Ripretinib Continues to Provide Meaningful Clinical Benefit in Heavily Pretreated GIST

John R. Zalcberg, MBBS, PhD

Intra-patient dose escalation (IPDE) of ripretinib (Qinlock) has served to improve survival in patients gastrointestinal stromal tumors (GISTs) who are receiving treatment in the fourth-line setting or beyond, according to John R. Zalcberg, MBBS, PhD, who added that the safety of a twice-daily dose of the agent proved to be comparable to that of the once-daily dose.

Results from the phase 3 INVICTUS trial (NCT03353753) presented during the 2021 ASCO Annual Meeting showed that the median progression-free survival (PFS) in patients who received ripretinib at a once-daily dose of 150 mg (PFS1; n = 43) was 4.6 months (95% CI, 2.7-6.4). In those who progressed, and went on to receive the agent at a twice-daily dose of 150 mg (PFS2; n = 43), the median PFS was 3.7 months (95% CI, 3.1-5.3).¹

Data from a long-term update of the trial presented at the 2021 ESMO Congress showed stable median PFS benefit with ripretinib, with no substantial changes since the primary data.² The median PFS was 6.3 months with ripretinib vs 1.0 month with placebo, and the median overall survival (OS) was 18.2 months and 6.3 months, respectively. In those on the placebo arm who crossed over to ripretinib, the median OS was 10.0 months.

“[Ripretinib is] very active when it is given as a fourth-line treatment for people who have progressed,” Zalcberg said. “Intrapatient dose escalation [IPDE]appears to provide additional benefits, so this is an option for patients, and it is reasonably well tolerated.”

In an interview with OncLive®, Zalcberg, head of cancer research at Monash University in Melbourne, Australia, discussed the INVICTUS trial examining ripretinib in patients with heavily pretreated GIST, the impact of the agent on the paradigm, and ongoing efforts to provide additional options to this population.

OncLive®: Could you speak to the significance of the INVICTUS trial examining ripretinib? What makes this agent unique?

Zalcberg: [INVICTUS] is a really important study [that evaluated] ripretinib, a new class of drug, in the management of [patients with] GIST. Ripretinib is an important new molecule because it's a first-in-class TKI; it’s a switch control inhibitor that [targets] both KIT and platelet-derived growth factor receptor A kinases.

This study randomized patients to receive ripretinib or placebo. [Those in the]placebo group were able to crossover [to receive ripretinib] upon [disease] progression. The study clearly demonstrated the benefit [with ripretinib] in terms of median PFS and overall survival [OS].

That was an important finding that led to the approval of ripretinib by regulators around the world. As such, patients who have progressed on more than 3 lines of therapy now have a fourth-line therapy option [available to them].

What was the rationale for utilizing IPDE of the agent in these patients?

The main rationale was that in the earlier phase 1 dose-escalation study, the maximum tolerated dose had not been reached, even at a dose of 400 mg a day or 200 mg twice daily. It felt that there was room from a toxicity point of view to increase the dose. We just did not know was whether the efficacy would be maintained.

[We] built [this] into the study, [keeping in mind] that if patients progressed on ripretinib, very few other options [are available] to them. Other TKIs with a variety of different targets [may be used in that case], but no known drugs have proven to be very active in [these patients], and no other drugs [have been] approved for use. We wanted to provide the maximum opportunity for patients to derive benefit from ripretinib. I had patients, even within the study and in my own experience, who progressed on the 150-mg daily dose [of the agent and were switched to the twice-daily dosing] continued to benefit.

Could you expand on the methods used to conduct this research?

INVICTUS [enrolled] 129 patients who were randomized 2:1 to ripretinib or placebo. Patients who received ripretinib at a daily dose of 150 mg and progressed were given the option of IPDE to 150 mg twice daily. [Disease] progression was defined by blinded independent central review.

Tumor [imaging] was performed every 28-day cycle for the first 4 cycles in the 150-mg daily doing period and then every other cycle. The primary end point of the study was PFS, and of course, we also looked at OS.

Of the 85 patients who were treated with ripretinib on the study, 43 progressed and underwent IPDE upon progression. The characteristics were similar to those who were on the once-daily dose; that's the group that we analyzed for the purposes of looking at whether there were any additional or new adverse effects (AEs), and then the PFS of the patients who had dose escalated.

What are some of the key findings that read out during the 2021 ASCO Annual Meeting?

The most important finding was that we saw a benefit for patients who dose escalated, so those who progressed on the once-daily dose; these patients had a subsequent benefit, with a median PFS on dose escalation of 3.7 months, which was substantially better than [what was seen in] the placebo group. That was the main finding, although [this benefit was] slightly less [impressive] than [what was seen in those who were in] PFS1, which was 4.6 months. Nevertheless, there appears to be a clear benefit [with ripretinib], particularly compared with placebo.

What were the safety findings?

The higher dose was well tolerated, without any new major safety concerns [reported]. Some toxicity was experienced. The most common treatment-emergent AE for patients [who received the twice-daily dose] was abdominal pain; approximately 30% of patients experienced all-grade effects, but only 7% experienced pain that was grade 3 or 4. That was just a little bit higher than what we saw in [those who received] the daily [dose].

Moreover, in the period of the intrapatient dose escalation, anemia was seen more commonly than what we saw [with the once-daily dose]. Grade 3 or 4 anemia was reported in 14% [of those who received the twice-daily dose] compared with 2% [of those who received the once-daily dose].

What has been the impact of ripretinib on the treatment paradigm?

In the management of patients with GIST, [we saw] the benefit of imatinib [Gleevec] and sunitinib [Sutent] soon thereafter. Then, we had a relatively long period without any other new drugs approved. Then, we saw the approval of regorafenib [Stivarga], and that is a third-line option that is available in many countries. With ripretinib, we have a new option for patients [in the fourth-line setting]. That’s a real advantage. Hopefully, this will stimulate further research [to bring even more options to patients].

What is your take-home message to colleagues who are treating these patients in practice?

GIST is a disease we are all very familiar with now. We see patients a little bit earlier now than we [have in the past]. Many [patients use to] initially [present] with advanced disease. We are now seeing those with early disease. Nevertheless, some patients have poor prognostic tumors that progress. It is important that [everyone is aware of] the opportunity to continue [treatment] with [additional] lines of therapy [in those who] progress on standard treatment. The field is starting to change now. Currently, an adjuvant study is looking at longer duration [treatment with] imatinib. Research efforts are ongoing.

References

1. Zalcberg JR, Heinrich MC, George S, et al. Intra-patient dose escalation (IPDE) of ripretinib after disease progression in patients with advanced gastrointestinal stromal tumor (GIST): Analyses from the phase 3 INVICTUS study. J Clin Oncol. 2021;39(suppl 15):11536. doi:10.1200/JCO.2021.39.15_suppl.11536
2. von Mehren M, Heinrich M, George S, et al. Ripretinib as ≥4th-line treatment in patients with advanced gastrointestinal stromal tumour (GIST): long-term update from the phase 3 INVICTUS study. Ann Oncol. 2021;32(suppl 15):S1120-S1121. doi:10.1016/j.annonc.2021.08.870

Editor’s note: This interview was conducted prior to the long-term data from INVICTUS, which read out at the 2021 ESMO Congress.