Ripretinib continues to show clinically meaningful benefit with an acceptable safety profile when used as a fourth- or later-line treatment for patients with advanced gastrointestinal stromal tumor.
Ripretinib (Qinlock) continues to show clinically meaningful benefit with an acceptable safety profile when usedas a fourth- or later-line treatment for patients withadvanced gastrointestinal stromal tumor (GIST), as demonstrated in the INVICTUS study, according to John Zalcberg, MD.
In May 2020, the FDA approved ripretinib for the fourth-line treatment of patients with advanced GIST who received previous treatment with 3 or more kinase inhibitor therapies, including imatinib (Gleevec). The decision was based on earlier results from the phase 3 INVICTUS trial, which showed that the agent resulted in an 85% reduction in the risk of disease progression or death versus placebo in heavily pretreated patients with advanced disease.1
Updated results from the trial were presented during the 2020 ESMO Virtual Congress and showed that patients on the ripretinib arm had a median progression-free survival (PFS) of 6.3 months (95% CI, 4.6-8.1) compared with 1.0 month in the placebo arm (95% CI, 0.9-1.7; hazard ratio [HR], 0.16; 95% CI, 0.1-0.27).2 Additionally, the median overall survival (OS) in the ripretinib arm had not yet been reached (95% CI 13.1–not evaluable) versus 6.3 months (95% CI 4.1−10) in the placebo arm. The objective response rates (ORRs) were 11.8% versus 0% in the investigational and control arms, respectively.
“[In] the management of [patients with GIST, several options are available. Sometimes, one can proceed through various sequences,” said Zalcberg. “It is possible to manage the adverse effects (AEs) of each of these options and provide patients with hope that as they progress through the use of imatinib, sunitinib (Sutent), and regorafenib (Stivarga), that at least there is another agent for them. [Ripretinib] will provide them with substantial benefit and help them maintain quality of life (QoL).”
In an interview with OncLive, Zalcberg, Prof & Tony Charlton Chair of Oncology, head of the Cancer Research Program, and NHMRC (MRFF) Practitioner Fellow in the School of Public Health and Preventive Medicine at Monash University, further discussed the updated findings from the INVICTUS trial and the next steps for ripretinib in advanced GIST.
Zalcberg: Ripretinib is a new agent for the treatment of [patients with] advanced GIST; it’s a switch kinase inhibitor, so it has a dual mechanism of action that helps to deal with resistant phenotypes. It was first used in a randomized study called INVICTUS, which was reported this year. In fact, ripretinib was approved by the FDA this year for advanced GIST. Essentially, we [now] have a fourth-line agent for [these patients]. Previously, we had imatinib, sunitinib, and regorafenib; [these agents are] generally considered to be active in GIST. Now with ripretinib, we have an effective fourth-line agent that will hopefully become available around the world.
INVICTUS was essentially a randomized trial of ripretinib versus placebo, although patients in the placebo arm could cross over to ripretinib upon disease progression. The primary end point of the trial was PFS determined by blinded independent central review (BICR). Secondary end points [included] ORR and OS. In the trial, patients with advanced GIST underwent a 2:1 randomization. Patients were stratified [based on the number of] prior treatments they received and their ECOG performance status. Participants were randomized to receive either ripretinib at a dose of 150 mg daily or placebo.
[The trial] was done in many countries around the world; accrual was fairly rapid because of the unmet need in this group of patients. [Data from the] study were reported for the first time at the 2019 ESMO Congress. At the 2020 ESMO Virtual Congress, [we revealed] updated [findings, with an additional] 9 months [of follow-up] after the previous data cutoff.
The median PFS on the ripretinib arm was 6.3 months versus 1 month on the placebo arm. The HR was 0.16 which was very significant. The HR shows quite a difference between the curves between ripretinib and placebo.
[While] it's important to emphasize that the primary end point was PFS, the response rate is worth mentioning; [it] was about 10% in the experimental arm and there were no RECIST responses in the control arm. The response rate wasn't very high from a RECIST [criteria v1.1] point of view; however, on the other hand, there were a large number of patients who achieved stable disease. The disease control rate was 14.5 months, so quite a number of patients had stabilized disease.
In terms of OS, which is another important end point, there was a significant difference in survival between the 2 arms—even with crossover. The median OS has not yet been reached in the ripretinib arm versus 6.3 months in the placebo arm; [there was] a very big difference in survival between the 2 arms.
The safety profile [of ripretinib] was pretty similar to that of most TKIs. Nothing very surprising [was observed] in terms of AEs. One toxicity that is a bit more common with ripretinib compared with the other classes of TKIs used in advanced GIST is alopecia; there appears to be somewhat more alopecia in this group. Otherwise, the drug was found to be reasonably well tolerated.
Also, the QoL of patients in the ripretinib arm was maintained or improved throughout the duration of treatment, as opposed to what happened in the placebo arm where QoL, unfortunately, deteriorated.
This is an important registration study for ripretinib; it demonstrated that the agent is active in this condition and not only does it improve PFS and OS, but it also improves QoL. The drug was approved by the FDA this year. In terms of future steps, the current study that is ongoing is called INTRIGUE. INTRIGUE is examining ripretinib versus sunitinib in the second-line setting of advanced GIST. That study is recruiting and is likely to be reported on in the not-too-distant future. [This research] is important because it brings ripretinib forward, earlier [on in the] management of advanced GIST.
The question of what happens next is a good one and there'll be many people thinking about where to place ripretinib. Should it be tested in the first-line setting? Should it be evaluated in the adjuvant setting? Should it be tested in those with high-risk disease? There are a number of [areas of potential exploration] but, at the moment, I don't know of any publicly announced plans.
Another important drug that has recently been approved by the FDA for the treatment of [patients with] advanced GIST is avapritinib (Ayvakyt); this drug was also tested and reported on this year. [The agent] has a major sweet spot in terms of activity in the group of patients with GIST who harbor a mutation in the PDGFRA gene. The common mutation that occurs there in exon 18 is D842V. Patients with a mutation in that particular exon achieved a very high response rate with avapritinib. Now, that drug is also on the market in some parts of the world. [Avapritinib] is an important part of the treatment armamentarium and the management of this disease.
Research [will] continue. This is an important disease; It's the most common sarcoma of the gastrointestinal tract and is a relatively rare disease in its own right. Research in this area has been an incredible effort over 2 decades; it has led to a very substantial benefit for many patients.