Full results from the phase 3 INVICTUS trial show stable progression-free survival advantage and improved overall survival with ripretinib in patients with an advanced gastrointestinal stromal tumor.
Ripretinib (Qinlock) treatment in patients with advanced gastrointestinal stromal tumor (GIST) showed a stable median progression-free survival (PFS) with no change since the primary analysis of the INVICTUS study as well as an improvement in the median overall survival (OS), according to a presentation given during the 2021 Connect Tissue Oncology Society Virtual Annual Meeting.
“These more mature data continued to support the clinically meaningful benefits in progression-free and overall survival for ripretinib with an acceptable safety profile in patients with advanced GIST,” said Robin L. Jones, BSc, MSSS, MD, a medical oncologist at The Royal Marsden NHS Foundation Trust and Institute of Cancer Research in London, England.
INVICTUS is a phase 3, interventional, double-blind, placebo-controlled trial (NCT03353753) during which ripretinib was compared with placebo. Patients were randomized 2:1 to receive either ripretinib 150 mg once daily for 28-day cycles or a matching placebo. For select patients, the dose of ripretinib was escalated to 150 mg twice daily and in the placebo arm, crossover to the ripretinib am was permitted in the case of disease progression.
The primary end point of the study was PFS per modified RECIST based on blinded independent committee review. The key secondary end points were objective response rate (ORR) and OS. To assess the efficacy of ripretinib, patients were stratified by the number of prior therapies they had received (3 vs ≥ 4), and ECOG performance status of 0 versus 1 or 2.
Baseline characteristics showed that in the overall population of 129 patients, the median age was 60 years (range, 20-83) with 61% of patients being between the ages of 18 and 64 and only 14% being aged 75 years or older. There was a good balance of male patients (57%) and female patients (43%).
The majority of patients in the study had an ECOG performance status of 1 or 2 (58%), and most had 3 prior lines of therapy (63%). In terms of primary mutation based on central testing, 58% of the population had a KIT exon 11 mutations, and KIT exon 9 mutations were the second most common, having been found in 16% of patients.
According to the Kaplan-Meier analysis of PFS in the intent-to-treat (ITT) population of 85 patients in the ripretinib arm versus 44 in the placebo arm, the median PFS was 6.3 months (95% CI, 4.6-8.1) versus 1.0 months (95% CI, 0.9-1.7), respectively (HR, 0.16; 95% CI, 0.10-0.27).
There were 84 PFS events in both arms and data were censored for 17% of the ripretinib arm versus 16% of the placebo arm. At 6 months, the PFS rate was 51.0% (95% CI, 39.4%-61.4%) with ripretinib versus 3.2% (95% CI, 0.2%-13.8%) with placebo. At the 12-month time point, ripretinib achieved a PFS rate of 22.2% (95% CI, 13.4%-32.4%), and the 12-month PFS rate was not evaluable (NE) for the placebo arm (95% CI, NE-NE). Finally, at 18 months, the PFS rate was 11.8% (95% CI, 5.6%-20.6%) in the ripretinib arm compared with NE in the placebo arm (95% CI, NE-NE).
The median OS observed was 18.2 months (95% CI, 13.1-30.7) in the ripretinib arm compared with 6.3 months (95% CI, 4.1-10.0) in the placebo arm. Notably, those who crossover to ripretinib after progressing during placebo had a median OS of 10.0 months (95% CI, 6.3-20.9).
OS events occurred in 54% of the ripretinib arm versus 82% of the placebo arm, and data were censored for 46% of patients versus 18%, respectively.
At the 6-month mark, the OS rate was 84.3% (95% CI, 64.5%-90.6%) with ripretinib versus 55.9% (95% CI, 39.9%-69.2%) with placebo. The 12-month OS rate was 65.1% (95% CI, 53.6%-74.5%) with ripretinib versus 29.7% (95% CI, 16.8%-43.7%) with the control group.
OS rates were also calculated at months 18 and 24. At the 18-month timepoint, the OS rate was 50.1% (95% CI, 38.5%-60.7%) in the ripretinib arm compared with 29.7% (95% CI, 16.8%-43.7%) with placebo. At 24 months, patients treated with ripretinib had an OS rate of 42.8% (95% CI, 31.5%-53.7%) versus 19.8% (95% CI, 9.4%-33.0%) in the placebo arm.
The ORR observed with ripretinib in INVICTUS was 11.8% (95% CI, 5.8%-20.6%) compared with 0% in the placebo arm (95% CI, 0.0%-8.0%). The median duration of response with ripretinib was 14.5% (95% CI, 3.7-NE) compared with NE (95% CI, NE-NE) in the placebo arm.
Compared with baseline measurements of the tumors, treatment with ripretinib showed a reduction in tumor size of more than 30%.
During the double-blind period of the study, treatment-emergent adverse events (TEAEs) occurred in ≥ 15% of patients. The TEAEs were grade 3 or 4 in severity in > 4% of patients.The most common TEAE of any grade observed in the ripretinib-treated group were alopecia (52%), fatigue (47%), nausea (41%), and abdominal pain (40%). Grade 3/4 TEAEs seen with ripretinib were most commonly dry skin (11%) and hypertension (7%).
“This is consistent with the primary analysis of the trial and confirms the favorable side effect profile of ripretinib. The additional grade 3/4 for treatment-emergent adverse events included 4% of patients with hypophosphatemia and lipase increase,” noted Jones.
Jones RL. Paper 10 - ripretinib as ≥4th-line treatment in patients with advanced gastrointestinal stromal tumor: long-term update from the phase 3 INVICTUS study. Presented at 2021 CTOS Virtual Annual Meeting. November 10–13, 2021; virtual.