This study is an observational multicentral retrospective chart review study in patients with
BRAF V600 positive advanced (unresectable or metastatic) cutaneous melanoma, who have treated
by BRAF inhibitors (BRAFi) or MEK inhibitors (MEKi) in routine clinical practice in Russia.
300 patients will be included in the study.
The study does not aim to prove any formal hypothesis and does not imply any intervention in
standard medical care, and all medical events recorded during the study have already
occurred. The data sources of this study will be medical records, patients' charts and other
related medical documentation that allows to fully follow the course of the disease and
collect all the necessary information according to Protocol.
For identification of molecular genetic markers that cause resistance and sensitivity to
targeted therapy, an analysis of tumor tissue will be provided in the laboratory of
biological microchips "Institute of Molecular Biology. V.A. Engelhardt" of the Russian
Academy of Sciences. The analyzed materials will be paraffin blocks with samples of tumor
tissue of only patients with primary resistance to targeted therapy (inhibitors BRAF / +/-
MEK inhibitor).
In the course of the study, the Contract Research Organization (CRO) "Crocus Medical B.V."
will conduct periodic monitoring visits to ensure that the data collected are accurate and
credible. Regular monitoring visits include Source Data Verification (SDV) in accordance with
the monitoring plan, monitoring compliance with the research procedures, as well as the
proper and timely maintenance of the main clinical study documents, including the reporting
provided for by the rules of good clinical practice, the legislation of the Russian
Federation and Standard Operating Procedures (SOPs) of the CRO.
The investigators will be responsible for the collection and provision of all clinical and
laboratory data, as well as safety data, that are entered in electronic Case Report Forms
(e-CRF), and must ensure data authenticity and compliance with the primary documentation.
Before hard database lock, the database will be inspected in order to reveal missing and
suspicious data. The queries will be generated to correct or fill-in such data. In case the
data failed to refine, their will be considered as missing, no data-imputation methods are
planned.
One of the efficacy endpoints of the study is defined as overall survival which represents
the time-to-event data, these data will be analyzed with Kaplan-Meyer method and Cox
regression. Time to event will be defined as a number of days passed from start of treatment
until any-cause death. Patients alive until the end of study will be right-censored by the
end-of-study day or by the day of preliminary withdrawal. Based on Kaplan-Meyer curves the
following parameters would be accessed: median survival, one- and two-year survival. The Cox
regression will include the following covariates: age, sex, baseline therapy, presence of
metastasis in brain, baseline level of lactic dehydrogenase (LDH), number of tissues with
metastasis, time from the beginning of the target therapy, etc. Additional covariates could
be also accessed when necessary. The hazard ratio (HR) along with 95% confidence interval
will be evaluated for each covariate.
Analyses of categorical efficacy endpoints (number of patients taken different therapies,
objective response rate, number of patients with molecular genetics alterations) will be
performed with chi-square criterion or Fisher's exact test in case of any expected
frequencies below 5. In addition, the logistic regression could be build based on the above
mentioned covariates. The odds ratio (OR) along with 95% confidence interval will be
evaluated for each covariate.
The progression-free survival (PFS) will be analyzed analogously as described above for the
overall survival data. Time to event will be defined as a number of days passed from
treatment start until either any-cause death or documented disease progression whichever
occurs first. Patients without event will be right-censored by the end-of-study day or by the
day of preliminary withdrawal. Based on Kaplan-Meyer curves the following parameters would be
accessed for all the patients as well as for the subgroups of baseline therapy (target
therapy, immunochemistry, chemotherapy): 6-, 12-, 18- and 24-months progression-free
survival. In addition, the PFS will be analyzed for the patients treated with BRAFi as a
monotherapy with successive inclusion of the MEKi.
Time to response and duration of response data will be analyzed similarly. Time to response
will be defined as a number of days passed from treatment start until first documented
response to the therapy. Non-responders will be right-censored by the end-of-study day or by
the day of preliminary withdrawal. This analyses will be conducted for all the patients as
well as for the subgroups of baseline therapy (target therapy, immunochemistry,
chemotherapy).
Analyses of the duration of response will be performed only among the responders. Duration of
the response will be defined as a number of days passed from the first documented response
until either any-cause death or documented disease progression whichever occurs first.
Patients responding until the study end will be right censored by the end-of-study day or by
the day of preliminary withdrawal.
The data on duration of the therapy will be presented with descriptive statistics for each
therapy line.
Adverse events (AE) and Serious Adverse Events (SAE) will be coded according to MedDRA. Each
AE/SAE will be summarized with counts and frequencies. The data on AE will be tabulated by
System Organ Classes (SOC) and presented with indication their preferred terms (PT) by
baseline therapy and severity. When necessary, the comparison of frequencies of AEs/SAEs
between subgroups will performed with chi-square criterion or Fisher's exact test in case of
any expected frequencies below 5.
