RESEARCH METHODS 3.1. Study design This is an observational retrospective study
including thyroid cancer patients with solid neoplasms with NTRK fusions.
The study will use secondary data retrieved from medical records from each patient.
The medical records include all the clinical variables defined in order to perform
the analysis and it is not necessary to access additional sources.
The assignment of a patient to a specific therapeutic strategy has been already
decided in advance by the usual clinical practice of medicine; the decision to
prescribe a specific treatment was clearly dissociated from the decision to include
a patient in the study. No intervention will be applied to patients, either
diagnostic or follow-up, other than the usual clinical practice. Epidemiological
methods will be used to analyze the data collected.
3.2. Setting and study population In total, 19 patients diagnosed with solid
neoplasms that have been confirmed to bear NTRK fusions in their tumors will be
included in the study. It is known that these patients have received the treatment
with Larotrectinib in 14 centers in Spain, prior to treatment reimbursement in
Spain.
3.3. Inclusion Criteria Infant and adult patients (all ages). Patients with
confirmed diagnosis of solid neoplasms. Patients must have detected NTRK fusions by
the following diagnostic methods NGS, fluorescence in situ hybridization (FISH)
and/or Immunohistochemistry (IHC).
Patients must be treated with Larotrectinib under the compassionate use program
(before the commercialization) in order to be included in the study.
Data should be available in order to evaluate effectiveness and consequent follow
up.
3.4. Exclusion Criteria Patients with solid neoplasms treated with Larotrectinib in
clinical trials or other settings different from clinical practice.
Patients that initiated treatment with Larotrectinib after the obtention of
prize-reimbursement and commercialization.
3.5. Study Size The sample size calculation is based on the actual number of
patients known to be treated in Spain with Larotrectinib. At the moment 19 patients
from 14 different healthcare centers have been localized that were treated in the
Spanish territory with Larotrectinib. We expect to include and collect data from all
of them.
3.6. Sampling and recruitment method Patients will be consecutively included, in
compliance with the previously established inclusion criteria.
According to the definition of study population and disease established in this
scientific report, patients will be selected from cases diagnosed with solid
neoplasms bearing NTRK fusions detected by any of these methods, NGS, FISH and/or
IHC, and treated with Larotrectinib. The 19 patients treated with Larotrectinib in
the Spanish territory are localized and belong to 14 different sites/healthcare
centers.
To prevent two or more reporting physicians from logging the same case, a
coordinator, who controls the cases included in his or her center, is appointed in
health centers with several reporting physicians, and preventive measures are
implemented in the tool controlling duplications in variables (such as birth date,
gender, center or diagnosis).
3.7. Case Definition A 'case' is defined as any patient, diagnosed, treated, or
followed in the different health centers where reporting physicians authorized by
the sponsor, who meets the inclusion criteria. A key point is that the patient was
diagnosed with solid neoplasms that harbors a NTRK fusion and he/she was receiving
treatment with Larotrectinib. Data from patient's treatment should have been
recorded and be available at the centers.
3.8. Data Logging Once the patient is compliant with inclusion/exclusion criteria
information on the clinical history will be collected to gather the necessary data
and to complete the electronic forms of the study designed for this purpose. All
data collected during treatment, as well as demographic data, will be provided for
the purpose of this study and completed at the electronic Case Report Form (eCRF) to
proceed to its analysis.
ENDPOINTS AND VARIABLES 4.1. Endpoints 4.1.1. Primary Endpoints Duration of response
(DoR): is defined as the time from first confirmed response (complete (CR) or
partial (PR) response), according to Objective response rate (ORR) defined below, to
the date of the documented progression of the disease (PD) as determined using
RECIST V1.1 criteria or death due to any cause, whichever occurs first. Those
patients with response and without PD or death event will be censored on the date of
their last tumor assessment.
Results will be presented as individual cases, not compiled as the patients have
different pathologies which may differ in prognosis.
4.1.2. Secondary Effectiveness Endpoints
Objective response rate (ORR): is assessed by the investigator analysis of
tumor growth through imaging follow-up (CT scan/MRI), using a method to
evaluate it as RECIST V1.1. This will be considered as the number of patients
with confirmed complete response (CR) or partial response (PR) as their overall
best response throughout the period of treatment with Larotrectinib. Tumor
measurements that were assessed locally by the clinician according to RECIST,
V1.1, should be recorded and indicate the change in size of tumors as compared
with baseline, at the first dose of study treatment.
Progression free survival (PFS): Time from first dosing date to the date of
confirmed PD according to RECIST 1.1. Patients alive and free of events at the
date of the analysis will be censored at their last known tumor assessment.
Patients who start a new treatment line without progression will be censored on
the date of first dose of the subsequent anticancer treatment.
Overall survival (OS): defined as the time elapsed from the first dose of study
treatment until death from any cause. Patients alive and free of events at the
date of the analysis will be censored at their last known contact. Survival
will be assessed by recording patients' status at each visit.
Results will be presented as individual cases, not compiled as the patients have
different pathologies which may differ in prognosis.
4.1.3. Secondary Safety Endpoints
-Safety: All safety information will be collected retrospectively according to data
available in the chart review. A descriptive analysis of adverse events collected in
medical charts will be done taking into account:
The frequency of Adverse events (AEs) will be reported per patient by MedDRA
System Organ Class (SOC) and Preferred Term (PT);
The maximum CTCAE grade will be reported per patient;
The causal relationship with the study drug will be assessed locally by the
investigator
Larotrectinib interruptions / Delays: number of interruptions and delays
of treatment reported per patient (frequency) and reason for dose
interruption / delay.
Larotrectinib dose reductions or modifications: Number of reductions or
modifications of doses reported per patient (frequency) and reason for
dose reduction / modification.
Larotrectinib treatment duration: Time elapsed between first dose and
permanent discontinuation of the study treatment.
4.2. Study Variables
Investigators will provide information of each of the following variables:
Variables for Demography:
Age at enrollment.
Sex (male, female).
Race (white, black, Asian, other)
Height (cm).
Weight (kg).
Body mass index.
Body surface area (BSA) - calculated from the reported height and weight
using Mostseller's formula:
BSA (m2)= (height (cm) x weight (kg) / 3600) 1/2
- Performance status.will be presented using the Eastern Cooperative
Oncology - Group (ECOG) scale.
Cancer history:
Primary cancer diagnosis.
Primary tumor type, histology and location
Stage of disease at initial diagnosis(I-IV).
Time since initial diagnosis.
Extent of disease at enrollment (metastatic, locally advanced, sites of
disease, presence of at least one measurable lesion). Stage of the disease
at inclusion
Time since diagnosis of metastatic or locally advanced disease (years).
Prior anticancer treatments:
-Prior systemic treatments type, start and end dates.
-Number of prior systemic regimens or treatment courses.
-Best overall response to the most recent prior systemic regimen or treatment
course (CR, PR, stable disease, progressive disease, unknown or inevaluable or
not applicable).
-Prior radiotherapy.
-Prior cancer-related surgery.
NTRK fusions:
-NTRK fusion gene: NTRK1, NTRK2, NTRK3.
-NTRK fusion isoform (i.e ETV6-NTRK3).
-Method of detection: NGS, FISH or IHC and dates of the determinations.
- Other oncogenic alterations present.
Treatment with Larotrectinib:
-Dose of Larotrectinib.
-Larotrectinib start and end date. Reasons for end of treatment
-Data records of dose reductions and/or interruptions and their reason.
-Best response and best response date
-Progression date.
-Frequency of AEs reported per patient by MedDRA System Organ Class (SOC) and
Preferred Term (PT); the maximum CTCAE grade will be reported per patient.
Causal relationship with the study treatment will be reported for all events.
Survival:
Patient status (alive, death, lost to follow-up)
Reasons of death (if applicable)
Subsequent anticancer treatments (type, start and end dates, best
response, progression dates)