NCT02143050 and NCT01638676; phenformin:
NCT03026517), HSP90 inhibitors (XL888:
NCT02721459; AT13387: NCT02097225), and
One complexity affecting management of
resistance in the targeted therapy landscape
remains tumor heterogeneity, particularly intra-and intertumoral heterogeneity, which may
explain the apparent contradiction between
continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting
slower progression of resistant tumors on cessation of BRAF inhibitors.91–94 These data provide
a rationale to investigate intermittent dosing
regimens with BRAF/MEK inhibitors; several
studies exploring this approach are ongoing
(NCT01894672 and NCT02583516).
Given the specificity, adaptability, and mem-
ory response associated with immunotherapy,
it is likely that these agents will be used to treat
the majority of patients regardless of mutational
status. Hence, identifying predictive biomarkers
of response to immune checkpoint inhibitors
is vital. The presence of CD8+ T-cell infiltrate
and IFN-γ gene signature, which indicate an
“inflamed” tumor microenvironment, are highly
predictive of clinical benefit from PD- 1 inhibi-
tors.95,96 However, not all PD- 1 responders have
“inflamed” tumor microenvironments, and not
all patients with an “inflamed” tumor micro-
environment respond to immune checkpoint
inhibitors. The complexity of the immune sys-
tem is reflected in the multiple non-redundant
immunologic pathways, both positive and nega-
tive, with checkpoints and ligands that emerge
dynamically in response to treatment. Given the
dynamic nature of the immune response, it is
unlikely that any single immunologic biomarker
identified pre-treatment will be completely pre-
dictive. Rather, the complexity of the biomarker
approach must match the complexity of the
immune response elicited, and will likely incor-
porate multifarious elements including CD8+
T-cell infiltrate, IFN-γ gene signature, and addi-
tional elements including microbiome, genetic
polymorphisms, and tumor mutation load. The
goal is to use multiple markers to guide devel-
opment of combinations and then, depend-
ing on initial response, to examine tumors for
alterations to guide decisions about additional
treatment(s) to improve responses, with the even-
tual goal being durable clinical responses for all
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