Article

Ripretinib Shows Dramatic PFS Improvement for Heavily Pretreated GIST

Author(s):

Treatment with the novel KIT and PDGFRA inhibitor ripretinib reduced the risk of progression or death by 85% compared with placebo for heavily pretreated patients with advanced gastrointestinal stromal tumors, according to findings from the phase III INVICTUS trial presented at the ESMO Congress 2019.

Margaret von Mehren, MD

Margaret von Mehren, MD

Margaret von Mehren, MD

Treatment with the novel KIT and PDGFRA inhibitor ripretinib reduced the risk of progression or death by 85% compared with placebo for heavily pretreated patients with advanced gastrointestinal stromal tumors (GIST), according to findings from the phase III INVICTUS trial presented at the ESMO Congress 2019.

In the double-blind study, the median progression-free survival (PFS) was 6.3 months with ripretinib compared with 1.0 months for placebo (HR, 0.15; 95% CI, 0.09-0.25; P <.0001). Additionally, there was a 64% reduction in the risk of death with ripretinib compared with placebo, which was a secondary endpoint. The median overall survival was 15.1 versus 6.6 months for ripretinib and placebo, respectively (HR, 0.36; 95% CI, 0.20-0.63; P = .0004). However, the hierarchical testing procedures utilized for the study prevented a conclusive establishment of statistical significance for OS.

"Ripretinib represents a potential new standard of care with broad activity in fourth-line GIST, a patient population with advanced refractory disease and no other approved options," said lead investigator Margaret von Mehren, MD, from the Fox Chase Cancer Center. “The OS data are clinically meaningful. Patients with disease progression on placebo were allowed to cross over to receive ripretinib. Patients who crossover had a substantial benefit in OS compared with those who did not and experienced rapid deterioration.”

Primary mutations in KIT and PDGFRA drive GIST in approximately 85% of cases, according to von Mehren. At this time, there are no currently FDA-approved therapies available in the fourth-line setting following imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga). Ripretinib works as a switch-control inhibitor of KIT and PDGFRA at the juxtamembrane domain (JMD) and the main activation loop switch. The agent restores the inhibitory JMD switch, which is often deactivated in GIST, and helps to stabilize the kinase in an inactive state.

The INVICTUS trial randomized patients in a 2:1 ratio to receive ripretinib at 150 mg daily (n = 85) or placebo (n = 44). The study was designed to assess open label ripretinib beyond progression but findings for this arm were not presented during EMSO. The median age of patients was 60 years, with more aged 75 or more in the placebo group (9% for ripretinib versus 23% for placebo). Two-thirds of patients had received 3 prior therapies, and a third had received more than 4 (range, 4-7). The most common mutation was at KIT exon 11 (58%) followed by KIT exon 9 (16%).

The objective response rate with ripretinib was 9.4% compared with no responses in the placebo group (P = .0504). These findings were not statistically significant, which impacted the ability to effectively test the significant of OS data, given the design of the INVICTUS statistical analysis. The median duration of response had not yet been reached, with 7 of 8 patients continuing to response at the time of the data cutoff of May 31, 2019.

The 6-month PFS rate was 51.0% (95% CI, 39.4%-61.4%) for the novel targeted therapy compared with 3.2% for placebo (95% CI, 0.2%-13.8%). PFS benefit was observed across all assessed patient subgroups. In those treated with 3 therapies, the HR for PFS was 0.15, in favor of ripretinib (95% CI, 0.08-0.29). In those treated with ≥4 therapies, the HR was 0.24 in favor of the switch kinase inhibitor (95% CI, 0.12-0.51).

The 6-month OS rate with ripretinib was 84.3% (95% CI, 74.5%-90.6%) compared with 55.9% for placebo (95% CI, 39.9%-69.2%). The 12-month OS rate was 65.4% for ripretinib (95% CI, 51.6%-76.1%) compared with 25.9% for placebo (95% CI, 7.2%-49.9%). A further analysis of OS was added to adjust for crossover. For this, the median in the placebo arm without crossover was 1.8 months compared with 11.6 months for those who crossed over to the investigational arm.

All-grade treatment-emergent adverse events (TEAEs), regardless of causality, were experienced by 98.8% of patients in the ripretinib arm compared with 97.7% with placebo. Treatment-emergent grade 3/4 adverse events, regardless of cause, were experienced by 49.4% of patients in the ripretinib group compared with 44.2% for placebo.

The most common all-grade TEAEs in the ripretinib and placebo groups, respectively, were alopecia (51.8% vs 4.7%), fatigue (42.4% vs 23.3%), nausea (38.8% vs 11.6%), abdominal pain (36.5% vs 30.2%), constipation (34.1% vs 18.6%), and myalgia (31.8% vs 11.6%). The most common grade 3/4 TEAEs between the ripretinib arm and the placebo group, respectively, were anemia (9.4% vs 14%), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).

TEAEs led to a dose reduction for 7.1% of patients in the ripretinib group versus 2.3% for the placebo arm. Treatment discontinuations due to TEAEs was required for 8.2% of patients in the investigational group versus 11.6% for the placebo arm. There were more TEAEs in the placebo arm than the ripretinib group (5.9% vs 23.3%).

“Ripretinib, a novel switch-control inhibitor, improves PFS and very likely also overall survival in a GIST patient population whose tumor has progressed on all 3 standard therapeutic agents," said ESMO discussant Heikki Joensuu, MD, PhD, from the Comprehensive Cancer Center Helsinki. "The current findings are likely practice changing."

Enrollment is currently ongoing in the phase III randomized INTRIGUE study, which is looking at ripretinib, formally DCC-2618, versus sunitinib for patients with GIST following prior imatinib. The second-line study plans to recruit 358 patients with advanced GIST and has an estimated completion date of June 2021 (NCT03673501).

"Results from the ongoing INTRIGUE trial that compares ripretinib with sunitinib as the second-line treatment of advanced GIST are awaited with much interest," said Joensuu. "Switch control inhibitors of tyrosine kinases other than KIT/PDGFRA seem an interesting field for further drug development. The current results are further good news to GIST patients."

Based on data from the INVICTUS trial, Deciphera, the manufacturer of ripretinib, plans to submit a new drug application to the FDA in the first quarter of 2020. The application will be for the treatment of patients with advanced GIST who previously received imatinib, sunitinib, and regorafenib.

van Mehren M, Attia S, 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). Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA87.

<<< View more from the 2019 ESMO Congress

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