Janku Highlights PFS Benefit With Dose-Escalated Ripretinib in Advanced GIST

Janku, MD, PhD

Upon progressive disease, a dose-escalated approach of ripretinib (Qinlock) yielded a progression-free survival (PFS) benefit in patients with gastrointestinal stromal tumor (GIST) across all lines of treatment in a phase 1 study (NCT02571036), according to Filip Janku, MD, PhD, adding that investigations continue with ripretinib in additional GIST scenarios.

For example, the phase 3 INTRIGUE study (NCT03673501) is now evaluating ripretinib vs sunitinib (Sutent) in the second-line setting.

“Although there are several effective KIT inhibitors in the GIST treatment landscape, most patients develop resistance after the initial response, resulting in a major unmet need in the space. After 3 lines of therapy on these inhibitors, including imatinib [Gleevec], sunitinib, and regorafenib [Stivarga], there are not many other treatment options for these patients. As such, this is where ripretinib plays a role,” Janku explained.

In the phase 1 dose-escalation study, 142 patients with GIST who received 2 (n = 31), 3 (n = 28), 4 or more (n = 83) prior lines of therapy were enrolled. Patients started off with the FDA-approved dose of 150 mg of ripretinib once daily and, upon progression, received an escalated dose of 150 mg of ripretinib twice daily. PFS was calculated from day 1 of cycle 1 to the time of progressive disease, while PFS2 was calculated from the time of dose escalation to the second onset of progressive disease or death.

Results showed that the median PFS was 11.0 months in the second-line setting, 8.3 months in the third-line setting, and 5.5 months after 4 or more prior lines of therapy.^1,2 PFS2 was 5.6 months, 3.3 months, and 4.6 months in the second-, third-, and fourth-line settings, respectively.

Regarding safety, treatment-emergent adverse effects (TRAEs) were reported in over 20% of the patients and included alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia, muscle spasms, rash, decreased weight, abdominal pain, diarrhea, back pain, vomiting, and decreased appetite. AEs were similar in patients who received the FDA-approved dose and the escalated dose.

In an interview with OncLive, Janku, an associate professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, highlighted the role of ripretinib in patients with GIST along with the rationale for the dose-escalation approved in this patient population.

OncLive: During the 2020 ESMO Virtual Congress, you highlighted findings from a phase 1 study that evaluated ripretinib in patients with GIST across all lines of therapy. Could you shed light on the significance of these findings?

Janku: In the large phase 1 study, we identified the recommended phase 2 dose, which was then used in the phase 3 Intrigue trial. This Intrigue trial randomizes patients who were treated with 3 prior lines of approved KIT inhibitors 2:1 to receive either ripretinib or placebo.

This study also detected promising signals of efficacy, which allowed us to fast track the development of ripretinib from a phase 1 trial directly to a phase 3 trial. This is quite unusual; the typical timeline could take up to 10 years. Although, in this case, the smart development strategy, along with the clear unmet need, sped up this trial. The first patients were treated in November 2015 and the approval was in May 2020.

In addition to that, the phase 1 study actually enrolled a substantial number of patients, even more than the phase 3 trial. This is another reason why the research progressed so quickly; we were able to learn a lot about the safety profile early-on.

We presented some of the latest findings during the 2020 ESMO Virtual Congress. These findings were from 67 patients who were initially treated with the recommended phase 2 dose, which is now the FDA-approved dose, of 150 mg daily. Some received an escalated dose of 150 mg twice daily at the time of disease progression, which is double the FDA-approved dose.

The findings were quite intriguing. We found that, in the patients who received an escalated dose, meaningful disease control was achieved. This was reflected by the median PFS of 5.6 months in patients who received ripretinib in the second-line setting, 3.3 months in patients who received ripretinib in the third-line setting, and 4.6 months in patients who received ripretinib after 4 or more lines of therapy. These responses were quite durable; however, we didn’t see much data in terms of partial or complete response. Only 1 patient achieved a partial response after dose escalation.

Additionally, we evaluated the adverse effects (AEs). When comparing the once-daily dosing to the twice-daily dosing, there was a slight increase in certain treatment-emergent AEs, including fatigue, diarrhea, decreased appetite, and along with others. Overall, the safety profiles were quite similar.

Could you spotlight some of the findings from the phase 3 INVICTUS trial?

The results, which read-out about 1 year ago, were quite intriguing, especially the PFS findings. The PFS was extended from 1 month on the placebo arm to 6.3 months on the ripretinib arm. Further, we also saw an overall survival advantage, which went from 6 months on the placebo arm to 15.1 months on the ripretinib arm. These are very encouraging data and certainly justifies the approval [of ripretinib in the fourth-line GIST setting].

What does the future look like for ripretinib in patients with GIST?

Due to its mechanism of action, ripretinib has the potential to advance into earlier lines of therapy. The phase 3 INTRIGUE trial is now comparing ripretinib vs sunitinib in the second-line setting. The field [of GIST] is highly anticipating these results.

References

1. Janku F, Chi P, Heinrich M, et al. Ripretinib intra-patient dose escalation (IPDE) following disease progression provides clinically meaningful progression-free survival (PFS) in gastrointestinal stromal tumor (GIST) in phase I study. Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract 1623MO.
2. George S, Chi P, Heinrich M, et al. Ripretinib intra-patient dose escalation following disease progression provides clinically meaningful progression-free survival in gastrointestinal stromal tumor in phase 1 study. Presented at: 2020 CTOS Annual Meeting; November 18-21, 2020; virtual. Abstract 25.