Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients ...with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring
, or
gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with
-rearranged lung cancer.
Gene fusions of
, and
(encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease.
.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ...ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood–brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.
In colorectal cancer patients, chromosomal rearrangements involving
gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the ...kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new
fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors. As suggested by other pieces of evidence, entrectinib - an orally available pan-TRK, ROS1 and ALK inhibitor - may have particular efficacy in patients with
rearrangements. Therefore, screening for rearrangements involving
genes may help identifying a subset of patients able to derive benefit from treatment with entrectinib or other targeted inhibitors.
RET inhibition: implications in cancer therapy Borrello, Maria Grazia; Ardini, Elena; Locati, Laura D ...
Expert opinion on therapeutic targets,
04/2013, Letnik:
17, Številka:
4
Journal Article
Recenzirano
Introduction: The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic ...rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas.Area covered: The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers.Expert opinion: Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.
In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor ...kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.
Tyrosine phosphorylation is controlled by a balance of tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Whereas the contribution of PTKs to breast tumorigenesis is the subject of ...intense scrutiny, the potential role of PTPs is poorly known. RPTPalpha is implicated in the activation of Src family kinases, and regulation of integrin signaling, cell adhesion, and growth factor responsiveness. To explore its potential contribution to human neoplasia, we surveyed RPTPalpha protein levels in primary human breast cancer. We found RPTPalpha levels to vary widely among tumors, with 29% of cases manifesting significant overexpression. High RPTPalpha protein levels correlated significantly with low tumor grade and positive estrogen receptor status. Expression of RPTPalpha in breast carcinoma cells led to growth inhibition, associated with increased accumulation in G0 and G1, and delayed tumor growth and metastasis. To our knowledge, this is the first example of a study correlating expression level of a specific bona fide PTP with neoplastic disease status in humans.
TPS4185
Background: Monopolar Spindle 1 (MPS1) kinase regulates the spindle assembly checkpoint (SAC) which ensures proper division of chromosomes during mitosis. MPS1 is overexpressed in several ...tumors, including hepatocellular carcinoma (HCC), where it correlates with tumor features and poor overall and disease-free survival. NMS-01940153E is a novel, highly potent and selective small molecule inhibitor of MPS1 kinase with long residence time and strong preclinical anti-tumor activity in different tumor types. In HCC lines, specifically, NMS-01940153E showed ~2-Log higher anti-proliferative activity compared to sorafenib, lenvatinib, and regorafenib. In a previous open-label first-in-human (FIH) study, CL1-81694-001 (EudraCT 2014-002023-10), signs of activity in HCC were detected. Recently, the treatment paradigm for advanced HCC has changed, with immunotherapy combinations in first line and TKIs shifted in later lines. However, the overall prognosis of patients with advanced HCC remains poor, and there is a strong need of new drugs in this setting. NMS-01940153E novel mechanism of action, inhibiting the SAC and interfering with genomic stability in HCC, may offer a new therapeutic option in HCC. Based on the promising FIH results, a Phase I/II study, MPSA-153-001 (EudraCT 2020-001002-26), was initiated in patients with HCC previously treated with more than one systemic therapy. Methods: The Phase II part of the MPSA-293-001 trial is designed as a two-stage study with an interim analysis for futility and safety rules for unacceptable toxicity. The primary objective is to assess the antitumor activity of NMS-01940153E in adult patients with unresectable HCC previously treated with systemic therapy measured as objective response rate (ORR) by investigator-assessed RECIST 1.1. Secondary endpoints are safety, PK, ORR as measured by investigator-assessed mRECIST, DoR, PFS and OS. Exploratory endpoints include biomarkers. NMS-01940153E is administered IV, on days 1, 8 and 15 every 4 weeks at the RP2D of 100 mg/m
2
/wk, which showed PK in a predicted active range. Key eligibility criteria are 1) diagnosis of HCC; 2) disease progression on standard-of-care treatment including an immune checkpoint inhibitor as first line and at least one TKI; 3) no more than 3 prior systemic treatment lines. Interim evaluation for futility will be undertaken as soon as the first 10 evaluable patients will be enrolled. If at least 1 responder is observed with no safety issues, enrollment will proceed up to 38 evaluable patients. Otherwise, the study will be terminated for futility. An independent DSMB will review the interim results and provide recommendation on the study progress. Recruitment is currently ongoing in Italy and Spain and an FDA “Study May Proceed Notification” was received in January 2023. Clinical trial information: NCT05630937 .
PDF
