P2/3, N=440, Not yet recruiting, Exelixis

P1/2, N=38, Not yet recruiting, Indiana University

P2, N=32, Not yet recruiting, Washington University School of Medicine

Results Among the 336 treated patients, 50.6% received FLT3-tyrosine kinase inhibitors (FLT3-TKIs) as first treatment after R/R event, of which 51.8% received gilteritinib...Conclusion This study reveals a trend toward increasing FLT3-TKI use and highlights the need for repeated FLT3 testing among R/R AML patients. Real-world evidence is vital in understanding R/R AML patient care amidst emerging therapies.

The analysis of mutation profiles and survival outcomes revealed that the transformation subtype affects prognosis. Additionally, the time taken to undergo transformation is critical for patient outcomes.

Bayesian NMAs found zanubrutinib to be the most efficacious treatment for high-risk patients, with significantly reduced risk of progression or death compared with ibrutinib (hazard ratio [95% credible interval (CrI)]: 0.49 [0.31, 0.78]), acalabrutinib (0.55 [0.32, 0.94]), and bendamustine + rituximab or idelalisib + rituximab (BR/IR) (0.12 [0.05, 0.26]). Rates of response also demonstrated trends favoring zanubrutinib compared to acalabrutinib, with significant results compared to ibrutinib. The NMA suggests that the most efficacious BTKi for patients with high-risk R/R CLL is zanubrutinib.

P1, N=36, Not yet recruiting, University of Chicago

P1, N=1274, Active, not recruiting, Exelixis | Recruiting --> Active, not recruiting | Trial completion date: May 2026 --> Jun 2030 | Trial primary completion date: Feb 2026 --> Jun 2030

ADCC was maintained upon exposure to specific ABL or JAK-inhibitors, in contrast to the multi-target TKI dasatinib impeding SYK-dependent ADCC. In conclusion, optimized ML-NK cell and CD19 antibody-based immunotherapy combined with carefully selected TKI demonstrates significant in vitro treatment efficacy in kinase-driven leukemia.

P1, N=12, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

Pharmacodynamic experiments of the three models showed that cmpd D6 (12.5mg/kg) could significantly inhibit tumor growth compared with cmpd 18, and had no obvious toxicity. Based on the above results, cmpd D6 is a potential candidate drug for the future treatment of FLT3-ITD positive AML.

This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib...Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation...By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.

Furthermore, crizotinib, ceritinib, and alectinib were significantly associated with hepatotoxicity, marked by elevated alanine aminotransferase, aspartate aminotransferase, and hepatic enzyme levels. These findings highlight the need for vigilant monitoring of unlabeled AEs and potential label updates, particularly for hepatotoxicity risks associated with crizotinib, ceritinib, and alectinib.

Combination treatment with ALK-TKI and anti-EGFR agents suppressed acquired resistance to ALK-TKIs caused by activation of EGFR in vitro and in vivo, suggesting that the combination of lorlatinib and an anti-EGFR agent could be effective in patients with lorlatinib-resistant NSCLC. This research provides insights into the mechanism of resistance to lorlatinib and suggests that it can be overcome by anti-EGFR treatment, offering a promising approach for treating resistance to lorlatinib mediated by EGFR activation in patients with ALK-positive NSCLC.

P1/2, N=15, Completed, Guangdong Raynovent Biotech Co., Ltd | Recruiting --> Completed | N=36 --> 15

P1/2, N=284, Active, not recruiting, Cullinan Therapeutics Inc. | Trial completion date: Dec 2024 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Jan 2026

P2, N=160, Recruiting, Taiho Oncology, Inc. | Active, not recruiting --> Recruiting | Trial completion date: Oct 2025 --> Aug 2026 | Trial primary completion date: Jun 2025 --> Feb 2026

P2, N=78, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P2, N=27, Completed, EyePoint Pharmaceuticals, Inc. | Recruiting --> Completed

High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.

In this study, we developed NSCLC cells resistant to EGFR-TKI gefitinib and osimertinib and assessed the effect and mechanism of action of ZZC4 on those cells. Further, the proteomic analysis revealed that ZZC4 inhibited HCC827-GR cell growth by upregulating CDKN1B and downregulating CCNA2 and CHEK1. In conclusion, ZZC4 overcomes resistance to gefitinib by altering the cell cycle pathway.

SPR analysis revealed that cannabinoids bind strongly to HER2-tyrosine kinase (HER2-TK), with CBD showing the highest affinity (K D = 6.16 μM), significantly better than afatinib (K D = 26.30 μM), and CBG demonstrating moderate affinity (K D = 17.07 μM)...In cell viability assays, CBD and CBG effectively inhibited the growth of HER2-positive SKOV3 cells (IC50 = 13.8 μM and 16.6 μM, respectively), comparable to traditional tyrosine kinase inhibitors. These findings underscore the therapeutic potential of cannabinoids, particularly CBD and CBG, as alternative or adjunct therapies for HER2-positive cancers, with the promise of mitigating resistance and adverse effects associated with existing treatments.

Except for TP53 and PTEN, recurrent mutations in other common oncogenes tested were not detected at baseline or at progression. Within the limitation of a small sample size, specific molecular events that drive small-cell transformation remain unclear.

Data suggest that combining chemotherapy with EGFR inhibitors offers promise for EGFR ex20ins-mutated NSCLC. REZILIENT3 is an ongoing phase III study evaluating the efficacy and safety of zipalertinib (an orally available, irreversible EGFR-TKI) plus first-line standard-of-care platinum-based chemotherapy with chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations.Clinical Trial Registration: NCT05973773 (ClinicalTrials.gov).

Comprehensive in vitro and in vivo evaluations demonstrated that the synergistic interplay between gefitinib and the CRISPR-dCas9 system significantly enhanced drug sensitivity. The finding underscores the potential of our approach in addressing the issue of lung cancer resistance, offering a promising avenue for personalized and effective cancer therapies.

Conversely, when resistant clone cells were cultured under conditions that excluded AZD4547, the ecDNA status became similar to that of the original clone cells, and the inhibitory effect on cell growth was restored. Implications: Our results show that dynamic quantitative and qualitative changes in ecDNA can drive the intratumoural genetic heterogeneity of RTKs and resistance to RTK inhibitors.

Finally, a xenograft mouse model showed that TTK significantly promotes MM development. In summary, we demonstrated that the TTK-RGN axis regulates cell apoptosis, G0/G1 phase arrest, and proliferation in MM, highlighting TTK as a potential target for therapeutic intervention in this cancer.

OS was higher in age < 70 years old and in patients with adverse events. PFS was higher in age < 70 years old and in female patients.

While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S...Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials...These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

To overcome the challenges associated with genetic screening by sequencing, in the current study we developed an artificial intelligence-based deep-learning （DL） model that uses convolutional neural networks (CNN) to analyze digitized hematoxylin and eosin staining in tumor histological sections to predict potential response to imatinib or avapritinib treatment in GIST patients. These results demonstrate the potential of a DL model to improve predictions of treatment response to TKI therapy from histology in GIST patients.

Enriched KEGG pathways included the MAPK, PI3K-Akt, and Ras signaling. This pharmacovigilance study identifies significant AE signals linking ALK TKIs to liver injury, highlighting potential mechanisms and providing insights for clinical management and patient outcomes.

The primary end point was not achieved; however, an observed trend toward potential benefit was noted in patients with FLT3-ITD AML who had not undergone prior HSCT.

Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416 × 3 and Seq × 3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3 significantly decreased tumor growth factor-β (TGF-β), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-β levels by PE-SU5416 suppresses CAF activation.

The most common grade ≥3 treatment-emergent adverse events were asymptomatic amylase elevation (23.1%), anemia (20.0%), and asymptomatic lipase elevation (18.5%). These data suggest clinical activity and acceptable tolerability for cerdulatinib in patients with relapsed/refractory PTCL.

P3, N=344, Active, not recruiting, Ocular Therapeutix, Inc. | Recruiting --> Active, not recruiting

The median age of CML patients in our study was notably young. The 3-month and overall hematologic responses were excellent. The initial phase of CML at diagnosis and treatment switch was associated with the 3-month CHR, while only treatment switch was associated with the overall CHR.

Not available.

In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability...NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies...However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes.

Among the 15 IQs screened, four compounds exhibited cytotoxic activity against a lung cancer cell line (A549) that was as potent as the known drug afatinib with lower cytotoxicity in Vero cells...Additionally, the compound complied with the extended rule of five. This class of compounds represents a novel class of EGFR-TK inhibitors, which may serve as a novel scaffold for the development of anticancer therapeutics targeting EGFR-TK.

P1, N=36, Not yet recruiting, Washington University School of Medicine

P2, N=69, Not yet recruiting, Qian Qin