P3, N=410, Recruiting, AVEO Pharmaceuticals, Inc.

P3, N=410, Recruiting, AVEO Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P3, N=410, Not yet recruiting, AVEO Pharmaceuticals, Inc.

Conclusions The YYB101 and irinotecan combination showed modest efficacy and tolerable adverse events in refractory metastatic/recurrent CRC. Ongoing biomarker analyses aim to identify genomic and transcriptomic variables associated with long-term disease control.

P2, N=78, Completed, University of Arizona | N=60 --> 78

Furthermore, MPA-PEG-r-ABT-510 exhibited an antiangiogenic effect via tube information assay with human umbilical vein endothelial cells. Overall, MPA-PEG-r-ABT-510 presents rapid and precise tumor delineation characteristics, thereby making it a desirable tool for CRC imaging and surgical navigation.

In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.

The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.

Our findings may suggest a novel role of matriptase as a tumor suppressor in MM pathogenesis.

P2; Active, not recruiting --> Completed

P1, N=292, Recruiting, Taiho Pharmaceutical Co., Ltd. | N=180 --> 292

Similarly, the serine protease inhibitors hepatocyte growth factor activator inhibitor-1 (HAI-1) and -2 (HAI-2) have been identified as prognostic markers for HPV-dependent cervical carcinomas. This review highlights the most crucial mechanisms involved in HPV-dependent carcinogenesis, and includes a section on the proteolytic cascades that are important for the progression of this disease and their impact on patient health, treatment, and survival.

P2, N=74, Active, not recruiting, University of Arizona | Trial completion date: Dec 2021 --> May 2022 | Trial primary completion date: Dec 2021 --> May 2022

Furthermore, EVs-miR-142-5p inhibited growth and radioresistance and accelerated the apoptosis of radiotherapy-resistant NPC cells in nude mice by inhibiting the HGF/c-Met and EGF/EGFR pathways. Collectively, our findings indicated that TEVs might inhibit the HGF/c-Met and EGF/EGFR pathways by delivering miR-142-5p into radiotherapy-resistant NPC cells to enhance radiosensitivity in NPC.

CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib...CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.

Interestingly, we found that the expression of HGF protein in conditioned media significantly decreased in Crispr-HGF-transfected group. Taken together, we found that inhibition of HGF through transfection of Crispr-HGF suppressed cell proliferation and induced apoptotic effects in HCC Huh7 and Hep3B cells.

The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases.

In addition, treatment of human malignant meningioma cells with the tyrosine protein kinase (c-MET) inhibitor (SU11274) or the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) suppressed HGF-induced migration and EMT. These findings indicate that HGF regulates EMT in human malignant meningioma cells through c-MET/PI3K/Akt/mTOR modulation. In conclusion, curcumin inhibits HGF-induced EMT by targeting c-MET and subsequently blocking the PI3K/Akt/mTOR pathway.

We found that the HGF/c-MET pathway affected the tumor microenvironment mainly by interfering with expression levels of other genes. Immune infiltration is another critical factor involved in changes to the tumor microenvironment. The downstream immune-related genes activated by the HGF/c-MET pathway regulate immune-related pathways, which in turn affect the degree of infiltration of immune cells. Immune infiltration is significantly associated with cancer development and prognosis.

P2, N=74, Active, not recruiting, University of Arizona | Trial completion date: May 2021 --> Dec 2021 | Trial primary completion date: May 2021 --> Dec 2021

METex14 is a complex oncogenic driver mutation requiring carefully optimized platforms for proper detection. To identify patients eligible for targeted therapies-including therapies targeting novel oncogenic drivers, such as MET inhibitors-community oncologists need to be aware of both the use of NGS platforms and the differences in their capabilities to detect certain oncogenic drivers.

Attrition rates related to targeted treatments were approximately 25-30% and similar for administration of a second-generation (2G) ALK inhibitor (22%, 17/79) or any subsequent systemic therapy (27%, 27/96) after crizotinib, and for the administration of lorlatinib (27%, 6/22) or any subsequent systemic therapy (25%, 15/61) after any 2G TKI. Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies.

We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

Non-small cell lung cancer (NSCLC) patients with oncogenic ROS1 rearrangements would inevitably develop drug resistance and disease progression after receiving targeted oncogene therapy. Here, we present a metastatic lung adenocarcinoma patient harboring a CD74-ROS1 fusion who initially responded to crizotinib and then developed resistance after acquiring a rarely reported BRAF V600E mutation.

Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Amongst them, crizotinib, foretinib, and Pha665752 exhibited the strongest radiosensitizing effect. Kinase activity profiling showed an association of crizotinib resistance with compensatory PI3K/AKT and MAP kinase signaling. Overall, our results indicate that c-MET is conferring radioresistance in HNSCC through modulation of intracellular kinase signaling and stem-like features.

All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs...Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.

P3, N=231, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2022 --> May 2023

The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy.

Sunitinib is a small molecule inhibitor of PDGFRß and was studied in this PDX independently and in combination with crizotinib. Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFRß would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations.

No abstract available

JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient's treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use)...To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.

Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.

The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation.

Crizotinib is an effective treatment option other than cytotoxic chemotherapy in the limited number of patients with MET amplification in the stage 4 lung adenocarcinoma subgroup. It is important to investigate this amplification, which can be detected especially in smoking patients in the appropriate patient group, and to use appropriate tyrosine kinase inhibitors in treatment.

Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids...Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAF, crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFR/RB1) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.

Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation.

Crizotinib has been the first-line standard of care treatment in ALK-rearranged NSCLC patients for a long time, while crizotinib still represents the best upfront therapeutic option in ROS1-positive NSCLC patients, followed by next-generation TKIs at the time of disease progression...Despite the positive correlation between personalized treatment and patients' outcome, access to next-generation TKIs and genomic profiling at the time of disease progression are major challenges to achieving this goal. In this review, we present updated evidence on ROS1- and ALK-rearranged NSCLC regarding epidemiology and diagnostics, current therapies and the most suitable sequential treatment approaches, as well as mechanisms of acquired resistance and strategies to overcome them.