Updated Data Demonstrate Continued PFS and OS Benefit With Ripretinib in Advanced GIST

The novel broad-spectrum KIT and PDGFRα inhibitor ripretinib (Qinlock) continued to demonstrate clinically meaningful benefit as a fourth- or later-line treatment for patients with advanced gastrointestinal stromal tumors (GIST), according to updated findings from the randomized phase 3 INVICTUS trial that were presented during the 2020 ESMO Virtual Congress.¹

The updated results showed that the median progression-free survival (PFS) was 6.3 months with ripretinib (95% CI, 4.6-8.1) versus 1.0 month with placebo (95% CI, 0.9-1.7; HR, 0.16; 95% CI, 0.1-0.27).

Moreover, 77.6% of patients who received ripretinib (n = 85) had a PFS event compared with 84.1% of patients who received placebo (n = 44). Additionally, 22.4% of patients were censored for PFS in the ripretinib arm compared with 15.9% in the placebo arm.

On May 15, 2020, the FDA approved ripretinib for the fourth-line treatment of patients with advanced GIST based on initial findings from the INVICTUS study.^2,3 The indication is specifically for patients who had received prior treatment with 3 or more kinase inhibitor therapies, including imatinib.

Previously reported PFS findings showed that, in the ripretinib arm, the 6-month PFS rate was 51.0% (95% CI, 39.4%-61.4%), the 12-month PFS rate was 23.6% (95% CI, 14.6%-34.0%), and the 18-month PFS rate was 12.6% (95% CI, 6.0%-21.9%). In the placebo arm, the 6-month PFS rate was 3.2% (95% CI, 0.2%-13.8%); the 12- and 18-month PFS rates were not evaluable (NE).

Notably, the PFS benefit with ripretinib was observed across all assessed patient subgroups, including age, gender, race, country, ECOG performance status, and number of prior systemic anticancer treatments.

“There are a number of options [for patients with advanced GIST],” said John Zalcberg, ​PhD, OAM, lead study author and head of the Cancer Research Program at Monash University, in an interview with OncLive®. “We can provide patients hope that as they progress through the use of imatinib [Gleevec], sunitinib [Sutent], and regorafenib [Stivarga], that there is another agent that could provide them substantial benefit and [good] quality of life.”

In INVICTUS, patients were randomized 2:1 to receive 150 mg of ripretinib once daily in 28-day cycles or placebo.

Eligible patients had advanced GIST and were previously treated with imatinib, sunitinib, and regorafenib.

Upon radiographic disease progression by blinded independent central review/unblinding, patients in the ripretinib arm went on to receive ripretinib (150 mg) twice daily, continue on ripretinib once daily, or discontinue treatment.

In the placebo arm, patients who progressed either crossed over to receive 150 mg of ripretinib once daily or discontinued treatment. Upon further progression in the placebo arm, patients went on to receive ripretinib twice daily, continue on ripretinib once daily, or discontinue treatment.

Additional findings revealed that, with 9 months of additional follow-up, the median overall survival (OS) extended from 15.3 months to not reached. The median OS was not reached with ripretinib (95% CI, 13.1–NE) versus 6.3 months with placebo (95% CI, 4.1-10.0; HR, 0.42; 95% CI, 0.26-0.67).

Previous data in the ripretinib arm showed OS rates of 84.3% at 6 months (95% CI, 74.5%-90.6%), 65.1% at 12 months (95% CI, 53.6%-74.5%), 53.0% at 18 months (95% CI, 41.3%-63.3%), and 50.6% at 24 months (95% CI, 38.5%-61.4%). Comparatively, the OS rates in the placebo arm were 55.9% (95% CI, 39.9%-69.2%), 29.7% (95% CI, 16.8%-43.7%), 29.7% (95% CI, 16.8%-43.7%), and NE, respectively.

Regarding OS, 44.7% of patients who received ripretinib experienced an OS event versus 70.5% of patients who received placebo. Furthermore, 55.3% of patients and 29.5% of patients were censored for OS, respectively.

Additionally, the overall response rate was 11.8% with ripretinib (95% CI, 5.8%-20.6%) versus 0% with placebo (95% CI, 0.0%-8.0%). The median duration of response was 14.5 months (95% CI, 3.7-NE) and NE (95% CI, NE-NE), respectively.

The toxicity profile of ripretinib was consistent with previous primary analysis results. Moreover, with 9 additional months of follow-up, the findings showed few new TEAEs leading to dose modifications or death.

Common treatment-emergent adverse effects (TEAEs) that occurred in more than 15% of patients included alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, decreased appetite, diarrhea, palmer-plantar erythrodysesthesia syndrome, vomiting, headache, weight decrease, arthralgia, muscle spasms, peripheral edema, increased blood bilirubin, anemia, dry skin, and hypertension.

“As you can see from this list of adverse effects, these are the types of events that are seen with many tyrosine kinase inhibitors, particularly those used in GIST,” said Zalcberg in a virtual presentation of the data.

Grade 3/4 TEAEs among evaluable patients treated with ripretinib (n = 85) included fatigue (n = 3), nausea (n = 3), abdominal pain (n = 6), constipation (n = 1), myalgia (n = 2), decreased appetite (n = 1), diarrhea (n = 1), vomiting (n = 3), peripheral edema (n = 1), increased blood bilirubin (n = 1), anemia (n = 9), and hypertension (n = 6). Comparatively, grade 3/4 TEAEs observed in evaluable patients treated with placebo (n = 43) included fatigue (n = 1), abdominal pain (n = 2), decreased appetite (n = 2), diarrhea (n = 1), and anemia (n = 6).

In the ripretinib arm, 8.2% of patients required a dose reduction due to TEAEs versus 2.3% of patients in the placebo arm. Moreover, 26% and 21% of patients required dose interruptions due to TEAEs, respectively.

Seven patients who received ripretinib (8.2%) discontinued treatment due to TEAEs compared with 5 patients who received placebo (12%). Finally, 6 patients experienced a fatal TEAE in the ripretinib arm versus 10 patients in the placebo arm. One death in each arm was considered possibly related to the blinded study drug.

The randomized, multicenter, interventional phase 3 INTRIGUE study is currently enrolling, evaluating ripretinib versus sunitinib in the second-line setting for patients with advanced GIST who received prior treatment with imatinib.

“INTRIGUE in an important study because it brings ripretinib forward in the earlier management of advanced GIST,” Zalcberg said. “The question of what happens next is a good one, and many people will be thinking about where to place ripretinib [in the sequence of treatment for patients with advanced GIST].”

References

1. Zalcberg J, Heinrich M, George S, et al. Clinical benefit with ripretinib as ≥4th line treatment in patients with advanced gastrointestinal stromal tumors (GIST): update from the phase 3 INVICTUS study. Presented at: 2020 ESMO Virtual Congress. September 19-21, 2020. Abstract 1622MO.
2. FDA grants full approval of Deciphera Pharmaceuticals’ QINLOCK (ripretinib) for the treatment of fourth-line gastrointestinal stromal tumor. May 15, 2020. Accessed September 18, 2020. https://yhoo.it/2LvkWNo.
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(suppl 5):LBA87. doi:10.1093/annonc/mdz394.087