripretinib Shows Preliminary Activity and Safety in Advanced Sarcoma

Article

Ripretinib demonstrated promising antitumor activity and was found to be well tolerated in patients with refractory advanced gastrointestinal stromal tumor.

Ripretinib (Qinlock) demonstrated promising antitumor activity and was found to be well tolerated in patients with refractory advanced gastrointestinal stromal tumor (GIST), according to findings from a phase 1 study (NCT02571036) that were published in the Journal of Clinical Oncology.1

At a data cutoff date of August 31, 2019, the confirmed objective response rate was 11.3% (n = 16/142) and ranged from 7.2% (n = 6/83) in patients who had received at least 4 prior lines of therapy to 19.4% (n = 6/31) in patients who had received 1 prior line of therapy. The investigator-assessed median progression-free survival ranged from 5.5 months to 10.7 months, respectively.

“Our study results support the further development of ripretinib as an active and well-tolerated therapy in advanced GIST in the second-, third-, and fourth-line or greater [settings]...,” the study authors wrote.

In advanced GIST, there is an unmet need for therapies that target primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.

“Treatments against a broad range of KIT/PDGFRA mutations in advanced GIST are needed. Efficacy for second-line sunitinib [Sutent] and third-line regorafenib [Stivarga] are minimal and avapritinib [Ayvakit] is limited to GIST with PDGFRA exon 18 mutations,” wrote the study authors.

On May 15, 2020, the FDA approved ripretinib for the fourth-line treatment of patients with advanced GIST. Ripretinib is specifically indicated for adult patients who have received prior treatment with 3 or more kinase inhibitors, including imatinib (Gleevec).2

The approval is based on findings from the phase 3 INVICTUS trial, in which the investigational broad-spectrum KIT and PDGFRα inhibitor ripretinib led to an 85% reduction in the risk of disease progression or death compared with placebo in heavily pretreated patients with advanced GIST.3

The first-in-human, phase I study consisted of a dose-escalation phase and a subsequent dose-expansion phase at the recommended phase 2 dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on 1 or more lines of systemic therapy, and other advanced malignancies.

Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated.

As of the data cutoff date, 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported, including grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). The MTD was not reached, with a maximum dose evaluation of 200 mg twice a day, and 150 mg once daily was established as the RP2D.

Regarding safety, the most frequent treatment-emergent adverse effects in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88; 62.0%), fatigue (n = 78; 54.9%), myalgia (n = 69; 48.6%), nausea (n = 65; 45.8%), palmar-plantar erythrodysesthesia (n = 62; 43.7%), constipation (n = 56; 39.4%), decreased appetite (n = 48; 33.8%), and diarrhea (n = 47; 33.1%).

References

  1. Janku F, Abdul Razak AR, Chi P, et al. Switch control inhibition of KIT and PDGFRA in patients with advanced gastrointestinal stromal tumor: a phase I study of ripretinib [published online ahead of print August 17, 2020]. J Clin Oncol. 2020. doi:10.1200/JCO.20.00522
  2. FDA approves first drug for fourth-line treatment of advanced gastrointestinal stromal tumors. May 15, 2020. Accessed August 19, 2020. https://bit.ly/3bHqmQo
  3. 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(5 suppl):LBA87. doi:10.1093/annonc/mdz394.087
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