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

Crenolanib (a PDGFR inhibitor) inhibited AOFB-01 cell proliferation...Therefore, PDGF-A produced by microvascular proliferations and tumor cells may promote the proliferation of PDGFR-α-expressing tumor cells in canine HGOG. PDGFR-α signaling has potential as a therapeutic target.

With inhibition of PDGFRα and PDGFRβ using AG1295 or AG1296, VM formation in gastric cancer cells decreased (P <0.05), but the number of VM structures increased while LOX was added (P < 0.05). LOX partially promotes the formation of VM in gastric cancer through the PDGF-PDGFR signaling pathway.

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.

P2, N=14, Completed, Arog Pharmaceuticals, Inc. | N=20 --> 14

Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

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

P2, N=30, Completed, Arog Pharmaceuticals, Inc. | Active, not recruiting --> Completed | N=48 --> 30

FLT3 tyrosine kinase inhibitors (e. g. , Crenolanib) have the potential to enforce surface expression of FLT3 by impairing its intracellular recycling, thus enhancing CAR-T mediated killing, but their use may be limited by overlapping toxicities on healthy hematopoiesis, in particular in the post-HSCT setting...In conclusion, we believe that epitope edited HSPCs may not only enable safe and effective CAR-T immunotherapies for AML, but also allow their combination with pharmacological blockade of leukemia survival/proliferative pathways to achieve synthetic lethality mechanisms, while still avoiding dose-limiting toxicities. Further exploration of immunotherapy-synergistic combinations will be fundamental to improve the outcomes of difficult-to-treat high-risk AML patients.

P3, N=54, Recruiting, Deciphera Pharmaceuticals LLC

To evaluate the effect of FLT3 inhibitors in ALL, we treated ex vivo primary leukemic cells of 6 adult ALL patients (FLT3 mut n=4; FLT3 wt n=2) with increasing concentrations of Gilteritinib, Midostaurin, Crenolanib, Sorafenib and Quizartibin for 24, 48 and 72h. AIRC IG 2019 (Project Code: 23810). Figure 1.

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.

We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.

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.

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.

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.

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.

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.

Conclusions NB003 has a manageable toxicity profile and promising clinical activity in heavily pretreated pts with advanced GIST harboring a broad spectrum of acquired imatinib-resistant mutations. The 20mg and 30mg BID doses are selected for further investigation in the phase I RP2D confirmation cohort.

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.

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.

"GeneCentric Therapeutics...announced today the initiation of its Alamance study, a multi-center bladder cancer study conducted in collaboration with investigators at Memorial Sloan Kettering Cancer Center and the University of Wisconsin – Madison Carbone Cancer Center....In this prospectively designed real-world evidence study, clinical response data and existing tumor samples are being collected from a multi-center cohort of approximately 250 patients with locally advanced or metastatic urothelial (bladder) cancer treated with FGFR-targeted therapy (e.g., erdafitinib) or other standards of care (e.g., anti-PD-(L)1 or platinum-based chemotherapy)."

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.

At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.

The comparators in the untreated population were pembrolizumab + pemetrexed + chemotherapy and pembrolizumab monotherapy. The comparators for the pre-treated population were docetaxel monotherapy, docetaxel + nintedanib, and platinum-based chemotherapy ± pemetrexed...The uncertainty of the clinical evidence and the estimates of cost effectiveness were too high to be considered a cost-effective use of NHS resources. Therefore, pralsetinib was not recommended for routine use.

P2; Trial completion date: Dec 2022 --> Feb 2025 | Trial primary completion date: Dec 2022 --> Feb 2025

Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.

Taken together, these results establish that SOC drugs failed to trigger apoptosis in senescent primary human lung fibroblasts, possibly due to enhanced Bcl-2 levels by nintedanib and the activation of the necroptosis pathway by pirfenidone. Together, these data revealed the inefficacy of SOC drugs to target senescent cells in IPF.

P2, N=32, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Aug 2022