Page 46 - ITPS-8-3

INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

on sorafenib, regorafenib inhibits multiple kinases involved including salivary gland tumors, thyroid cancer, and some
in tumor angiogenesis, oncogenesis, and the TME. The sarcomas. These fusions result in constitutive activation
RESORCE trial reported a median OS of 10.6 months for of TRK proteins, driving uncontrolled cell growth and
regorafenib compared to 7.8 months for placebo. 51 survival.
3.7. Anaplastic lymphoma kinases (ALK) Larotrectinib and entrectinib are first-generation TRK
inhibitors approved for tumor-agnostic use in NTRK
ALK belongs to the insulin receptor superfamily. These genes fusion-positive cancers. Larotrectinib demonstrated an
play crucial roles in alternative splicing, mutations, and ORR of 75% in a pooled analysis of adult and pediatric
amplifications linked to inflammatory myofibroblastoma patients, with durable responses and minimal toxicity.
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and NSCLC. ALK rearrangements can also induce T cell Entrectinib, which also targets c-ros oncogene 1 and ALK,
activation, cytokine release, and immune surveillance in has shown particularly strong efficacy in central nervous
tumors. TKIs such as crizotinib, alectinib, and lorlatinib have system-involved tumors due to its ability to penetrate the
gained approval for advanced ALK+ NSCLC due to their blood–brain barrier. 57
ability to significantly improve efficacy compared to standard
chemotherapies. Second-generation ALK-TKIs, like alectinib, Routine comprehensive genomic testing is critical for
demonstrate greater clinical efficacy in terms of median PFS, detecting NTRK fusions, and these therapies underscore
ORR, duration, and higher central nervous system response the potential of histology-agnostic treatment strategies.
rates compared to crizotinib, a first-generation ALK-TKI. Clinical trials continue to explore mechanisms of resistance
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Alectinib functions as a selective inhibitor and substrate and next-generation inhibitors.
that easily penetrates through the blood–brain barrier and 3.10. CAR T-cell therapy
prevents downstream tumor survivability, avoiding the
collateral damage of chemotherapy regimens. 53 CAR T-cell therapy involves collecting a patient’s T cells
and genetically modifying them to express CARs that
3.8. Rearranged during transfection gene fusions recognize specific antigens on cancer cells (Figure 1). Once
inhibitors infused back into the patient, these engineered T-cells
RET (rearranged during transfection) gene fusions are can identify and destroy malignant cells expressing the
oncogenic drivers found in a small subset of solid tumors, target antigen. Tisagenlecleucel (Kymriah®), the first FDA-
including NSCLC and thyroid cancers. These gene approved CAR T-cell therapy, is used for treating relapsed or
rearrangements result in constitutive kinase activity that refractory B-cell acute lymphoblastic leukemia in patients
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promotes tumorigenesis, making them actionable targets up to 25 years old. Clinical trials have demonstrated high
for precision therapies. remission rates, offering hope to patients with limited
treatment options. Axicabtagene ciloleucel (Yescarta®)
Selpercatinib and pralsetinib are highly selective RET and tisagenlecleucel have been approved for adult patients
inhibitors that have demonstrated significant clinical efficacy with relapsed or refractory diffuse large B-cell lymphoma
in RET fusion-positive NSCLC and thyroid cancers. The after two or more lines of systemic therapy, showing
LIBRETTO-001 trial showed that selpercatinib achieved significant response rates. CAR T-cell therapies targeting
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an ORR of 64% in previously treated NSCLC patients and B-cell maturation antigen, such as idecabtagene vicleucel
85% in treatment-naive patients. In medullary thyroid (Abecma®), have been approved for patients with relapsed
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cancer with RET mutations, selpercatinib also showed or refractory multiple myeloma after four or more prior
durable responses with manageable toxicity profiles, lines of therapy. Real-world data on idecabtagene vicleucel
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including hypertension and elevated liver enzymes. 55 for relapsed/refractory multiple myeloma showed a 69%
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Given its clinical activity and favorable safety profile, response rate with manageable toxicity, though prolonged
RET inhibition represents a critical component of precision hematologic toxicity remains a challenge, highlighting the
therapy in cancers harboring RET rearrangements. Genomic need for optimizing CAR T-cell expansion.
profiling for RET fusions or mutations is essential for patient
selection, and ongoing trials are exploring combination 4. Therapies in preclinical/clinical trials
strategies to enhance response and mitigate resistance. After the success of targeted therapies and immunotherapies
in lung cancer, breast cancer, and hematological cancer, the
3.9. Neurotrophic tyrosine receptor kinase (NTRK) use of targeted therapies has been expanded to other types
inhibitors
of advanced-stage cancer with high metastatic potential,
NTRK gene fusions are rare but actionable alterations such as HCC, CRC, and pancreatic ductal adenocarcinoma
found across various adult and pediatric solid tumors, (PDAC). For HCC, the primary tumor generated from

Volume 8 Issue 3 (2025) 40 doi: 10.36922/ITPS025140018