Elsevier

The Lancet Oncology

Volume 21, Issue 7, July 2020, Pages 923-934
The Lancet Oncology

Articles
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(20)30168-6Get rights and content

Summary

Background

Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.

Methods

In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.

Findings

Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2–8·2) in the ripretinib group and 1·6 months (1·1–2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6–6·9) with ripretinib compared with 1·0 months (0·9–1·7) with placebo (hazard ratio 0·15, 95% CI 0·09–0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep).

Interpretation

Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments.

Funding

Deciphera Pharmaceuticals.

Introduction

Gastrointestinal stromal tumours most often harbour oncogenic mutations in receptor tyrosine kinase proto-oncogene, receptor tyrosine kinase (KIT), or platelet-derived growth factor receptor α (PDGFRA).1, 2 Standard treatment for patients with locally advanced metastatic gastrointestinal stromal tumours are KIT and PDGFRA-directed tyrosine-kinase inhibitors (TKIs).3, 4, 5 First-line treatment with imatinib for patients with advanced gastrointestinal stromal tumours results in response or tumour control in more than 80% of patients.2, 3 However, approximately 50% of patients with advanced gastrointestinal stromal tumours have progressive disease by 24 months and estimated 10-year progression-free survival is around 9%.3, 6, 7 Progressing metastases often harbour secondary mutations in the ATP-binding domain or activation loop of KIT, which represent a major mechanism of resistance to TKIs.8, 9, 10 Both sunitinib and regorafenib, approved for second-line (sunitinib) and third-line (regorafenib) treatment for advanced gastrointestinal stromal tumours, inhibit some of these resistance mutations,11, 12 but neither drug covers the full spectrum of possible mutations,12, 13 yielding a median progression-free survival of 5·6 months for sunitinib and 4·8 months for regorafenib.4, 14, 15, 16 Avapritinib is only approved for gastrointestinal stromal tumours with PDGFRA exon 18 mutations, which account for approximately 6% of the overall population of patients with gastrointestinal stromal tumours.17, 18, 19

Research in context

Evidence before this study

We searched PubMed for articles published in English between January 1, 2005, and January 1, 2020, using the terms “gastrointestinal stromal tumor” or “GIST” combined with “KIT” or “PDGFRA”. Data from studies show that approved TKIs do not fully cover these secondary resistance mutations, leading to suboptimal efficacy results for progression-free survival and overall survival with second-line and third-line therapies. Patients who had disease progression on approved TKIs (ie, imatinib, sunitinib, regorafenib, or avapritinib [avapritinib is only approved for gastrointestinal stromal tumours with PDGFRA exon 18 mutations]) had no other approved treatment options, creating a high unmet clinical need.

Added value of this study

Our study results showed efficacy of ripretinib as a fourth or further line therapy in patients with advanced gastrointestinal stromal tumours, in terms of a significant improvement in median progression-free survival compared with the group receiving placebo. To our knowledge, ripretinib is the first agent to show an improvement in progression-free survival of such magnitude and a median overall survival above 15 months in this patient population. Ripretinib was also generally well tolerated and associated with an acceptable safety profile.

Implications of all the available evidence

Our results showed the clinical activity of ripretinib as fourth-line (or further line) therapy in patients with advanced gastrointestinal stromal tumours. In May, 2020, the US Food and Drug Administration approved ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumours who have received previous treatment with three or more kinase inhibitors, including imatinib.

Ripretinib (DCC-2618) is a switch-control TKI that broadly inhibits KIT and PDGFRA kinase signalling through a dual mechanism of action.20 Ripretinib specifically and durably binds to both the switch pocket and the activation loop to lock the kinase in the inactive state, preventing downstream signalling and cell proliferation. This dual mechanism of action provides broad inhibition of KIT and PDGFRA kinase activity, including for wild-type KIT and PDGFRA mutations and multiple primary and secondary mutations associated with drug-resistant gastrointestinal stromal tumours.

In in-vitro enzyme assays, ripretinib inhibited platelet-derived growth factor receptor β (PDGFRB), angiopoietin-1 receptor (TIE2), vascular endothelial growth factor receptor 2 (VEGFR2), and serine and threonine-protein kinase B-raf (BRAF), among other kinases.20

A first-in-human, phase 1 study in patients with gastrointestinal stromal tumours or other advanced solid tumours determined the recommended phase 2 dose of ripretinib as 150 mg once daily, which was associated with a favourable tolerability profile and was active in patients with advanced gastrointestinal stromal tumours that were refractory to multiple previous TKIs. Notably, doses of ripretinib 150 mg twice daily were well tolerated without clinically meaningful dose-limiting side-effects.21 In this phase 3 INVICTUS study, we aimed to evaluate the safety and efficacy of ripretinib as fourth-line therapy (or further-line therapy) versus placebo in patients with advanced gastrointestinal stromal tumours.

Section snippets

Study design and participants

INVICTUS is a double-blind, randomised, placebo-controlled, phase 3 study done at 29 specialised hospitals in 12 countries across North America, Europe, and Asia (appendix p 1).

Key inclusion criteria were patients aged 18 years or older with a diagnosis of gastrointestinal stromal tumour with at least one measurable lesion according to modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1). The mRECIST modifications followed those described by Demetri and colleagues,15

Results

Between Feb 27, 2018 and Nov 16, 2018, 154 patients were assessed for eligibility, of whom 129 were randomly assigned to either the ripretinib group (n=85) or the placebo group (n=44; figure 1). Baseline characteristics are in table 1. At the data cutoff (May 31, 2019), the median follow-up time in the double-blind period was 6·3 months (IQR 3·2–8·2) for the ripretinib group and 1·6 months (1·1–2·7) for the placebo group. The median relative dose intensity in the double-blind period was 100%

Discussion

Results of the INVICTUS study showed that ripretinib as fourth-line (or further line) therapy for patients with advanced gastrointestinal stromal tumours significantly improved median progression-free survival compared with placebo. Patients were stratified by ECOG performance status and number of previous therapies, which are known prognostic variables. The difference in the objective response rate between the groups was not significant; however, the median overall survival seemed to be

Data sharing

Deciphera will share the redacted INVICTUS study protocol online. Qualified scientific and medical researchers can make requests for individual participant data that underlie the results reported in this Article, after de-identification, at [email protected]. Proposals for data will be evaluated and approved by Deciphera in its sole discretion. All approved researchers must sign a data access agreement before accessing the data. Data will be available as soon as possible but no later than

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