Deciphera Pharmaceuticals Qinlock (ripretinib) has a realistic shot at Phase III success in second-line (2L) gastrointestinal stromal tumours (GIST) due to available efficacy data, experts said. However, with the Phase III comparing Qinlock versus Pfizer’s Sutent (sunitinib), it is still possible for the latter to be competitive due to patient heterogeneity, they noted. Qinlock may still have the edge due to its relatively specific mechanism and superior safety profile, they added.

Sutent, the 2L standard of care (SOC), is a multitargeted tyrosine kinase inhibitor (TKI). Qinlock specifically targets KIT and PDGFRA, two types of tyrosine kinase receptors. While Sutent may impact a wider range of patients, Qinlock may be superior in GIST as it is specifically designed for this indication and Sutent comes with a higher risk of off-target side effects, experts said.

Qinlock may only need to match Sutent in the Phase III Intrigue’s (NCT03673501) primary endpoint of progression-free survival (PFS) due to Stutent’s poor side-effect profile, some said. However, others noted superiority of at least two to three months is still needed, as the trial is not designed as a noninferiority trial. Intrigue data is expected in 4Q, as per a June 2021 company presentation.

The company has indicated it is looking to explore Qinlock in combination with Pfizer’s Mektovi (binimetinib) in 2L GIST, with a spokesperson noting the Phase Ib/II trial will initiate in the coming months. Experts welcomed the combination as the components target different parts of the disease pathway. However, some experts noted overlapping toxicities would have to be monitored.

Deciphera attended this month’s American Society of Clinical Oncology (ASCO) virtual meeting to present updated data from the Phase III INVICTUS trial (NCT03353753) data in fourth-line (4L) GIST, and showed patients who progressed from once-daily 150mg Qinlock can be dosed again with the drug at a higher, twice-daily dosing schedule. Experts noted this data is also relevant in the Intrigue study, which is only investigating once daily 150mg Qinlock.

Qinlock was FDA approved on May 2020 in 4L GIST. It has peak sales of $1.06bn estimated for 2026, according to GlobalData’s consensus forecasts. Deciphera has a $2.15bn market cap.

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Qinlock 2L trial success likely though patient heterogeneity a spoiler

In Intrigue, Qinlock should improve upon 2L SOC Sutent by at least two to three months in the primary endpoint PFS, experts agreed. If this benchmark is reached, Qinlock would be the new 2L SOC, and Sutent would be shifted to the post-Qinlock setting, added INVICTUS investigator Dr César Serrano, principal investigator, Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain.

Qinlock has a positive shot at succeeding in Intrigue due to its positive efficacy profile thus far, Serrano noted. In a Phase I trial’s (NCT02571036) 2L GIST cohort recruiting 31 patients, Qinlock led to a 19.4% objective response rate, which was a trial coprimary endpoint, as well as 10.7 months median PFS (Janku, F., et al., J Clin Oncol., 38(28), pp. 3294–3303).

Sutent was approved in 2006 for 2L GIST, and its registrational PFS data is not expected to be replicated in Intrigue, Serrano said. Sutent was approved based on six-month PFS data, but has a higher PFS of eight months in practice due to more clinician experience and improved patient profiles, he noted. Still, Intrigue uses Sutent as its active comparator to take this into account, which is reassuring, he added.

Nevertheless, Sutent may have a mechanistic advantage in 2L GIST as it has a broad-spectrum mechanism, said INVICTUS investigator Dr Jean-Yves Blay, director, Centre Léon Bérard, Lyon, France. While GIST is mainly driven by KIT, other tyrosine kinase pathways cannot be excluded as a notable element of the disease, Serrano added. Additionally, many patients who progress from 1L SOC Novartis’ (SWX:NOVN) Gleevec (imatinib) have a KIT exon 13 V654A mutation, which Sutent is potent against, he noted.

Qinlock’s specificity to target KIT in GIST patients should give it an edge, noted Dr Jason Sicklick, coleader, Sarcoma Disease Team, Moores Cancer Center, University of California San Diego Health, La Jolla. Over time, 2L patients may have other KIT mutations, and they would benefit with Qinlock as a pan-KIT inhibitor, Serrano added. Only about 40% of post-Gleevek patients have the KIT exon 13 V654A mutation, which Qinlock is also active against, he noted. However, Qinlock may be more potent against certain types of KIT than others, he added. While Qinlock is specific for KIT, it cannot be discounted that it does not have an impact in other receptor kinases, he said.

It may be categorically challenging to tease if Sutent or Qinlock would perform better, as they both have some degree of broad activity and GIST patients are heterogeneous, said Dr Robin Jones, team leader, Sarcoma Clinical Trials, The Institute of Cancer Research, The Royal Marsden, London, UK. It is hard to screen for patients who may be most receptive to Qinlock as biopsies from the same patient can yield different conclusions, Blay added. Blood samples can be collected to check circulating tumour DNA, but these tests are not reliable either, Serrano said. The spokesperson noted a patient must have a molecular pathology report to be recruited into Intrigue, and if this is not available or insufficient, an archival or fresh biopsy is required.

Qinlock is more attractive than Sutent due to the former’s superior side effect profile, experts agreed. Sutent is a multitargeted TKI, which presents the opportunity for a variety of off-target side effects, while Qinlock’s risk of such an issue is much narrower, Blay and Sicklick explained. Sutent has a boxed warning for hepatotoxicity, which is not the case for Qinlock. Anaemia and fatigue are notable but manageable common side effects for Qinlock, Sicklick added.

Given Qinlock’s superior side-effect profile, even noninferior efficacy versus Sutent in Intrigue may be enough for it to be considered a success, Blay and Sicklick said. Still, Intrigue is not designed as a noninferiority trial, Serrano noted.

2L combo with Mektovi logical; increased dose in 4L to increase utility

The rationale behind the new Phase Ib/II trial in combination with Mektovi in 2L GIST is that it would target separate disease aspects, Serrano explained. Qinlock would target KIT, which is upstream, and Mektovi would target MEK, which is downstream, he noted. The Phase Ib portion will investigate dose-limiting toxicities and maximum tolerated dose, and the Phase II will look into efficacy and safety, as per a company presentation.

While the combination has a mechanistic rationale, clinicians would have to be cognizant of side effects, Sicklick said. There are overlapping toxicities between the two drugs, and some patients may not tolerate MEK inhibitors at higher doses, he explained. Mektovi’s FDA label shows clinicians should be alert for cardiomyopathy, venous thromboembolism, and ocular toxicities, among others. Qinlock’s FDA label notes of several warnings including risk for cardiac dysfunction, hypertension, and palmar-plantar erythrodysesthesia syndrome. The spokesperson said preclinical data shows the combination demonstrates promising tolerability and efficacy.

Deciphera attended this year’s ASCO to present Qinlock data showing a double dose of the drug is efficacious in patients who have progressed from Qinlock’s original dosing schedule. The effect of this data is likely to be immediate, with clinicians who have access to Qinlock to increase dosing in patients who have progressed on an off-label basis, Blay said. The increased dosing is already being practiced by clinicians who have had substantial experience with Qinlock, Sicklick noted.

Qinlock was approved in 4L GIST based on positive INVICTUS trial data. In the ASCO update, 43 patients who progressed from once-daily 150mg Qinlock had a median PFS of 4.6 months. On the second round of treatment with increased dosing to twice-daily 150mg, they had a median PFS of 3.7 months (Abstract #11536).

There are currently no approved options for patients who progress from Qinlock, so this would extend the drug’s use, Blay noted. In the 2L Intrigue study, a once-daily 150mg Qinlock dose is under investigation and dose escalation is not offered, but the updated INVICTUS data may also be relevant for Intrigue, experts said.

While it is possible to skip once-daily dosing and go straight to a twice-daily approach, there is limited data supporting the latter, Blay said. It is still unclear which type of patient progresses from the once-daily dosing, he added. However, patients may metabolise the drug differently, causing some to expel the drug much quicker than the others before Qinlock can work, so the higher dose is needed in some, Blay and Serrano agreed.

Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.