54 AACR Cancer Progress Report 2013
Just 16 percent of lung
cancer patients survive five
years after diagnosis ( 1).
Figure 15: Signaling Networks: The Cell’s Circuitry. Just as a circuit board has many interacting circuits to perform its various
functions, so too, do cells. Cellular circuits are referred to as signaling networks, each of which carries out a primary function, and also
interacts with other parts of the network or other networks. Here, a few of the interacting cellular signaling networks are depicted as
electronic circuits; the highlighted circuit is a simplified representation of the MAPK signaling network critical to many cancers. Although
there are two points in the highlighted circuit at which it can be inactivated, there are multiple points at which the MAPK signaling
network can potentially be inactivated. Mutations in the BRAF component of the MAPK signaling network (switch) that enhance network
activity often drive melanoma. However, drugs that inactivate this point in the network (vemurafenib and dabrafenib) do not eliminate
all BRAF-activated melanoma cells. By inactivating a second component of the MAPK signaling network, MEK (switch), with the drug
trametinib, more of the melanoma cells can be eliminated.
patients with metastatic non-small cell lung carcinoma driven by either of the mutations detected by the
diagnostic — EGFR exon 19 deletions or an EGFR exon 21 L858R substitution. Prior to the approval of
the companion diagnostic, oncologists could only use erlotinib to treat patients with metastatic non-small
cell lung carcinoma after they had received at least one other therapy. Thus, the companion diagnostic is
helping a substantial number of patients with non-small cell lung carcinoma save time in their quest to
find the best drug to treat their cancer.
In July 2013, the FDA approved a new EGFR-targeted therapy, afatinib (Gilotrif), for the treatment of
patients with non-small cell lung carcinomas with EGFR exon 19 deletions or an EGFR exon 21 L858R
substitution. Patients with these mutations can be identified using the cobas EGFR Mutation Test or
the therascreen EGFR RGQ PCR Kit, which was FDA approved at the same time as afatinib. The ability
of these companion diagnostics to hone in on those patients most likely to benefit from afatinib (151)
provides an example of the importance of developing new anticancer drugs alongside companion
diagnostics to ensure that they reach the patients who need them as quickly as possible.