NTRK fusions are found at low frequencies (commonly <1%) in a range of common tumour types and at high frequencies (up to or greater than 90%) in rare cancer types (secretory breast carcinoma, ...mammary analogue secretory carcinoma and infantile fibrosarcoma). The fusions typically occur in a mutually exclusive fashion with other strong mitogenic drivers, and it is of significant importance to identify patients in order to offer transformative treatment with TRK inhibitors. Larotractinib or entrectinib have resulted in fast and durable response with few and reversible adverse events. Even though on-target resistance may occur, second generation TRK inhibitors are in development and have shown promising activity. Diagnostic strategies must be applied, considering available assays and specific tumour types.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Oncogenic somatic chromosomal rearrangements involving the
NTRK1
,
NTRK2
or
NTRK3
genes (
NTRK
gene fusions) occur in up to 1% of all solid tumors, and have been reported across a wide range of tumor ...types. The fusion proteins encoded by such rearranged sequences have constitutively activated TRK tyrosine kinase domains, providing novel therapeutic anticancer targets. The potential clinical effectiveness of TRK inhibition in patients with tumors harboring
NTRK
gene fusions is being assessed in phase I and II trials of TRK inhibitors, such as larotrectinib and entrectinib. Clinical trial results have demonstrated that larotrectinib is generally well tolerated and has shown high response rates that are durable across tumor types. These data validate
NTRK
gene fusions as actionable genomic alterations. In this review, we present the clinical data, discuss the different approaches that might be used to routinely screen tumors to indicate the presence of
NTRK
gene fusions, explore the issue of acquired resistance to TRK inhibition, and reflect on the wider regulatory considerations for tumor site agnostic TRK inhibitor drug development.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can ...be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients – what they understand about precision oncology medicine and their hopes for the future.
Precision oncology offers individualized treatment of cancer on a per-patient basis, based on the unique DNA fingerprint of a patient’s cancer. New, advanced technologies for DNA sequencing have led to rapid advancement in developing novel therapies. Decision-making tools have followed pace, leading to improved matching of therapy to patient, ultimately improving outcomes (including quality of life), building trust between patient and physician, and increasing hope for the future.
Fusions involving tropomyosin receptor genes are noted in cancers affecting children and adults. The TRK inhibitor larotrectinib induced a response in 75% of patients, regardless of age, tissue of ...origin, or
TRK
fusion partner. Toxic effects were generally mild.
Background: advanced-stage non-small cell lung cancer (NSCLC) is characterized by having limited treatment options and thus a poor prognosis. However, new treatment options, in the form of targeted ...agents (TA), have emerged during recent years. This systematic review aims to provide an overview of the accessible literature in PubMed evaluating TA used on NSCLC patients, and the resulting survival outcomes.
Method: this systematic literature review was conducted by reviewing all relevant literature in PubMed. Six separate searches were performed: Three searches where controlled entry terms were used and three free text searches. Furthermore, other relevant publications were included manually. A total of seventy-two studies met the search criteria and were thus further analyzed and evaluated.
Results: In the included studies, various TAs and their effect on different molecular targets have been evaluated. Clinical responses vary considerably among the different genetic aberrations. The majority of studies evaluated TA for epidermal growth factor receptor (EGFR) mutations and TA for echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements. Studies regarding the use of TA for Rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), ROS proto-oncogene 1 (ROS1) rearrangement, Receptor tyrosine-protein kinase erbB-2 (ERBB2), Phosphatidylinositol 3-kinase (PIK3CA)/v-akt murine thymoma viral oncogene homolog; protein kinase B(AKT)/Phosphatase and tensin homolog deleted on chromosome 10(PTEN), The mammalian target of rapamycin (mTOR), and Mesenchymal-epithelial transition factor (MET) were included as well. In general, studies comparing treatment outcomes in EGFR-mutated patients and EML4-ALK (ALK) rearranged patients after use of either TA or standard chemotherapy, present significant better results after TA.
Conclusions: This systematic review provides an overview of available literature in PubMed regarding NSCLC and TA. Included studies point toward that TA appears to be a promising therapeutic tool in treating NSCLC patients and use of TA is expected to result in improved treatment outcomes.
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Daratumumab was associated with impressive antitumor responses, including complete and very good partial responses, in heavily pretreated patients with myeloma. Infusion reactions were the main ...adverse effect.
Current therapies, including proteasome inhibitors and immunomodulatory agents, have improved outcomes substantially in patients with multiple myeloma.
1
Unfortunately, the majority of these patients have a relapse and have limited treatment options after exposure to these classes of agents.
2
,
3
Patients with disease that is refractory to both proteasome inhibitors and immunomodulatory drugs have poor prognoses; the estimated median overall survival is 9 months, and the estimated event-free survival is 5 months at best.
2
,
3
CD38 is a 45-kD, type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca
2+
flux, and mediates signal transduction in lymphoid . . .
Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib ...is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods.
ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients < 18 years old will be enrolled under a 'pediatric' cohort regardless of tumor type and will be followed for 5 years to evaluate the risk of potential long-term adverse effects of larotrectinib on their growth and development. The effectiveness of larotrectinib in the overall study population as well as in patient subgroups will also be evaluated. Procedures avoided in patients with infantile fibrosarcoma (e.g., amputation) and the number of patients who were able to undergo surgery with a curative intent (excluding amputation) because of the use of larotrectinib will be described. Larotrectinib treatment patterns in real-world practice, including dosing and duration of treatment, will be described.
The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA.
This study is registered at ClinicalTrials.gov ( NCT04142437 ).
v2.5, 25 March 2021.
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Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients ...succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.
Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained unchanged since the ...implementation of the STUPP regimen in 2005 with concomitant radio-/chemotherapy and adjuvant chemotherapy with temozolomide.In the context of Hanahan and Weinberg's six hallmarks and two emerging hallmarks of cancer, we discuss up-to-date status and recent research in the biology of GBM. We discuss the clinical impact of the research results with the most promising being in the hallmarks ‘enabling replicative immortality’, ‘inducing angiogenesis’, ‘reprogramming cellular energetics’ and ‘evading immune destruction’.This includes the importance of molecular diagnostics according to the new WHO classification and how next generation sequencing is being implemented in the clinical daily life. Molecular results linked together with clinical outcome have revealed the importance of the prognostic biomarker isocitratedehydrogenase (IDH), which is now part of the diagnostic criteria in brain tumours. IDH is discussed in the context of the hallmark ‘reprogramming cellular energetics’. O-6-methylguanine-DNA methyltransferase status predicts a more favourable response to treatment and is thus a predictive marker. Based on genomic aberrations, Verhaak et al have suggested a division of GBM into three subgroups, namely, proneural, classical and mesenchymal, which could be meaningful in the clinic and could help guide and differentiate treatment decisions according to the specific subgroup.The information achieved will develop and improve precision medicine in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Knowledge of what the pharmaceutical industry emphasizes when assessing trial sites during site selection is sparse. A better understanding of this issue can improve the collaboration on clinical ...trials and increase knowledge of how to attract and retain industry-sponsored trials. Accordingly, we investigated which site-related qualities multinational biopharmaceutical companies and clinical research organizations (CROs) find most important during site selection.
An online survey among decision-makers for trial site selection in the Nordic countries employed at multinational biopharmaceutical companies and CROs was conducted. The respondents' experiences with and perceptions of site selection were addressed to evaluate the relative importance of site-related qualities. We included up to four respondents per company, representing different geographic regions. Descriptive statistics were used to summarize findings.
Of 49 eligible companies, 20 biopharmaceutical companies and 23 CROs participated. In total, 83 responses were analyzed (estimated response rate 78%). A relative importance of site-related qualities was identified: For example, 88% (binomial 95% confidence interval CI ±7%) preferred reaching enrollment goals at trial sites in their region 10% quicker rather than cutting the costs at all sites by 20%. Likewise, 42% (CI ±11%) of the respondents preferred that trial sites were best at having the first patients ready for inclusion right after site initiation visit compared to having good data entry, documentation, and reporting practice (25% CI ±9%), easily reachable site personnel and backup (23% CI ±9%), fast contractual procedure times (6% CI ±5%), a key opinion leader associated with the site (3% CI ±4%), and updated equipment and facilities (1% CI ±2%). In total, 75% CI ±9% agreed that their company would be interested in cooperating with an inexperienced trial site if the site had access to a large patient population and 52% CI ±11% had experienced that their company selected an inexperienced trial site in favor of an experienced site due to a higher level of interest and commitment.
This study indicates that recruitment-related factors are pivotal to the pharmaceutical industry when assessing trial sites during site selection. Data quality-related factors seem highly valued especially in early phase trials whereas costs and investigator's publication track record are less important. Experience in conducting clinical trials is not imperative. However, this applies primarily to late phase trials.
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