Among the many drugs now available for the treatment of advanced gastrointestinal stromal tumors (GIST), where does the relative newcomer ripretinib (Qinlock) fit in ?

This is the question posed in an editorial recently published in the Journal of Clinical Oncology, which notes the treatment of advanced GIST has evolved significantly over the past two decades.

“The revolution in the treatment of this disease began with the identification of the oncogenic driver c-KIT and the subsequent identification of a series of KIT inhibitors which have literally transformed this disease,” comments editorialist Gary Schwartz, MD, Columbia University, New York City.

The first of these drugs was imatinib (Gleevec), approved by the US Food and Drug Administration in 2002, followed by sunitinib (Sutent) in 2006, and then regorafenib (Stivarga) in 2013.

Then 2020 saw the approval of both avapritinib (Ayvakit) and ripretinib.

Ripretinib was approved by the FDA on the basis of a clinical trial that showed the drug significantly improved progression-free survival (PFS) vs placebo.

However, a more recent study, which used an active comparator, had negative results. This was the phase 3 INTRIGUE study, which showed that  ripretinib did not prolong PFS compared with sunitinib when both were used in patients with advanced GIST previously treated with imatinib.

But ripretinib was better tolerated than sunitinib and achieved a higher response rate in certain subgroups of patient compared with its earlier counterpart, the same study indicates.

“Ripretinib did not meet the primary endpoint of superior PFS vs sunitinib [but] PFS observed with ripretinib was comparable to PFS with sunitinib in the KIT exon 11 (8.3 v 7.0 months) and the ITT (intent-to-treat) populations (8.0 v 8.3 months), demonstrating clinical activity of ripretinib in second-line GIST,” conclude the investigators, led by Sebastian Bauer, MD, West German Cancer Centre, Essen, Germany.

The study was published in the Journal of Clinical Oncology, and prompted editorialist Schwartz to ask: given the negative findings in the INTRIGUE study, where do we go from here and what do we do with these results?

“Unfortunately, this study is underpowered to make any conclusions regarding equivalency so, at this time, it is just not possible to say whether this [ripretinib] would be an adequate replacement for sunitinib,” he said.

All one can conclude is that ripretinib is clinically active with a PFS that is comparable with sunitinib in both the intention-to-treat analysis and in patients with exon 11 mutation, he continues.

Schwartz also pointed out is that the schedule of sunitinib used in this study (once-daily sunitinib 50 mg (4 weeks on/2 weeks off) is not the same as the approved dose or schedule that is generally used to treat patients with GIST. “Rather, a daily sunitinib dose of 37.5 mg is used,” he notes.

At this generally approved dose, dose reductions appear to be lower compared with those required in current clinical trial where intermittent dosing of 4 weeks on/2 weeks off led to many more patients requiring a dose reduction, compared with only about 20% that is seen when patients are treated with the approved daily doses, Schwartz commented.

Another issue raised by the editorialist, but not the study authors, is the relative cost of the two drugs. A 1-month supply of ripretinib at the dose used in the study costs approximately $37,000 US vs at least half that with generic sunitinib.

“Overall, one can conclude from this study that sunitinib remains the drug of choice in the second-line setting for patients who progress on imatinib or who find imatinib intolerable,” Schwartz writes.

“However, for the patients for whom sunitinib is intolerable, ripretinib could remain a safe alternative with clinical efficacy in the second-line setting, but only for patients with exon 11 mutations,” he concludes.

In the trial, the majority of the 453 enrolled patients (72%) had a primary KIT exon mutation.

The results show that ripretinib did not significantly improve PFS in the KIT exon 11 intention-to-treat analysis or in the overall patient population.

However, among the patients with KIT exon 11 mutation, the median PFS by investigator definition was numerically longer for ripretinib at 13.3 months vs 10.8 months for sunitinib. The overall response rate (ORR) in the subgroup of  patients with a KIT exon 11 mutation was 23.9% with ripretinib vs 14.6% with sunitinib (P = .03), while the ORR in the overall population was 21.7% with ripretinib vs 17.6% with sunitinib (nominal P value difference).

In contrast, PFS was greater among patients treated with sunitinib in patients harboring a KIT exon 9 mutation at 13.8 months compared with those with an exon 11 mutation at only 7 months. Comparatively speaking, PFS was only 5.5 months among patients with an exon 9 mutation treated with ripretinib

The median duration of response for ripretinib was similar to that for sunitinib at 16.7 months and 20.1 months, respectively.

Overall survival data was too premature to comment on, the study authors wrote.

“Ripretinib was generally well tolerated and its safety profile was consistent with existing prescribing information,” Bauer and colleagues comment.

However, there were fewer treatment-emergent adverse events (TEAEs) with ripretinib and fewer patients who received ripretinib needed dose modification, at about 38% compared with about 63% for those treated with sunitinib. There was also a high incidence of dermatologic AEs with sunitinib.

“To our knowledge, INTRIGUE is the largest randomized phase III trial in second-line GIST with an active comparator arm,” the investigators observed.

“In this study, the primary KIT mutation appeared to predict ripretinib activity in second-line treatment,” they suggest.

The study was funded by Deciphera Pharmaceuticals.

Bauer reports relationships with Novartis, Pfizer, Bayer, PharmaMar, GlaxoSmithKline, Deciphera, Blueprint Medicines, Lilly, Nanobiotix, Incyte, Daiichi Sankyo, Exelixis, Janssen-Cilag, ADC Therapeutics, Mundipharma, Adcendo ApS, and Boehringer Ingelheim.

Schwartz reports relationships with GenCirq, Bionaut Labs, January Therapeutics, Bionaut Labs, Ellipses Pharma, Gencirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, OnCusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech, and Killys Therapeutics.

J Clin Oncol. Published online September 2, 2022. Full text, Editorial

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