NCCN Adds Ripretinib to Guidelines for Second-line Treatment of GIST

Steve Hoerter

Ripretinib (Qinlock) has been added to the National Comprehensive Cancer Network (NCCN) Guidelines as a preferred regimen in the second-line treatment of patients with gastrointestinal stromal tumor (GIST) who are intolerant to sunitinib (Sutent).^1,2

Additionally, the FDA has granted a breakthrough therapy designation to ripretinib for the treatment of adult patients with unresectable or metastatic GIST who received prior treatment with imatinib (Gleevec) and harbor KIT exon 11 and 17/18 mutations.¹

“The breakthrough therapy designation reflects the substantial clinical benefit of [ripretinib] in [patients with] second-line GIST harboring mutations in KIT exon 11 and 17/18 that we observed in the circulating tumor DNA [ctDNA] analysis from the [phase 3] INTRIGUE study [NCT03673501],” Steve Hoerter, president and chief executive officer of Deciphera Pharmaceuticals, stated in a press release. “If approved, we believe [ripretinib] has the potential to become the standard of care for this group of [patients with] second-line GIST around the world.

“GIST key opinion leaders and physicians have long been proponents of clinical drug development targeted at specific molecular subtypes of GIST, and we are pleased with the FDA’s recognition that the ctDNA data indicates [ripretinib] may demonstrate substantial improvement over the current standard-of-care in this population. Further, the inclusion of [ripretinib] in the latest NCCN clinical practice guidelines underscores both the need for additional treatment options for [patients with] GIST in the post-imatinib setting and the significance of the results from the INTRIGUE study, which demonstrated that [ripretinib] is an active and well-tolerated agent.”

The updated NCCN guidelines are based on the primary analysis of the INTRIGUE trial, which showed that in the intention-to-treat (ITT) population (n = 453), ripretinib (n = 226) produced a median progression-free survival (PFS) of 8.0 months compared with 8.3 months for sunitinib (n = 227; HR, 1.05; 95% CI, 0.82-1.33; nominal P = .72).³

In patients with KIT exon 11 mutations treated with ripretinib (n = 163), the median PFS was 8.3 months vs 7.0 months for those given sunitinib (n = 164; HR, 0.88; 95% CI, 0.66-1.16; P = .36). Notably, the PFS findings in the ITT and KIT exon 11 mutation populations were not statistically significant.

In the KIT exon 11 mutation population, ripretinib elicited an objective response rate (ORR) of 23.9% compared with 14.6% for sunitinib (nominal P = .03).

In the ctDNA analysis of INTRIGUE, patients with KIT exon 11 and 17/18 mutations treated with ripretinib (n = 27) experienced a median PFS of 14.2 months compared with 1.5 months for those treated with sunitinib (n = 25; HR, 0.22; 95% CI, 0.11-0.44; nominal P < .0001).4 Additionally, ripretinib elicited an ORR of 44.4% vs 0% with sunitinib, translating to a response difference of 44.4% (95% CI, 23.0%-62.7%; nominal P = .0001). The median overall survival (OS) was not estimable (NE; 95% CI, 24.4-NE) in the ripretinib arm vs 17.5 months (95% CI, 7.9-30.9) in the sunitinib arm (HR, 0.34; 95% CI, 0.15-0.76; nominal P = .0061).

However, patients with KIT exon 11 and 13/14 mutations given ripretinib (n = 21) experienced a median PFS of 4.0 months (95% CI, 1.5-7.1) compared with 15.0 months (95% CI, 5.6-NE) for those administered sunitinib (n = 20; HR, 3.94; 95% CI, 1.71-9.11; P = .0005). The ORR for this subgroup was 9.5% and 15.0% for ripretinib and sunitinib, respectively. The median OS for this population treated with ripretinib was 24.5 months (95% CI, 13.5-NE) compared with NE (95% CI, 19.5-NE) for sunitinib (HR, 1.75; 95% CI, 0.72-4.24; P = .2085).

The phase 3 INTRIGUE trial enrolled patients with advanced GIST who were previously treated with imatinib. Patients were randomly assigned 1:1 to receive 150 mg of ripretinib once per day or 50 mg of sunitinib once per day on a 4-weeks-on/2-weeks-off schedule.³

The trial’s primary end point was PFS per independent radiologic review using modified RECIST v1.1 criteria. Secondary end points included ORR, safety, and patient-reported outcomes (PROs).

Regarding safety in the ITT population, 41.3% of patients treated with ripretinib experienced grade 3/4 treatment-emergent adverse effects, compared with 65.6% of those given sunitinib (nominal P < .0001). Additionally, measures of tolerability were better for ripretinib vs sunitinib on PROs.

In May 2020, the FDA approved ripretinib for the fourth-line treatment of patients with advanced GIST, with the indication specifically given for adult patients who have received prior treatment with 3 or more kinase inhibitors, including imatinib.⁵

References

1. Deciphera Pharmaceuticals announces Qinlock^® included in NCCN Guidelines^® for the treatment of second-line GIST patients and FDA grants breakthrough therapy designation for Qinlock in second-line GIST patients with mutations in KIT exon 11 and 17/18. News release. Deciphera Pharmaceuticals. March 14, 2023. Accessed March 15, 2023. https://investors.deciphera.com/news-releases/
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) Gastrointestinal Stromal Tumors Version 1.2023. March 13, 2023. Accessed March 15, 2023. https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf
3. Bauer S, Jones RL, Blay JY, et al. Ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor after treatment with imatinib (INTRIGUE): A randomized, open-label, phase III trial. J Clin Oncol. 2022;40(34):3918-3928. doi:10.1200/JCO.22.00294
4. Bauer S, Jones RL, George S, et al. Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE. J Clin Oncol. 2023;41(suppl 36):397784. doi:10.1200/JCO.2023.41.36_suppl.397784
5. FDA approves ripretinib for advanced gastrointestinal stromal tumor. FDA. News release. May 15, 2020. Accessed March 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/