Precision medicine and its implementation in patients with NTRK fusion genes: perspective from developing countries

Abstract

<jats:p> Precision oncology is the field that places emphasis on the diagnosis and treatment of tumors that harbor specific genomic alterations susceptible to inhibition or modulation. Although most alterations are only present in a minority of patients, a substantial effect on survival can be observed in this subgroup. Mass genome sequencing has led to the identification of a specific driver in the translocations of the tropomyosin receptor kinase family (NTRK) in a subset of rare tumors both in children and in adults, and to the development and investigation of Larotrectinib. This medication was granted approval by the US Food and Drug Administration for NTRK-positive tumors, regardless of histology or age group, as such, larotrectinib was the first in its kind to be approved under the premise that molecular pattern is more important than histology in terms of therapeutic approach. It yielded significant results in disease control with good tolerability across a wide range of diseases including rare pediatric tumors, salivary gland tumors, gliomas, soft-tissue sarcomas, and thyroid carcinomas. In addition, and by taking different approaches in clinical trial design and conducting allocation based on biomarkers, the effects of target therapies can be isolated and quantified. Moreover, and considering developing nations and resource-limited settings, precision oncology could offer a tool to reduce cancer-related disability and hospital costs. In addition, developing nations also present patients with rare tumors that lack a chance of treatment, outside of clinical trials. This, in turn, offers the possibility for international collaboration, and contributes to employment, education, and health service provisions. </jats:p><jats:p> The reviews of this paper are available via the supplemental material section. </jats:p>

Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services

“…It is the first agent to receive approval for the treatment of a specific genetic target indiscriminate of whichever tumour type it arises in from the point of initial authorisation. 16 Pembrolizumab has previously been granted initial authorisation by the FDA for the treatment of patients with recurrent gastric or gastroesophageal adrenocarcinoma in patients with PD-L1 positive tumours in 2017, 17 which was later updated to include treatment of any tumour type which expresses microsatellite instability or DNA mismatch repair deficiency. 18 In the UK, NICE granted approval for Larotrectinib for NTRK in all positive solid tumours in May 2020 19 while Japan granted approval in January 2019.…”

“…19,20 This approach opens the possibility that future targeted therapies will be granted approval across multiple malignant disease states at the point of authorisation thereby making treatments available to a wider patient cohort than would historically have been able to access. 16 Should this approach be supported consistently the implications for patients, particularly those with malignancies which express gene targets at low rates across multiple conditions, such NTRK mutations, is likely to be significant. [25][26][27] This change is also likely to have an impact on clinical healthcare staff and the manner in which they provide care.…”

“…30 The scale of investment in immunohistopathology services to provide such comprehensive data may present another barrier in the ability of healthcare systems in developing nations to provide patients with access to targeted therapies to treat genetic mutations which occur with low frequency across multiple tumour types. 16 As previously discussed NTRK mutations occur across multiple cancer types with an estimated frequency of 1% 2 with the implication that comprehensive whole DNA sequencing across all tumour types to identify patients who may benefit from NTRK inhibitors will result in a high number of negative tests. In order to better utilise resources in resource-restricted healthcare environments it may be beneficial to adopt a more traditional authorisation model for NTRK screening and restrict testing to conditions which carry a higher rate of the mutation to maximise the potential benefit and minimise the impact of multiple negative assays.…”

“…In order to better utilise resources in resource-restricted healthcare environments it may be beneficial to adopt a more traditional authorisation model for NTRK screening and restrict testing to conditions which carry a higher rate of the mutation to maximise the potential benefit and minimise the impact of multiple negative assays. 16 The acceptance of Larotrectinib by international healthcare authorities for the treatment of NTRK positive tumours, irrespective of tissue of origin represents another milestone in the movement towards individualised treatment of malignant disease informed by immunohistopathology. The potential implications on healthcare systems are significant and will require additional resource investment to fully realise the benefits that targeted NTRK gene mutation therapy can have to patients.…”

“…In order to better utilise resources in resource-restricted healthcare environments it may be beneficial to adopt a more traditional authorisation model for NTRK screening and restrict testing to conditions which carry a higher rate of the mutation to maximise the potential benefit and minimise the impact of multiple negative assays. 16…”