Rozlytrek (entrectinib)

Among the tested compounds, entrectinib exhibited consistently strong binding affinities across all variants (-9.7 to -10.7 kcal/mol), whereas reduced binding affinities were observed for several inhibitors against E734K, A756D, and R897G variants...Clinical databases reported that p.Met918Thr (pathogenic) and p.Arg897Gln (risk factor) emerged as significant variants linked to MEN2-related cancers and Hirschsprung disease. As a conclusion, this integrative in silico study identifies deleterious RET nsSNPs with potential structural, functional, and therapeutic significance providing mechanisms for precision oncology and future clinical investigation.

This multicentre real-world cohort describes longitudinal ROS1 management with evolving treatments. Favourable survival likely reflects reflex molecular testing, access to ROS1i, and high clinical trial enrolment.

Ponatinib emerged as the top-ranked computational candidate (mean: - 10.07 kcal/mol), followed by Regorafenib (- 9.64), Sorafenib (- 9.46), and Entrectinib (- 9.45), while non-oncology drugs including antrafenine, betrixaban, and maraviroc demonstrated novel multi-target binding profiles...MM-GBSA calculations revealed a binding hierarchy concordant with docking scores (R2 = 0.92): Ponatinib-VEGFR2 (ΔGbind = - 42.38 kcal/mol) > Entrectinib-CDK6 (- 38.56) > Ponatinib-EGFR (- 33.24) > Entrectinib-HER2 (- 28.47) > Dacomitinib-HDAC3 (- 24.63 kcal/mol)...As the present study is entirely computational, the identified compounds should be regarded as hypothesis generating leads requiring experimental validation through in vitro kinase and HDAC3 inhibition assays, cell based studies, and target engagement confirmation before any translational conclusions can be drawn. The online version contains supplementary material available at 10.1007/s40203-026-00681-w.

The efficacy of tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, lorlatinib, entrectinib, and repotrectinib was systematically evaluated. Our findings underscore that although G2032R and L2026M mutations reside within the kinase active site, their impact extends far beyond steric hindrance, altering overall kinase domain dynamics. Collectively, these data establish a robust panel of patient-derived ROS1 cell lines that recapitulate clinical resistance patterns and, together with complementary computational modeling, provide a valuable framework to dissect ROS1 tumor biology and support rational design of next-generation inhibitors.

We report the case of a 61-year-old woman diagnosed with stage IV lung adenocarcinoma with brain metastasis harboring an EGFR exon 19 deletion (p.E746_A750del), who acquired resistance to osimertinib through a ROS1 fusion bypass pathway. The patient achieved a survival of over 6.5 years from initial diagnosis through ongoing adjustments to targeted therapy, including sequential treatment with crizotinib, entrectinib, and lorlatinib...Notably, we observed an interesting phenomenon with both crizotinib and entrectinib: while initial treatment led to intolerable adverse reactions requiring discontinuation, subsequent reintroduction of the same agent was well-tolerated. This case report aims to provide potential treatment strategies for patients with similar complex co-mutations.

The patient was treated with temozolomide concurrently with radiotherapy, followed by tumor treating fields with adjuvant temozolomide...Various tyrosine kinase inhibitors, including entrectinib, larotrectinib, repotrectinib, and selitrectinib, along with bevacizumab, were considered to potentially prolong progression-free survival and overall survival and improve quality of life. We expect to highlight the rarity of this case while discussing the effectiveness of second-generation tyrosine kinase inhibitors in high-grade glioblastomas with rare gene fusions. We also hope to identify the appropriate timeline and treatment sequence for post-standard care, given the lack of official guidelines regarding cases this infrequent.

Knockdown of NTRK1, which encodes TrkA, reduced cell viability and sensitized ATC cells to paclitaxel. Entrectinib was well tolerated at the administered dose, with no significant changes in body weight and serum biochemical markers. Collectively, these findings identify TrkA as a potential therapeutic target in ATC and support further investigation of entrectinib-based combination strategies to improve ATC treatment outcomes.

These findings in rat models and in silico docking indicate that nicardipine increases entrectinib exposure. While these results underscore the risk of significant DDIs, further clinical studies in humans are required to confirm this interaction and determine if entrectinib dose adjustments are necessary to mitigate adverse events.

P2, N=534, Active, not recruiting, Hoffmann-La Roche | Trial completion date: May 2026 --> Jun 2027 | Trial primary completion date: May 2026 --> Jun 2027

In this cohort, the DNA+RNA-based panel showed a higher detection rate for TK fusions, although the panels were applied to different patient groups and the sensitivity and specificity could not be determined. Future studies evaluating different test types on the same tumor specimens are warranted to clarify whether the dual-sequencing approaches can improve the identification of actionable genetic events.

P1/2, N=1000, Recruiting, Oslo University Hospital HF | N=6000 --> 1000