**Rationale and objectives**
- The rapidly expanding knowledge in genomics, proteomics, and
transcriptomics has led to the discovery of new molecular alterations
and markers of immune phenotypes shared by multiple tumor types
regardless of their site of origin [1]. Since 2017, the Food and Drug
Administration (FDA) has approved six anticancer agents with a
"histology-agnostic" indication: two immune checkpoint inhibitors
(for both cancers with high tumor mutational burden or
mismatch-repair deficiency/microsatellite instability) [2-4] and four
targeted therapies (for tumors harboring a BRAF V600E mutation or a
neurotrophic tyrosine receptor kinase [NTRK] gene fusion) [5-7].
- Two oral targeted agents are currently available for unresectable
locally advanced or metastatic cancer patients harboring an NTRK gene
fusion: larotrectinib [6] and entrectinib [7]. Among the clinical
trials that led to the approval of these two TRK inhibitors, enrolled
patients were mostly affected by soft tissue sarcomas, lung, and
salivary gland cancers [8-9]. In contrast, some tumor histologies
were under or not-represented, such as gastrointestinal (except for
colorectal cancer), genitourinary and gynecological malignancies
[8-9]. However, as next-generation sequencing (NGS) assays for
comprehensive genomic profiling have become increasingly available in
both clinical and research settings in recent years [10], health care
providers may have the chance to detect an NTRK gene fusion even in
patients with tumor histologies under or not represented in clinical
trials [8-9], thus facing the opportunity to provide patients with
TRK inhibitor treatment despite a lack of data.
- To this aim, we will systematically review the available literature
to evaluate the benefit of TRK inhibitors in a virtual cohort of
patients affected by NTRK gene fusion-positive solid tumors derived
from case reports (CR) and case series (CS).
**Search strategy**
- MEDLINE will be systematically searched from inception to August 31,
2022, for eligible studies without any filters, according to the
“Preferred Reporting Items for Systematic Reviews and Meta-Analyses”
(PRISMA) guidelines [11]. All references of included studies will be
hand-searched later.
**Inclusion Criteria**
- CR and CS on adult patients affected by NTRK gene fusion solid tumors
and treated with TRK inhibitors will be evaluated. Only papers
written in English or European languages will be considered. CS will
have to provide single descriptions of the reported cases otherwise
they will not be selected. Letters to the editor providing
single-case descriptions will be included, subject to all the
previous criteria. Publications on NTRK gene fusion-positive solid
tumor patients enrolled in the clinical trials that led to the
approval of larotrectinib and entrectinib will be excluded
**Data selection and extraction**
- The literature search, the title, and abstract filtering will be
conducted independently by two groups of Authors using reference
management software (Zotero). Firstly, all titles and abstracts will
be initially evaluated for potential relevance. Secondly, full texts
of results considered eligible will be searched and further assessed
for eligibility. Two additional Authors will be required to resolve
disagreements on study selection by consensus.
- Subsequently, three Authors will develop a data-charting form using
Microsoft Excel to define the variables to extract. The two groups of
Authors that selected the publications will independently chart the
data and discuss the results in an interactive process.
The following data will be extracted:
- **Study characteristics:** first author, journal of publication, year of publication, type of evidence (CR or CS);
**Patient characteristics:** age and sex of the patient, site of the primary tumor, histological subtype, site of metastases (before being
treated with NTRK inhibitors), NTRK gene fusion diagnostic modality,
specific NTRK gene fusion detected;
**Exposure characteristics:** previously received treatments, type of TRK inhibitor administered, best radiological response (according to
Response Evaluation Criteria in Solid Tumors [RECIST]), and outcomes.
- We will report aggregated data obtained from the variables extracted
from included publications. Due to the expected limited sample size,
no inferential or predictive statistics analyses will be performed.
**Risk of bias assessment**
- Publications included in the review will be assessed for bias with a
tool proposed by Murad et al. [12]. A binary response will be
assigned to every question, and then an aggregate score will be
formulated for every publication.
**References**
[1] Tsimberidou AM, Fountzilas E, Nikanjam M, Kurzrock R. Review of precision cancer medicine: Evolution of the treatment paradigm. Cancer Treat Rev. 2020;86:102019. doi:10.1016/j.ctrv.2020.102019.
[2] FDA Grants Accelerated Approval to Pembrolizumab for First Tissue/Site Agnostic Indication. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
[3] FDA Approves Pembrolizumab for Adults and Children with TMB-H Solid Tumors. Available online: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors.
[4] FDA Grants Accelerated Approval to Dostarlimab-Gxly for dMMR Advanced Solid Tumors. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors.
[5] FDA Grants Accelerated Approval to Dabrafenib in Combination with Trametinib for Unresectable or Metastatic Solid Tumors with BRAF V600E Mutation. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grantsaccelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid.
[6] FDA Approves Larotrectinib for Solid Tumors with NTRK Gene Fusions. Available online: https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions.
[7] FDA Approves Entrectinib for NTRK Solid Tumors and ROS-1 NSCLC. Available online: https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc.
[8] Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448.
[9] Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6.
[10] Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. doi:10.1186/s13073-019-0703-1.
[11] PRISMA—Transparent Reporting of Systematic Reviews and Meta-Analyses. Available online: http://prisma-statement.org/.
[12] Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018;23(2):60-63. doi:10.1136/bmjebm-2017-110853.
