72 AACR CANCER PROGRESS REPORT 2017
responds to the ALK-targeted therapeutic eventually
relapse because the cancer becomes resistant to the agent.
In many cases, crizotinib resistance emerges because
NSCLC cells acquire additional ALK mutations. Research
has shown that brigatinib is able to block many of the
unique forms of ALK that result from these new mutations
(153). It was approved after phase II clinical trial results
showed that brigatinib treatment caused complete or
partial tumor shrinkage in about 50 percent of patients
with advanced, crizotinib-resistant NSCLC driven by
ALK (154). Brigatinib was also able to shrink tumors that
had metastasized to the brain in more than 40 percent of
patients who had measurable brain metastases, which is
something that not all ALK-targeted therapeutics are able
to do so effectively.
Brigatinib is the fourth ALK-targeted therapeutic to be
approved for treating patients with metastatic NSCLC
fueled by ALK mutations. Two, crizotinib and ceritinib
(Zykadia), are approved for use as the initial treatment
for patients newly diagnosed with this disease. The other
two, brigatinib and alectinib (Alecensa), are approved only
for treating patients whose cancer has either progressed
after treatment with crizotinib or has failed to respond to
crizotinib in the first place. Identifying the order in which
the four FDA-approved ALK-targeted therapeutics should
be used to provide the maximum benefit for patients is
an area of intensive research investigation. Initial results
from one large phase III clinical trial recently showed that
alectinib treatment significantly lengthened the time before
disease progressed among patients newly diagnosed with
metastatic NSCLC fueled by ALK mutations compared
with crizotinib treatment (155). Whether this holds true
for patient survival and how it affects long-term outcomes
following sequential use of the four FDA-approved ALK-targeted therapeutics requires further research.
Treatment with Immunotherapeutics
Cancer immunotherapeutics work by unleashing the power
of a patient’s immune system to fight cancer the way it fights
pathogens like the virus that causes flu and the bacterium
that causes strep throat. Not all immunotherapeutics work
in the same way (see sidebar on How Immunotherapeutics
Work, p. 73).
The use of immunotherapeutics in the treatment of cancer
is referred to as cancer immunotherapy. In recent years, it
has emerged as one of the most exciting new approaches
to cancer treatment that has entered the clinic. This is in
part because some of the patients with metastatic disease
who have been treated with these revolutionary anticancer
treatments have had remarkable and durable responses,
raising the possibility that they might be cured. It is also
because some of the immunotherapeutics have been shown
to work against an increasingly broad array of cancer types
(see Figure 15, p. 74).
Despite the significant advances that have been made,
only a minority of patients who are treated with an FDA-approved immunotherapeutic have a remarkable and
durable response. In addition, the current FDA-approved
immunotherapeutics are not highly active against all
types of cancer. Identifying ways to increase the number
of patients for whom treatment with an immunotherapeutic
yields a remarkable and durable response is an area of
intensive basic and clinical research investigation.
Several approaches are already being tested in clinical
trials for a wide array of cancer types, including evaluating
how well immunotherapeutics that are already FDA
approved work in combination and how well they work
in combination with investigational immunotherapeutics
that function in novel ways, such as by directly boosting
the killing power of cancer-fighting immune cells.
Also being tested are various ways to combine FDA-approved immunotherapeutics with other types of
anticancer treatments, including radiotherapy, cytotoxic
chemotherapeutics, and molecularly targeted therapeutics
(see Improving Outcomes by Combining Existing
Treatments, p. 56).
As research deepens our scientific understanding of the
immune system and how it interacts with cancer cells,
we are likely to develop many new immunotherapeutics
and identify novel ways to use those that we already have.
One approach that is already showing incredible promise, in
particular for children with acute lymphocytic leukemia, is
referred to as CAR T-cell therapy (156, 157). Here, however,
we focus on immunotherapeutics that were approved by
the FDA in the 12 months covered by this report, August
1, 2016, to July 31, 2017.
Releasing the Brakes on the Immune System
Research has shown that immune cells called T cells are
naturally capable of destroying cancer cells. It has also
shown that some tumors evade destruction by T cells
because they have high levels of proteins that attach to and
trigger brakes on T cells, stopping them from attacking
the cancer cells. These brakes, which are on the surface of
T cells, are called immune-checkpoint proteins.
This knowledge has led researchers to develop
immunotherapeutics that release T-cell brakes. These
immunotherapeutics are called checkpoint inhibitors.
The first checkpoint inhibitor to be approved by the
FDA was ipilimumab (Yervoy). It targets the immune-
checkpoint protein CTLA4, protecting it from the proteins
continued from p. 69