Clinical Trial Details
— Status: Terminated
Administrative data
NCT number |
NCT03224208 |
Other study ID # |
VECODUE |
Secondary ID |
|
Status |
Terminated |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
May 17, 2018 |
Est. completion date |
January 8, 2021 |
Study information
Verified date |
April 2021 |
Source |
Fondazione Melanoma Onlus |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced
melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF,
was associated with prolonged overall survival (OS) and progression-free survival (PFS)
compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a
selective inhibitor of MEK, yielded a significant improvement in PFS and response rate,
compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the
pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with
mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible
therapeutic options, with the former and latter agents being associated with more durable and
earlier responses, respectively.
As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined
BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also
feasible, but it is not supported by category 1 evidence, in view of the lack of studies
conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the
combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received
first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
Description:
In the BRIM-3 trial, which was conducted in patients with previously untreated advanced
melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF,
was associated with prolonged OS and PFS compared to dacarbazine. In the same setting,
combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a
significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along
with an advantage in OS, which did not cross the pre-specified significance bounderies
(COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based
immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and
latter agents being associated with more durable and earlier responses, respectively.
As suggested by NCCN guidelines, the use of combined BRAF and MEK inhibitors in patients with
progressive disease after immunotherapy, is also feasible, but it is not supported by
category 1 evidence, in view of the lack of studies conducted in this setting.
The main objective of this phase II trial is to evaluate the efficacy and safety of the
combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received
first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.
As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in
50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and
a statistically significant improvement in OS in patients with unresectable stage III and IV
melanoma.
However, the clinical utility of BRAF-I treatment is limited by the development of drug
resistance. Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E
melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E,
elevated closely related serinethreonine kinase activity, activating NRAS mutations,
increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor
upregulation. Most of these alterations cause BRAF-I resistance by reactivating the MAPK
pathway which plays a major role in the proliferation, survival, and metastatic potential of
melanoma cells [Shi 2014a, Shi 2014b, Van Allen 2014].
Inhibition of MEK by the novel MEK-I, trametenib or cobimetinib, has been demonstrated to
overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to
increase both OS and OvRR of melanoma patients when combined with BRAF-I [Flaherty 2012a,
Flaherty 2012b, Hoeflich 2012, Ribas 2014]. The above-described phase III study, 495 patients
with previously untreated unresectable locally advanced or metastatic BRAF V600
mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib, as
compared with vemurafenib alone, resulted in an improvement in PFS and objective responses,
with early evidence of improved OS and a somewhat increased toxicity profile [Larkin 2014].