The EGFR mutation and precision therapy for
lung cancer
Outcomes in advanced lung cancer have seen meaningful improvement in the
past decade thanks to new precision drug therapies. Because tumors usually
develop resistance to the drugs, scientists are pursuing second-generation agents
to regain control.
one of the early
Background
liferation and
No form of cancer is as deadly to Americans as lung cancer, which is expected
to cause 159,260 deaths in 2014 with an estimated 224,210 new diagnoses of the
disease. In patients with advanced lung cancer, surgery, radiation, and chemotherapy have failed to significantly improve the results.
In the late 1990s, researchers began to develop a new strategy that identified
specific alterations, such as mutations, in the genetic code of tumors that allowed
cancer cells to survive and grow. These DNA alterations became the focus of
“targeted” drugs that blocked the cancer-driving effects of the mutations, slowing their growth or shrinking the tumor. Unlike chemotherapy, these new drugs
limited their attack to cancer cells carrying the mutations – sparing normal cells
and reducing toxic side effects.
In 2004, researchers at Dana-Farber and elsewhere identified vulnerability in
some patients’ lung cancers – and began exploiting that weakness with designer
cancer drugs. It was the opening of precision “targeted therapy” for lung cancer,
and for certain patients in advanced stages of the disease, these treatments have
made a meaningful difference.
growth of cells.
Targeting EGFR
targets in lung
cancer was
the epidermal
growth factor
receptor (egfr),
a component
of the molecular
signaling
pathway that
controls pro-
One of the early targets in lung cancer was the epidermal growth factor receptor (EGFR), a component of the molecular signaling pathway that controls proliferation and growth of cells. The EGFR protein sits on the surface of the cell,
where it responds to stimulation by several different proteins (ligands), setting
off a chain of signals inside the cell all the way to the nucleus, turning on growth
genes when needed.
The mutation in the EGFR gene leads to overactivation, and activation independent of the ligand, of the EGFR protein in the cancer cells. The effect is to
prod cells in the lungs to surge with uncontrolled, dangerous division and spread.
At the same time, the mutation blocks signals that normally cause unwanted cells
to self-destruct.
Iressa (gefitinib), a drug that selectively inhibits EGFR, had been tried against
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The EGFR mutation and precision therapy
for lung cancer
prior to matching
targeted drugs to
the egfr mutation
in patients’ tumors
when present,
chemotherapy was
the only option
for patients with
advanced, metastatic
lung cancer.
non-small cell lung cancer (NSCLC) without much success – except, that is,
with a small minority of patients whose lung tumors were dramatically beaten
back by the drug. Often, these patients were nonsmokers.
These “exceptional responses” were interesting, but too rare in most experts’
opinion to pursue Iressa as a lung cancer treatment in the United States. Yet in
Japan, Iressa was more successful and an approved lung cancer treatment there.
Delving into this disparity, Dana-Farber scientists analyzed the DNA of
NSCLC tumors from American and Japanese patients. The gene that makes
the EGFR protein, they found, was mutated in lung tumors from 15 Japanese
patients but only in one patient from the United States.
Another part of the puzzle dropped into place when a Dana-Farber team identified the same EGFR mutation in a tumor from a woman with the adenocarcinoma type of NSCLC. These patients with the EGFR mutation – never smokers,
Japanese, women, and those with adenocarcinoma – were the very same group
where Iressa treatment had succeeded. A further study found EGFR mutations
in lung tumors that had shrunk with Iressa treatment. Tumors from patients who
hadn’t responded to the drug lacked the EGFR mutation.
The Dana-Farber scientists published these results in 2004, along with similar
reports from other researchers. Using a new gene test, physicians could now
identify the 10-15 percent of NSCLC patients in the United States and Europe
who were likely to respond to Iressa. (In Asia, the mutant EGFR protein is
present in the tumors of about 40 percent of patients with NSCLC.) EGFR
mutation testing is now part of every single treatment guideline in oncology
and is endorsed by major cancer organizations including the American Society
of Clinical Oncology.
It was the first demonstration that a targeted therapy could be an effective
treatment in lung cancer. A different oral EGFR-inhibitor drug, Tarceva (erlotinib) has since been approved for first-line treatment for advanced patients with
EGFR-mutant NSCLC, and for second or third-line treatment for patients whose
cancer has continued to spread after chemotherapy. A second agent, Afatinib
(Gilotrif) is also now approved for first-line treatment for advanced EGFR
mutant NSCLC.
Bruce Johnson, MD, Dana-Farber’s chief clinical research officer, co-led the
2004 study along with colleagues Pasi Jänne, MD, PhD; Matthew Meyerson,
MD, PhD, and William Sellers, MD (now at the Novartis Institutes for Biomedical Research). Prior to matching targeted drugs to the EGFR mutation in
patients’ tumors when present, chemotherapy was the only option for patients
with advanced, metastatic lung cancer, with only 20 to 40 percent of such patients responding to the traditional treatment.
The outlook is much better for patients whose tumors test positive for the
EGFR mutation and receive a targeted drug. Remissions, and average survival,
is much longer.
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2.
The EGFR mutation and precision therapy
for lung cancer
Beyond EGFR
investigators are
evaluating whether
genetic mutations
can be identified from
small pieces of dna
that tumors have
shed in the blood.
Researchers at Dana-Farber and elsewhere have identified other genetic subsets
of lung cancer that may be targeted, as well. About five percent of non-small cell
lung cancers have a glitch in a gene called ALK that fuels their growth. The oral
drugs Xalkori (crizotinib) and Zykadia (ceritinib) can shrink these tumors in
many cases.
Dana-Farber/Brigham and Women’s Cancer Center has, for several years, tested
patients with adenocarcinoma of the lung – which accounts for about 40 percent
of all lung cancers in the United States –for nearly a dozen mutations that can
potentially be targets of precision drugs. In 2013, scientists introduced targeted next
generation sequencing which increased the number of genes evaluated to about
300. Today, all patients with lung cancer are offered this detailed testing which has
vastly increased our ability to both study genetic alterations in lung cancers and use
this information to guide therapy.
Today, about half of all lung cancer patients at Dana-Farber/Brigham and Women’s Cancer Center are cared for with targeted drugs. In addition, investigators
in the Thoracic Oncology Program, led by Geoffrey Oxnard, MD, are evaluating
whether genetic mutations can be identified from small pieces of DNA that tumors
have shed in the blood. This “liquid biopsy” approach allows real-time monitoring of changes that may be occurring within a tumor as a result of treatment with
targeted therapies. In addition, it may offer an alternative approach to tumor-based
genotyping.
Unfortunately, the most common tumor-driving mutation in lung adenocarcinomas has proved the toughest. Mutations in the oncogene KRAS are present in about
30 percent of these adenocarcinomas; no drugs can block KRAS because of its
particular configuration.
Rather than aim drugs at mutant KRAS directly, scientists are testing new strategies that attack other parts of the overactive KRAS signaling pathway. In early
2014, researchers led by David Barbie, MD, and Kwok-Kin Wong, MD, Ph.D of
Dana-Farber reported that two drugs that inhibit the action of proteins, including
MEK, “downstream” from the KRAS protein -- that is, they help carry out orders
from KRAS -- shut down growth of lung tumor cells in the laboratory and in mice.
These results, researchers feel, merit clinical testing in lung cancer patients. Another MEK inhibitor, selumetinib, is currently being evaluated in a DFCI-led phase
3 clinical trial in conjunction with the chemotherapy drug docetaxel for patients
with KRAS-mutant lung cancer. This is the first and largest phase 3 trial conducted
specifically with patients who have KRAS mutant lung cancer.
Over time, targeted drugs may lose their effectiveness when tumor cells develop
resistance. It may take months or years, but inevitably the cancer will “learn” to
grow again.
Resistance can develop when additional mutations cause the original target
protein to shape-shift: its configuration changes so the drug molecules no longer
bind with it effectively. In addition, the tumor may develop new growth signaling
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3.
The EGFR mutation and precision therapy
for lung cancer
scientists and clinicians are already
combining egfr
inhibitors with
drugs that inhibit
other critical
cancer cell signaling proteins, or
with immunotherapy
pathways that don’t depend on the mutated pathway that the drug had blocked.
Dana-Farber scientists led by Jänne were the first to show how NSCLC tumors
change to escape the grip of EGFR inhibitor drugs like Iressa or Tarceva. After a
year or more on these drugs, the scientists found, tumors in 50 percent of patients
acquired an additional mutation that opened another route to growth. Moreover,
tumors in 20 percent of the patients revealed that the cells had amplified – made
extra copies of -- another gene, MET. When amplified, this protein can promote
cancer cell survival. In some cases, the scientists reported, a small number of these
resistant lung cancer cells were present in the tumor even before treatment with
Iressa or Tarceva, strengthening the tumor against the EGFR-targeted drugs. The
findings suggest that a combination of drugs from the very start of therapy can
produce longer remissions in these patients.
Dana-Farber scientists are developing second-generation treatments for EGFRmutant lung cancers that have acquired resistance to the original inhibitors. Jänne,
Nathanael Gray, PhD, and colleagues reported in 2009 that they had designed a
compound that binds to a “resistance mutation” in the EGFR protein in lung tumors
that are resistant to Iressa and Tarceva. The compound showed encouraging activity
in EGFR inhibitor-resistant mouse models of lung cancer.
Early clinical studies of similar compounds (including AZD9291 and CO-1686)
have shown encouraging activity with patients who have developed resistance to
current EGFR inhibitors and whose cancers harbor a specific resistance mutation
(called EGFR T790M). These agents, currently in late-stage clinical trials, have
been granted breakthrough therapy status by the Food and Drug Administration
based on their encouraging early clinical efficacy.
Scientists from Dana-Farber and elsewhere have shown that therapies targeting
EGFR mutations constitute a new weapon against deadly lung cancer. But cancer’s
ability to evolve and escape these precision treatments means continued persistent
and innovative research is needed to stay one step ahead. Scientists and clinicians
are already combining EGFR inhibitors with drugs that inhibit other critical cancer
cell signaling proteins, or with immunotherapy. These approaches are now in earlystage clinical development and researchers are hopeful that they will vastly improve
outcomes.
Selected References
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4;304(5676):1497-500.
Jänne PA1, Gurubhagavatula S, Yeap BY, et al Outcomes of patients with
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The EGFR mutation and precision therapy
for lung cancer
advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on
an expanded access study. Lung Cancer. 2004 May;44(2):221-30.
Jänne PA, Engelman JA, Johnson BE, et al. Epidermal growth factor receptor
mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol. 2005 May 10;23(14):3227-34.
Johnson BE, Jänne PA. et al. Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Res. 2005 Sep 1;65(17):7525-9.
Engelman JA1, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to
gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007
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Cappuzzo F1, Jänne PA, Skokan M, et al. MET increased gene copy number and
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Oncol. 2009 Feb;20(2):298-304. doi: 10.1093/annonc/mdn635.
Hammerman PS1, Jänne PA, Johnson BE, et al. Resistance to Epidermal Growth
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Turke AB1, Zejnullahu K, Wu YL, Song Y, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010 Jan
19;17(1):77-88. doi: 10.1016/j.ccr.2009.11.022.
Sasaki T1, Koivunen J, Ogino A, Yanagita M, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res.
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Xu L1, Kikuchi E, Xu C, et al. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers co-driven by mutant EGFR
containing T790M and MET. Cancer Res. 2012 Jul 1;72(13):3302-11. doi:
10.1158/0008-5472.CAN-11-3720.
Chong CR1, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013 Nov;19(11):1389-400. doi: 10.1038/nm.3388.
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5.