Encouraging efficacy data for ripretinib as a later-line therapy for patients with advanced gastrointestinal stromal tumor have investigators hypothesizing new approaches to derive even greater benefit with the agent.
Encouraging efficacy data for ripretinib (Qinlock) as a later-line therapy for patients with advanced gastrointestinal stromal tumor (GIST) have investigators hypothesizing new approaches to derive even greater benefit with the agent. Some approaches include moving the therapy forward in the treatment landscape and administering at a higher dose for patients who progress on treatment, according to Gina Z. D’Amato, MD.
Ripretinib is a tyrosine kinase inhibitor (TKI) that broadly hinders KIT- and PDGFRA mutated kinases through a dual mechanism of action that controls the kinase switch pocket and activation loop. Specifically, the agent inhibits both primary and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18 that are involved in GIST. The switch- control TKI also impedes primary PDGFRA mutations in exons 12, 14, and 18.1,2
The FDA approved ripretinib in May 2020 as the first therapy specifically approved for the fourth-line treatment of patients with GIST. Data from the phase 3 INVICTUS trial (NCT03353753) showed that the agent demonstrated a statistically significant improvement in progression-free survival (PFS) compared with placebo (HR, 0.15; 95% CI, 0.09-0.25; P < .0001).1
The study enrolled 129 patients previously treated with 3 or more prior TKIs, including imatinib (Gleevec). In an updated analysis of the trial presented at the Connective Tissue Oncology Society (CTOS) 2020 virtual meeting in November, investigators noted that ripretinib continued to demonstrated a clinically meaningful benefit as well as a tolerable safety profile (Table).3 Specifically, patients randomized to ripretinib (n = 85) had a median PFS of 6.3 months (95% CI, 4.6-8.1) vs 1.0 month (95% CI, 0.9-1.7) for patients who received placebo (n = 44), with an HR of 0.16 (95% CI, 0.1-0.27). The objective response rate was 11.8% compared with 0%, respectively.
TABLE. Updated Efficacy Data for Ripretinib vs Placebo in Heavily Pretreated Patients With GIST3
With an additional 9 months follow-up from the primary analysis, investigators reported the median for overall survival (OS) for patients randomized to ripretinib extended from 15.1 months to not reached (95% CI, 13.1-not evaluable). The median OS in the placebo group was 6.3 months (95% CI, 4.1-10.0); the HR was 0.42 (95% CI, 0.26-0.67).3
In October, the National Comprehensive Cancer Network expert panel added ripretinib to the treatment guidelines for GIST as the preferred selection in fourth line (Figure).4 The guidelines also recommend switching to ripretinib in fifth line for patients with a performance score of 0 to 2 following widespread, systemic progression following regorafenib (Stivarga).4
Figure. NCCN Preferred Systemic Agents for Unresectable GIST With Significant Morbidity4
The current recommended dose of ripretinib is 150 mg orally once daily, but there is clinical evidence that patients could benefit from increasing to 300 mg per day following progression, explained D’Amato, an associate professor and assistant director of clinical research with the University of Miami Sylvester Comprehensive Cancer Center in Florida, in an interview with OncLive®.
“I am recommending that if patients progressed on ripretinib that they go up to twice-a-day dosing with the hope that they could still get some sort of response or disease control before switching to a different TKI,” she said.
Data presented at CTOS 2020 showed that patients derived a PFS benefit in the second-, third- and fourth-line settings when the higher dose was administered using the intrapatient dose escalation (IPDE) method.5 Investigators defined PFS1 as PFS on ripretinib at 150 mg daily from day 1 of cycle 1 until disease progression. PFS2 was defined as PFS on ripretinib at 150 mg twice daily from the date of IPDE to disease progression or death.
Results showed that the median PFS1 was 11.0 months (95% CI, 3.5-22.1) when administered in the second line (n = 10), 8.3 months (95% CI, 1.8-11.1) in the third line (n = 17), and 5.5 months (95% CI, 2.1-8.1) in the fourth line or later (n = 40). The median PFS2 was 5.6 months (95% CI, 1.4-12.9), 3.3 months (95% CI, 2.3-7.4), and 4.6 months (95% CI, 2.8-5.6), respectively.5
D’Amato recommended the twice-daily dosing to patients who progressed on standard dosing in her practice and, anecdotally, has noticed an improvement. “I have some patients with some response for a few months. Some [responses] are longer and some [patients] don’t respond, but with others, you can get several more months out of it. It’s worth it to try, especially while you’re trying to figure out the next treatment.”
By the time patients get to ripretinib, they have already had several rounds of therapy with imatinib, sunitinib (Sutent), and/or regorafenib, D’Amato explained. Despite this, she added that those patients can still respond to other TKIs. “The fourth-line data were very compelling, and the toxicity profile is very compelling, as is the mutation resistance profile and the fact that it can be effective across multiple mutations,” D’Amato said. “I think that’s what drove them to say, ‘Look, I think this could be good for a second line.’ I think we’re going to be hard pressed to come up with a drug that’s as good as imatinib.”
Ripretinib is under investigation as a second-line therapy vs sunitinib in the phase 3 INTRIGUE trial (NCT03673501). Investigators are comparing the regimens in patients who had disease progression or were intolerant to first-line treatment with imatinib. The trial reached its target enrollment of approximately 426 patients in November 2020.2
The primary end point is median PFS per independent radiologic review in accordance with modified RECIST criteria. Top-line results are scheduled for release in the second half of this year.2
Ripretinib may provide an advantage over other kinase inhibitors because patients being treated with such agents tend to develop secondary mutations, according to Margaret von Mehren, MD. In an interview, she explained that certain mutations prevent the kinase inhibitors from binding the molecule or stopping inhibition. von Mehren is chief of the Division of Sarcoma Medical Oncology, physician director of the Clinical Trials Office, associate director of clinical research, and professor in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.
“Simplistically, in GIST, these kinases or proteins that are present are mutated and altered in driving the growth of the tumor. I like to think of them as light switches—they’re always turned on and telling the cell to grow and divide,” she said. “And when a drug like imatinib is effective, it’s able to turn off the light switch and stop the cell from growing and dividing. But with these secondary mutations, the drugs are no longer able to turn off the light switch. Ripretinib is one of the ways we can do that.”
In additional findings presented at CTOS 2020, ripretinib demonstrated clinically meaningful activity in patients with several heterogeneous genetic subsets of KIT/PDGFRA mutations treated in the fourth line or later.6 Approximately 80% of patients with GIST have KIT mutations and 10% to 15% emerge in PDGFRA, with the most common alterations occurring in KIT exon 11 (approximately 67%).7
Findings from an exploratory analysis of INVICTUS showed that ripretinib improved PFS across 4 primary mutation subgroups analyzed vs placebo, as well as in all secondary mutation subgroups. In patients whose tumors harbored KIT exon 11 mutations, the HR was 0.15 (95% CI, 0.08-0.29). In those with KIT exon 9 mutations the HR was 0.22 (95% CI, 0.07-0.69). In patients who did not have specimen sequencing, the HR was 0.13 (95% CI, 0.02-0.66). And the HR for patients with other mutations including those who were KIT/PDGFRA wild type was 0.38 (95% CI, 0.11-1.37).6 Investigators of the analysis also combined liquid and tumor biopsy to detect secondary mutations and ripretinib demonstrated a clinical benefit in all subgroups.