Combining Therapeutics to
Melanoma is the deadliest form of skin cancer: It accounts
for only 1 percent of all U.S. skin cancer cases but the
majority of skin cancer deaths ( 3). Before Jan. 1, 2011,
the FDA had not approved a new systemic treatment for
melanoma in more than 20 years. Since that time, the
agency has approved a wide array of molecularly targeted
therapeutics and immunotherapeutics, for use as single
agents or in combination, to treat patients with metastatic
melanoma (see Figure 15).
The most recent of these approvals came in November
2015, when the FDA approved a combination of
molecularly targeted therapeutics, cobimetinib (Cotellic)
and vemurafenib (Zelboraf), for treating metastatic
melanoma fueled by certain mutations in the BRAF gene.
About 50 percent of melanomas are driven by genetic
mutations that lead to an abnormal protein called BRAF
V600E (144). This knowledge led to the development and
subsequent FDA approval of two BRAF V600E–targeted
therapeutics, vemurafenib and dabrafenib (Tafinlar).
Although these molecularly targeted therapeutics benefit
many patients with melanoma fueled by the BRAF V600E
protein, the majority of those whose cancers initially
respond to vemurafenib and dabrafenib have disease
progression within a year of starting treatment owing to
treatment resistance (145, 146).
Trametinib and cobimetinib block the activity of two
proteins, MEK1 and MEK2, that function in the same
signaling network as abnormal BRAF proteins. Trametinib
is FDA approved for use alone or in combination
with dabrafenib for treating patients with metastatic
MAKING UP FOR LOST TIME FIGURE 15
The DNA synthesis inhibitor hydroxyurea was the first
therapeutic for the systemic treatment of metastatic melanoma
approved by the U.S. Food and Drug Administration (FDA).
Its approval in 1968 was followed by the approval of the DNA-
damaging agent dacarbazine (DTIC) in 1975. Twenty-three
years passed before another systemic therapeutic, the immune
system stimulator recombinant interleukin- 2 (aldesleukin;
Proleukin), was approved for the treatment of melanoma.
In 2011, ipilimumab (Yervoy) became the first immune-
checkpoint inhibitor approved by the FDA and the first new
systemic treatment for melanoma in 23 years. That year also
saw the approval of vemurafenib (Zelboraf), a therapeutic
that selectively inactivates the mutant form of the protein
BRAF that occurs in approximately 50 percent of melanomas.
In 2013, the FDA approved a second mutant BRAF–targeted
agent, dabrafenib (Tafinlar), as well as trametinib (Mekinist), a
therapeutic that targets other proteins in the BRAF signaling
pathway, MEK1 and MEK2. The combination of dabrafenib
and trametinib was FDA approved in 2014, as were two new
immune-checkpoint inhibitors, nivolumab (Opdivo) and
pembrolizumab (Keytruda). In 2015, the FDA approved the
use of ipilimumab and nivolumab in combination, as well
as a new MEK-targeted therapeutic, cobimetinib (Cotellic),
for use in combination with vemurafenib for the treatment
of BRAF-mutant metastatic melanoma. Note: this timeline
focuses on systemic, primary treatments for regional and
metastatic melanoma; other therapeutics have been approved
for the prevention of disease recurrence or the treatment of
localized lesions (see Supplemental Table 2, p. 131).
Figure adapted from Ref. ( 24)
1968 1975 1998 2011 2013 2014 2015
Combination of trametinib (Mekinist)
and dabrafenib (Tafinlar)
and nivolumab (Opdivo)