Ripretinib demonstrated a significantly improved progression-free survival compared with placebo in patients with gastrointestinal stromal tumors being treated in the fourth-line setting or beyond, according to topline results from the phase III INVICTUS trial. An NDA for ripretinib is planned for the first quarter of 2020.
Margaret Von Mehren, MD
Ripretinib (DCC-2618) demonstrated a significantly improved progression-free survival (PFS) compared with placebo in patients with gastrointestinal stromal tumors (GIST) being treated in the fourth-line setting or beyond, according to topline results from the phase III INVICTUS trial.1
The broad-spectrum KIT and PDGFRα inhibitor induced a median PFS of 6.3 months compared with 1.0 month in the placebo arm (HR, 0.15;P<.0001), which represented a reduction in the risk of disease progression or death by 85% compared with placebo. This met the primary endpoint of the pivotal phase III trial.
Following these positive findings, Deciphera, the company developing the KIT/PDGFRα inhibitor plans to submit a new drug application to the FDA for ripretinib as a treatment for patients with advanced GIST who have received prior imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga) in the first quarter of 2020. Further findings from the phase III INVICTUS trial are expected to be presented at an upcoming medical meeting.
“Today’s announcement represents a significant milestone in our mission to deliver important new medicines for the treatment of cancer,” said Steve Hoerter, president and CEO of Deciphera, in a press release. “The data from INVICTUS reinforce our belief that ripretinib has the potential to transform the treatment of GIST, and our focus now turns to working closely with the FDA as they evaluate ripretinib for those patients with GIST who, having failed all currently approved therapies, are in desperate need of a treatment option.”
INVICTUS is a randomized, double-blind, placebo-controlled, international, multicenter phase III trial that is investigating the use of ripretinib compared with placebo in patients with advanced GIST who have received prior anticancer therapies (NCT03353753). The trial enrolled 129 patients who were randomized 2:1 to receive 150 mg daily of ripretinib or placebo.
Patients must have progressed on imatinib, sunitinib, and regorafenib among their prior therapies or be intolerant to any of these treatments. Additionally, the patients were required to have an ECOG performance status of 0 to 2, adequate organ function, and resolution of prior toxicities to manageable levels within 1 week of starting ripretinib.
Exclusion criteria included patients previously treated with ripretinib, those with additional malignancies requiring treatment within the past 3 years, class II-IV heart disease, arterial thrombotic or embolic events within the past 6 months, venous thrombotic events within the past 3 months, history of long QT interval corrected syndrome, left ventricular ejection fraction <50%, use of recent proton-pump inhibitors or breast cancer resistance protein transporters, major surgeries within 4 weeks of treatment, known hepatitis C infection or HIV, and gastrointestinal abnormalities.
The primary endpoint of the trial is PFS and secondary endpoints include objective response rate (ORR), time to tumor progression, overall survival (OS), quality of life, and disease control rate (DCR).
Topline results demonstrated that the ORR with ripretinib was 9.4% compared with 0% with placebo (P= .0504), which was not statistically significant. Although formal hypothesis testing was not performed for OS, the median OS was found to be 15.1 months versus 6.6 months with ripretinib and placebo, respectively (HR, 0.36;P= .0004). The OS data for the placebo arm also included patients who crossed over to receive ripretinib after progression.
“There is a dire unmet need for new therapies that can deliver effective disease control for patients with advanced GIST who have failed currently approved treatment options,” said investigator Margaret von Mehren, MD, of the Department of Medical Oncology, Fox Chase Cancer Center, in a statement. “These top-line data from a phase III, randomized, placebo-controlled study are highly impressive and suggest that ripretinib’s approach of targeting the broad spectrum of KIT and PDGFRα mutations known to drive GIST can significantly improve progression-free survival in the most heavily pretreated patients. Particularly notable is the magnitude of benefit observed for overall survival in this study.”
Of the 128 patients included in the safety analysis, any-grade treatment-emergent adverse events (TEAEs) were observed in 99% of patients in the ripretinib arm compared with 98% in the placebo arm; grade 3/4 TEAEs were reported in 49% and 44% of patients, respectively. The most common grade 3/4 TEAEs in the ripretinib arm was anemia (9%), abdominal pain (7%), and hypertension (7%). In the placebo arm, the most common grade 3/4 TEAE was anemia in 14%. These results were considered with the safety profile seen in the phase I study results.
Deciphera also announced updated findings from the phase I study of ripretinib in patients with previously treated GIST.2The ongoing open-label, first-in-human, dose-escalation phase I study is investigating the activity and safety of ripretinib in patients with advanced, refractory malignancies (NCT02571036). The study included a dose-escalation part and a dose-expansion part, with a particular focus on GIST.
Currently, 178 patients with advanced GIST have been treated with ripretinib at doses of ≥100 mg daily with cohorts representing each line of therapy from the second-line to beyond the fourth-line.
Findings from the phase I study were previously presented at the 2018 ESMO Annual Congress.3The recommended phase II dose for ripretinib was selected as 150 mg daily and intra-patient dose-escalation to 150 mg twice daily was permitted at progression.
Ripretinib induced prolonged PFS across all lines of treatment, including in patients who were escalated to receive twice daily treatment.
Patients receiving ripretinib in the second- or third-line setting demonstrated prolonged treatment duration if they tolerated treatment well, with 26 patients active more than 6 months and 6 active more than 1 year across both cohorts (n = 67).
The updated findings represent an extra 6 months of maturity from the last data cutoff.2
In the second-line cohort (n = 37), the ORR was 30%, with 22% of responses confirmed, and the DCR was 81% at 3 months. The median PFS was 42 weeks with 38% of patients censored with median PFS, and the median treatment duration was 44 weeks.
In the third-line cohort (n = 31), the ORR was 23% with 13% of responses confirmed, and the DCR was 80% at 3 months. The median PFS was 40 weeks with 32% of patients censored, and the median treatment duration was 48 weeks.
Of 60 patients in the fourth-line cohort, the ORR was 15% with 8% confirmed as responding and at 3 months the DCR was 73%. The median PFS was 30 weeks with 30% of patients censored, and the median treatment duration was 46 weeks.
Of the 110 patients treated in the fourth-line and beyond cohort, the ORR was 11% with 7% confirmed responses and a DCR of 66% at 3 months. The median PFS was 24 weeks with 22% of patients censored and the median treatment duration was 29 weeks.
Overall, 13% of patients discontinued treatment due to a TEAE, 17% required dose reduction, and 49% required drug interruption.
“In the updated data from the second-line cohort, we believe ripretinib has demonstrated encouraging clinical benefit based on the objective response rate, disease control rate and median progression free survival rates observed. These results strengthen our confidence in the INTRIGUE pivotal phase III clinical study comparing ripretinib to sunitinib, the standard of care for patients receiving second-line treatment for GIST,” Hoerter said in a press release.
The randomized, open-label, international, multicenter phase III INTRIGUE study has already begun to investigate ripretinib compared with sunitinib in patients with GIST who progressed on or were intolerant to first-line treatment with imatinib (NCT03673501). About 358 patients are expected to be enrolled and randomized 1:1 to either 150 mg daily of continuous ripretinib or 50 mg daily of sunitinib for 6 cycles of 4 weeks on and 2 weeks off.
The primary endpoint of the INTRIGUE study is PFS and secondary endpoints are ORR and OS.