Furthermore, the results from quantitative prediction research suggested that the combination of entrectinib at 600 mg/day with substrates primarily metabolized by hepatic UGT2B15 or intestinal UGT1A7 and UGT1A8 might cause clinical DDIs. Thus, special attention should be paid to avoid adverse reactions induced by DDIs when co-administration of entrectinib and drugs metabolized by UGTs.

On the other hand, there are some approved drugs, such as pembrolizumab for TMB-H or entrectinib or larotrectinib for NTRK fusion gene, for which there is no stand-alone companion diagnostics and the eligibility for these drugs cannot be judged without the results of CGP test. This paper discusses the current status and issues of companion diagnostics in cancer genomic medicine.

The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered...The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

Drug synergy was seen using trametinib and rapamycin in combination with entrectinib.

After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.

Among patients who exhibited resistance to crizotinib, follow-up treatment of entrectinib and lorlatinib showed remarkable survival benefits. Newer-generation ALK/ROS1-targeted drugs showed efficacy in a cohort of crizotinib resistant ROS1 + patients. These results, when validated, could assist efficiently accruing ROS1 + patients.

P1, N=12, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

P1/2, N=69, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2023 --> Jun 2025

Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib.

P2/3, N=30, Recruiting, Cancer Research UK | Initiation date: Dec 2023 --> Jun 2024

Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.

© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

Activated Cdc42-associated kinase 1 (ACK1) alterations have been considered to mediate bypass acquired resistance to the third-generation EGFR inhibitors (ASK120067 and osimertinib) in NSCLC. In the ASK120067-resistant lung cancer cell line (67R), 10zi dose-dependently inhibited the phosphorylation of ACK1 and downstream AKT pathway and showed a strong synergistic anti-tumor effect in combination with ASK120067 in vitro. Additionally, 10zi also exhibited reasonable PK profiles with an oral bioavailability of 19.8% at the dose of 10 mg/kg, which provided a promising lead for further development of new anticancer drugs.

After noting clinical improvement after a day of topical steroids, he was started on oral prednisolone, eventually achieving a quiescent state whilst on vemurafenib. Vemurafenib is a potent oral BRAFV600 inhibitor effective against advanced cutaneous melanoma and ECD. With increased use of this novel drug, it is important for clinicians to realise the potential side effects of this medication. In such cases where treatment is crucial for malignancies, it is often a dilemma between stopping treatment versus treating symptomatically.

In eight NTRK fusion ctDNA-positive patients, larotrectinib induced objective response in 75% of patients and median progression-free survival was 16.3 months...Blood samples collected from a patient with disease progression after larotrectinib treatment revealed NTRK3 G623R as the potential resistance mechanism. This study revealed previously unreported NTRK fusion partners, associations of NTRK fusion with MSI and TMB, and the potential utility of ctDNA to screen candidates for TRK inhibitors and monitor drug resistance.

This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions...Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

This study describes the different tests used to detect a rare type of cancer called TRK (tropomyosin receptor kinase) fusion cancer in people taking part in three clinical trials testing the medication larotrectinib...This plain language summary also includes insights and perspectives from a person affected by TRK fusion cancer, and from patient advocates. Clinical Trial Registration: NCT02122913 (ClinicalTrials.gov) Clinical Trial Registration: NCT02637687 (ClinicalTrials.gov) Clinical Trial Registration: NCT02576431 (ClinicalTrials.gov).

However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.

The EVICT study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in undertsnidng potential mechanisms of resistance.

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.

BRAF, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Mechanistically, DSF/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for BRAF-mutated thyroid cancers.

This case and the review of current data confirm the benefit of BRAF inhibition in BRAF-mutated ATC, limited by acquired resistance to targeted therapy.

We identified the variations in target cleavage efficiency, even in optimized sgRNA libraries, that pose a strong bias in phenotype and developed an analysis method that corrects phenotype score by the measured differences in the targeting efficiency among sgRNAs. Collectively, we expect that our new analysis method will more accurately identify genes that confer the phenotype of interest.

It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival. eudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.

P1/2, N=37, Completed, Sun Yat-sen University | Recruiting --> Completed

P2, N=40, Recruiting, Oslo University Hospital

P1, N=8, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=32 --> 8

We demonstrated that the ability of pigmentable cells to increase the number of intracellular melanosomes fully accounts for their higher resistance to vem compared to non-pigmentable cells. In addition, we identified a network of miRNAs and mRNAs that are involved in melanosome maturation and/or trafficking. Finally, we provide the rationale for testing BRAFi in combination with inhibitors of these biological processes, so that pigmentable melanoma cells can be turned into more sensitive non-pigmentable cells.

Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAF) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAF human melanoma cell lines...Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAF-mutated melanoma...Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.

Therefore, we wondered whether inhibition of EZH2 would be a way to overcome resistance to vemurafenib...When we inhibited both BRAF and PLK1, we achieved an improved response of BRAFi-resistant melanoma cells, which was comparable to the combined inhibition of BRAF and EZH2. These results thus reveal that targeting EZH2 or its downstream targets, such as PLK1, in combination with BRAF inhibitors are potential novel therapeutic options in melanomas with BRAF mutations.

Interestingly, all the tested compounds 3a-e had higher anti-BRAF activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Additionally, molecular docking of 3a and 3b against BRAF and EGFR enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a-e revealed safety and good pharmacokinetic profile.

In Europe, the TRK inhibitors (TRKi) entrectinib and larotrectinib, both showing high clinical activity and favorable safety profiles, have received tumor-agnostic approval based on pooled data of non-comparative phase I/II clinical trials with limited patient numbers. Conclusions REALTRK provides valuable data on NTRK testing and treatment reality of pts with NTRK fusion-positive solid tumors and generates clinically relevant real-world evidence. Table: 67P

No treatment discontinuations due to TRAEs occurred. CONCLUSION In this larger dataset with longer follow-up, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases.

After the inhibition of PCK1 by 3-mercaptopropionic acid (3-MPA), the therapeutic sensitivity of vemurafenib is restored. In conclusion, this study disclosed that drug-resistant cells appeared to regulate their own proliferation, oxidative stress and tumor dryness by activating Akt/PCK1/ROS pathway, and shed new insights into acquiring drug resistance in melanoma.

The possibility of introducing targeted therapies into the treatment algorithm represents a paradigm shift for patients with BRAF V600E mutant recurrent high-grade and low-grade glioma and BRAF routine testing should be considered in clinical practice. The focus of this review is to summarize the molecular landscape of BRAF across glioma subtypes and the novel therapeutic strategies for BRAF V600E mutated tumors.

The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma.

For BRAF-mutant advanced melanoma, the vemurafenib-cobimetinib strategy could be considered the most cost-effective treatment at the willingness-to-pay threshold of $150,000.

P1, N=21, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

No abstract available