Qinlock (ripretinib)

Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

P1, N=13, Active, not recruiting, Deciphera Pharmaceuticals LLC | N=30 --> 13 | Trial primary completion date: Aug 2024 --> Nov 2023

P1, N=30, Active, not recruiting, Deciphera Pharmaceuticals LLC | Recruiting --> Active, not recruiting

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts.

Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA...However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

P3 | N=453 | INTRIGUE (NCT03673501 ) | Sponsor: Deciphera Pharmaceuticals LLC | "Deciphera Pharmaceuticals, Inc...announced that Nature Medicine has published results from a circulating tumor DNA (ctDNA) analysis of the INTRIGUE Phase 3 study of QINLOCK (ripretinib) in GIST patients with mutations in KIT exon 11 and 17/18 only previously treated with imatinib....In the AP-ITT population, QINLOCK demonstrated similar efficacy with a median progression-free survival (PFS) of 8.0 months versus 8.3 months for sunitinib (HR 1.05, nominal p=0.72). There were fewer patients with Grade 3-4 drug-related treatment emergent adverse events (TEAE) with QINLOCK (26.5%) compared with sunitinib (55.2%)."

P3, N=453, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial completion date: Mar 2022 --> Dec 2024

P3, N=54, Recruiting, Deciphera Pharmaceuticals LLC

While KIT ATP-BP mutations were associated with clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of KIT mutations to predict the clinical benefit of second-line therapy in pts with advanced GIST. These data were presented in part at the Jan 2023 ASCO plenary session.

Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Emerging evidence shows that ripretinib is superior to sunitinib as second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the precision of targeted GIST treatment.

As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.

An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib...While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care...Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

The recommended third-line TKI medicine is called regorafenib (brand name STIVARGA). Patients should always talk to their medical team before making any decisions about their treatment. Clinical Trial Registration: NCT03673501 (INTRIGUE study) (ClinicalTrials.gov).

Ripretinib demonstrated effectiveness and a tolerable safety profile, making it a viable option as a fourth- or later-line treatment in Chinese patients with advanced GISTs, especially for non-gastric GISTs.

Apart from approved drugs (imatinib, sunitinib, regorafenib, ripretinib, and avapritinib, we evaluated cabozantinib, pazopanib, dasatinib, and sorafenib... Preclinical testing suggests that dose-escalation of or retreatment with imatinib is not effective in exon 11 mutant GIST with secondary mutations. Pazopanib appears highly ineffective against any secondary mutation but shows notable activity in exon 9 mutant GIST. Cabozantinib is the only drug with strong activity against the gatekeeper T670I and the AL D820Y mutation.

In comparison to parental GIST-T1, GIST-BSF1 treated with SCF displayed 4.3-29.3-fold higher GR50-values for all tested KIT inhibitors, except for sunitinib (1.4-fold) and nintedanib (3.1-fold)...GIST-BSF1 sublines with secondary mutations in-cis in both the ATP binding pocket (AP) and activation loop (AL) of KIT, called AP/AL mutations, display the same inhibitory profile towards ripretinib as seen in AP/AL mutations previously modelled in GIST-T1 (GR50 values for AP/AL mutants >20-fold higher than corresponding AL mutants)... GIST-BSF1 is the first KIT-WT, SCF-dependent GIST cell line, which allows study of the impact of KIT inhibitors on WT KIT. Reintroduction of KIT mutations leads to SCF-independent growth and yielded anticipated TKI profiles. This cell line platform allows the rapid validation of novel variants of KIT and other oncogenic kinases in a GIST-specific cellular background.

As sunitinib and regorafenib are only effective against certain secondary mutations, ripretinib can broadly inhibit a wide range of primary and secondary KIT mutations. The proportion of secondary mutations in KIT Exon 11 primary mutations is significantly higher than that in KIT Exon 9 primary mutations following progression on first-line imatinib treatment. Furthermore, the main resistance mechanism of KIT Exon 11 mutant GISTs continues to rely on complex secondary mutations in KIT signaling. Differences in resistance mechanisms among various primary mutations imply that subsequent treatment should take into account both the patient 's primary and resistance mutations.

Objective: There remains an unmet need for effective and well tolerated systemic therapy for metastatic gastrointestinal stromal tumors (GISTs) after disease progression on imatinib is challenging. In the real world setting, ripretinib has durable benefit in metastatic GISTs harbouring non KIT exon 11 primary mutations. Ripretinib at a dose of 150 mg BD can be safely administered. Ripretinib is generally well tolerated with toxicity profile consistent with previous reports.

Approximately 70% and 77% of patients develop secondary resistance to first-line imatinib or at least three lines of treatment. The prevalence of secondary mutations among patients with primary exon 11 mutations seemes higher than those with exon 9 mutations. Ripretinib demonstrated promising mPFS and mOS benefit for patients with both primary and secondary KIT mutations, which was numerically superior to previously reported mPFS for sunitinib and regorafenib in patients with any secondary mutations.

Other analyses showed that duration of therapy(DOT)of imatinib did not seem to affect the survival data of ripretinib, while DOT of sunitinib seemed to have a trend to affect OS and DOT of regorafenib affected both the PFS and OS of ripretinib. Ripretinib has significant clinical benefit and good safety in Chinese patients with advanced GISTs. Earlier use of ripretinib may benefit the survival of the patients as well as for Chinese patients harboring exon 11 mutations. Dose escalation or combination of ripretinib with other TKIs after disease progression may provide additional clinically meaningful benefit with an acceptable safety profile.

Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.

Ripretinib can effectively control the disease progression of advanced GIST in patients who have failed first-line or multiple-line treatments, with mild adverse events and good tolerability. Compared to patients who discontinued ripretinib, those who continued treatment had more significant survival benefits. Financial reasons were the main factors leading to treatment discontinuation.

If a patient progresses on imatinib, there are additional FDA-approved treatments (sunitinib, regorafenib, ripretinib), which are not currently available for those patients that progress on avapritinib. Our model has the potential to identify which PDGFRA exon 18 mutant GIST patients would benefit from front-line imatinib therapy, while subsequently identifying those that would require avapritinib treatment. Avapritinib was recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST in the United States. Imatinib has been used clinically for over two decades, and is more cost-effective and has a superior safety and tolerability profile compared to avapritinib.

P1/2, N=170, Recruiting, Deciphera Pharmaceuticals LLC | Not yet recruiting --> Recruiting

P1/2, N=170, Not yet recruiting, Deciphera Pharmaceuticals LLC

The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as ncRNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.

The active agents in our analysis as post-first-line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post-first-line treatment for advanced GIST following imatinib failure.

Ripretinib is a switch-control TKI approved for the treatment of adult patients with advanced GIST who received prior treatment with three or more TKIs, including imatinib. The information provided here should help inform advanced practitioners on the effective management of patients with GIST who have progressed on multiple therapies. Advanced practitioners are well positioned to provide the necessary supportive care to achieve optimal outcomes and drug compliance.

Real-world results are comparable to that of phase III INVICTUS study and its Chinese bridging study. Hence, ripretinib can be used for the clinical management of advanced GIST patients.

These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501.

In conclusion, mitochondrial damage/loss can be one of the underlying causes of ripretinib-induced skeletal muscle toxicity. However, further studies are needed to confirm the results in vivo.

The prediction results of in vitro-in vivo extrapolation (IVIVE) demonstrated that ripretinib might bring the potential risk of DDIs when combined with substrates of UGT1A1, UGT1A3, UGT1A4, UGT1A7 or UGT1A8. Therefore, special attention should be paid when ripretinib is used in conjunction with other drugs metabolized by UGTs to avoid risk of DDIs in clinic.

Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.

Imatinib mesylate revolutionized the management of advanced/metastatic GIST, and remains the standard first-line therapy in this setting. Upon development of secondary resistance, sunitinib and regorafenib are used as subsequent treatments, although clinical benefit is often non-durable...Ripretinib is safe and effective therapy for the fourth-line setting in advanced/ metastatic GIST. Future studies should evaluate combination schedules and the identification of markers predictive of benefit from ripretinib.

PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia.

P1, N=282, Completed, Deciphera Pharmaceuticals LLC | Active, not recruiting --> Completed

Ripretinib has acceptable tolerability, with the most common drug-related grade 3 or 4 adverse events being lipase increases, hypertension, fatigue and hypophosphataemia. Ripretinib is therefore a valuable additional line of therapy available for the management of gastrointestinal stromal tumours.

In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively...Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments...Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

In cases of progressive disease after successive treatment with imatinib, sunitinib, and regorafenib, a fourth-line therapy with ripretinib was recently approved. Approved in 2020, avapritinib is the first effective targeted therapy for advanced stage GIST harboring an imatinib-resistant PDGFRA D842V mutation.