Until about 5 years ago, non–small cell lung cancer was considered
a homogeneous disease and was treated the same way in all patients, with only
factors such as age and performance status to serve as markers of how well a
patient might respond to treatment.
Virtually all patients with the disease received platinum-based
chemotherapy. But now, advanced NSCLC has been shown to have a variety of
different phenotypes, varying in histology and molecular markers that indicate
treatment for the disease is not a one-size-fits-all approach.
“Over the past 5 years, we’ve started recognizing differences
in effectiveness and toxicity of therapies in squamous cell cancers vs.
non-squamous cell cancers,” Edward Kim, MD, associate professor and
chief of Head and Neck Medical Oncology at The University of Texas MD Anderson
Cancer Center, told HemOnc Today. “More recently, we have had
the integration of biomarker assessment in a very early setting to
individualize therapy and not treat patients just based on histology or
There have been several practice-changing studies regarding the
treatment of NSCLC, ranging from the inclusion of bevacizumab (Avastin,
Genentech) in treatment for non-squamous NSCLC, to the addition of therapies
that target mutations in the epidermal growth factor receptor or translocations
in the anaplastic lymphoma kinase (ALK), to maintenance therapy after
completing induction chemotherapy.
Together, EGFR mutations and ALK translocations are present in
approximately 20% of patients with NSCLC. These discoveries, among others, have
led to an era of truly personalized medicine for advanced non-squamous NSCLC.
“Five years ago, when a diagnosis of NSCLC was made, everyone
received the same chemotherapy. The fact that we have changed this represents a
real paradigm shift in how we approach these patients,” Mark Kris,
MD, chief of the thoracic oncology service and the William and Joy Ruane
Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center, said in
an interview. “There are now early initiatives to do the same thing in
squamous cell NSCLC. Within the next 5 years, every lung cancer is going to be
analyzed at diagnosis, and treatment will likely be recommended because of
information obtained from the initial biopsy.”
Mark Kris, MD, chief of the thoracic oncology
service at Memorial Sloan-Kettering Cancer Center, said recent discoveries have
led to an era of personalized medicine for advanced non-squamous NSCLC.
Photo courtesy of Mark Kris, MD
HemOnc Today spoke with lung cancer experts to discuss
advances in treatment for advanced NSCLC, the most important changes to the
treatment paradigm within the past 5 years, and future directions in research
for what is now known as a heterogeneous disease.
The first step after diagnosing a patient with NSCLC is to determine the
histology, according to Corey Langer, MD, professor of medicine and
director of thoracic oncology at the University of Pennsylvania.
“In the past, we were somewhat cavalier about this,” Langer
said in an interview. “If the pathologist said it was NSCLC, they
didn’t really test the biopsy for other histologies. Now, we need to know
whether the NSCLC is squamous cell carcinoma or non-squamous cell carcinoma.
The pathologist has become a major partner in our interdisciplinary care of
This is important because the results of two trials in the past 5 years
have shown a clear difference in treatment effectiveness based on the different
For example, the ECOG 4599 trial — published in The New
England Journal of Medicine in 2006 — was a phase 3 trial of 898
patients with recurrent or advanced NSCLC who were randomly assigned to
paclitaxel (Taxol, Bristol-Myers Squibb) plus carboplatin alone or with
bevacizumab. Overall, patients who received bevacizumab plus chemotherapy had a
PFS of 12.3 months vs. 10.3 months for patients who received chemotherapy
alone. But the treatment benefit was confined to patients with non-squamous
cancers, as patients with squamous cell cancers had a higher incidence of
“This trial irrevocably changed the therapeutic landscape for
advanced NSCLC,” Langer said. “It is the first trial I know of in
advanced NSCLC that makes a histologic distinction between patients who would
benefit or not benefit from treatment. The trial is also significant because
bevacizumab is the first targeted therapy to be approved in combination with
chemotherapy for advanced NSCLC.”
In another trial, published in the Journal of Clinical
Oncology in 2008, researchers compared cisplatin plus gemcitabine
(Gemzar, Lilly) with cisplatin plus pemetrexed (Alimta, Lilly) in
chemotherapy-naive patients with advanced NSCLC. They found the OS was similar
for both regimens. However, for patients who had adenocarcinoma instead of
squamous cell cancer, the OS was superior for those who received the cisplatin
plus pemetrexed: 12.6 months, compared with 10.9 months for the cisplatin plus
“This trial is very important because of the inclusion of histology
as a pre-specified comparator,” Langer said. “Molecular models had
shown that pemetrexed might work better in adenocarcinoma than in squamous cell
cancer, and it panned out clinically.”
One of the most significant discoveries in NSCLC is that approximately
10% to 12% of patients with NSCLC harbor an EGFR mutation. This is significant
because these patients are eligible to receive an EGFR inhibitor as their
single treatment, compared with the chemotherapy regimen that is much more
In the IPASS study — a phase 3, open-label study conducted in Asia
— more than 1,200 previously untreated patients with advanced
adenocarcinoma were randomly assigned to receive gefitinib (Iressa,
AstraZeneca) or the standard treatment of carboplatin plus paclitaxel.
The 12-month rate of PFS was 24.9% for patients who received gefitinib
and 6.7% for patients who received carboplatin and paclitaxel, demonstrating
the noninferiority of gefitinib, and also the superiority of gefitinib in the
intent-to-treat population. Perhaps the most significant finding of this study
is the fact that, in a subgroup of 261 patients with EGFR mutations, PFS was
significantly longer in patients who received gefitinib compared with those who
received carboplatin and paclitaxel. In the subgroup of patients without the
EGFR mutations, PFS was significantly longer in those who received carboplatin
and paclitaxel compared with gefitinib.
This practice-changing study, published in The New England Journal
of Medicine in 2009, included patients who fit the bill for EGFR
“What we know from these years of experience is that patients with
EGFR mutations define a distinct subset of patients,” Alice Shaw, MD,
PhD, assistant professor of medicine at Harvard Medical School and
attending physician in the Thoracic Cancer Program at Massachusetts General
Hospital, told HemOnc Today. “They tend to be never-smokers,
have adenocarcinoma and are more often women than men. Almost all oncologists
are aware of the importance of EGFR mutations and nowadays will screen for
these mutations upfront, especially in patients with those particular
Although gefitinib was the EGFR inhibitor used in the IPASS study, these
data were extrapolated and applied to erlotinib (Tarceva, Genentech), the
EGFR-inhibitor used in the United States. Erlotinib is not indicated for this
use, but its use for this setting is recommended in both ASCO and National
Comprehensive Cancer Network (NCCN) guidelines, and most insurance companies
cover its use for this purpose, according to Kim.
There is some question as to whether patients should receive front-line
erlotinib. To determine whether a patient would benefit from it, tumors must
undergo gene sequencing to identify the presence of EGFR mutations. This is not
always done before the patient begins therapy.
“Clearly, anyone with an EGFR mutation should receive erlotinib as
soon as possible,” Roy S. Herbst, MD, professor of medicine and
chief of medical oncology at the Yale Cancer Center, said in an interview.
“Some may say that the order in which you give the drugs doesn’t
matter. But chemotherapy is more toxic than an EGFR inhibitor, and some
patients may not make it through their chemotherapy to receive the erlotinib.
Earlier truly is better when it comes to erlotinib.”
However, in a second-line or third-line setting, erlotinib’s
benefit is not necessarily restricted to patients with EGFR mutations. In the
INTEREST study published in The Lancet in 2008, researchers
compared gefitinib with docetaxel (Taxotere, Sanofi-Aventis) in 1,466 patients
with advanced or metastatic NSCLC who previously were treated with
The study found gefitinib was not inferior to docetaxel for OS. More
importantly, gefitinib was not superior to docetaxel in patients with EGFR
mutations, indicating gefitinib also worked as a second-line or third-line
treatment in patients with EGFR wild-type.
“This was an important paradigm because, prior to this data, most
people thought that erlotinib should be saved as a last-ditch effort for
patients who were really sick,” Kim said. “We’re finding that
erlotinib, aside from being better for the population of patients with EGFR
mutations, is also effective in the non-mutated population.”
It now is necessary to use genetic analysis to determine which patients
without the EGFR mutation also will benefit from erlotinib, Herbst said. In the
BATTLE trial, researchers found a gene signature that might identify which
patients who are EGFR wild-type might respond to erlotinib. This is being
validated now in large data sets.
The biggest newcomer to affect the treatment of NSCLC is the ALK
translocation, Shaw said. ALK, discovered as a new target for NSCLC about 4
years ago, is present in about 6% to 8% of all non-squamous lung cancers.
“This is very exciting because ALK, like EGFR, is a kinase that can
be turned off with kinase inhibitors,” Shaw said. “When this
discovery was made, there was already an ALK inhibitor in the clinic that
hadn’t originally been developed for this purpose. When the first report
came out, the inhibitor was already being tested in a phase 1 trial. In the
beginning, nobody knew that this drug was going to be very relevant to a subset
of lung cancer patients.”
Patients with the ALK translocation often have characteristics similar
to those patients with EGFR mutations. They tend to be never-smokers and have
In a study published in The New England Journal of Medicine
in 2010, researchers analyzed the effect of ALK inhibition in 82 patients who
had advanced ALK-positive disease. The patients received 250 mg of the
ALK-inhibitor crizotinib (Xalkori, Pfizer) twice daily in 28-day cycles. After
a mean treatment duration of 6.4 months, the overall response rate was 57%.
The FDA granted the drug accelerated approval based on the results of
two single-arm studies. The first study included 136 patients with locally
advanced or metastatic ALK-positive NSCLC, according to the FDA’s summary
review document. After a median duration of treatment of 22 weeks, the overall
response rate was 50%. The second study included 119 patients with locally
advanced or metastatic ALK-positive NSCLC. The median duration of treatment was
32 weeks, and the overall response rate was 61%.
The ALK translocation is present in approximately 6,000 to 11,000
patients with lung cancer per year, according to Kris. That number is high
compared with other cancers.
“That’s more than the number of people with testes cancer, and
about 11,000 people per year have chronic myelogenous leukemia, which has had
staggering success with imatinib,” Kris said. “Is it the number of
people with prostate cancer? No. But it’s quite a substantial number, and
for those people, it makes a huge difference in their lives.”
There are two active phase 3 trials that are testing crizotinib in
patients with ALK-positive NSCLC. In the PROFILE 1007 trial, patients are being
randomly assigned to crizotinib or standard-of-care chemotherapy with
pemetrexed or docetaxel. The trial will include an estimated 318 patients, and
the primary objective is PFS. In the PROFILE 1014 trial, patients are being
randomly assigned to crizotinib or chemotherapy with pemetrexed and cisplatin
or pemetrexed and carboplatin. This trial will include an estimated 334
patients, and the primary objective also is PFS.
Exempt from mutation or translocation status, maintenance therapy is a
potential option for all patients with NSCLC, a paradigm that also has shifted
within the last 5 years.
“When patients finished their chemotherapy, the traditional
approach was to watch and wait,” Langer said. “This is still an
option, but there is certainly justification for using a maintenance therapy
that could extend survival.”
Among the options for maintenance therapy is erlotinib, which has shown
a benefit as a second- or third-line treatment and as a maintenance therapy
even among patients without an EGFR mutation. But the big player in maintenance
therapy is pemetrexed.
In a 2009 study published in The Lancet, researchers
randomly assigned 663 patients with stage IIIB or stage IV NSCLC to maintenance
pemetrexed plus best supportive care or placebo plus best supportive care. All
of the patients had received four cycles of platinum-based chemotherapy and had
not progressed. Patients who received pemetrexed had a significantly improved
PFS of 4.3 months vs. 2.6 months for those who received placebo. OS also was
significantly improved for those taking pemetrexed: 13.4 months vs. 10.6
“Maintenance therapy for lung cancer is a terminology that we never
really used or taught to our fellows,” Kim said. “Now it is part of
the common verbiage. Is it required that patients take maintenance? No. But is
it a standard option? Yes.”
As exciting as the research findings have been within the past 5 years,
there still is a long way to go.
“Patients with EGFR mutations or ALK translocations comprise only
20% of the patient population with NSCLC,” Kim said. “We’ve got
another 80% of the population to go.”
According to Kim, one protein that is being explored is Met. Some lung
cancers have Met overexpression, which leads to resistance to erlotinib. In a
phase 2 study, the drug MetMAb (Roche) was shown to double the PFS when
combined with erlotinib, compared with erlotinib alone, in patients with Met
overexpression. The addition of MetMAb to erlotinib also tripled the OS in
patients with Met overexpression: The OS was 12.6 months for patients who
received the combination vs. 3.8 months for patients who received erlotinib
alone. Those patients without Met overexpression had worse outcomes when given
the combination treatment compared with those who received only erlotinib.
KRAS proteins also are a potential target in NSCLC, according to Langer.
Patients who have the KRAS mutation are not likely to have an EGFR mutation or
an ALK translocation, making this another potential new group of patients.
However, a specific drug to target this mutation has not yet been identified.
There is a striking need to help patients with this mutation, as they tend to
have tumors that are resistant to most therapies, Kim said.
“Understanding how to target mutant KRAS is going to be key to
future progress in this disease,” Herbst said. “As we start to
sequence tumors more fully, this is going to result in better understanding of
all the different mutations that can occur in these tumors, and how to combine
drugs better. It will also help identify early on resistance pathways so that
we can combine drugs to prevent resistance. Clearly, it’s important to
understand exactly the kind of lung cancer we are dealing with to treat it in
the most effective way.” – by Emily Shafer
For more information:
- Ciuleanu T. Lancet. 2009;374:1432-1440.
- FDA. Summary review. 2011.
Accessed Oct. 31, 2011.
- Kim ES. Lancet. 2008;372:1809-1818.
- Kwak EL. N Engl J Med. 2010;363:1693-1703.
- Mok TS. N Engl J Med. 2009;361:947-957.
- Sandler A. N Engl J Med. 2006;355:2542-2550.
- Scagliotti GV. J Clin Oncol. 2008;26:3543-3551.
Disclosure: Dr. Herbst reports no relevant financial disclosures. Dr.
Kim received research support/honorarium and is a consultant for Lilly,
Genentech and ImClone. Dr. Kris is a consultant to Pfizer, Boehringer Ingelheim
and Roche China. Dr. Langer serves on the advisory board for Lilly, Genentech,
Bristol-Myers Squibb, Pfizer, Bayer and Celgene, and receives research support
from GlaxoSmithKline and Genentech. Dr. Shaw is a consultant for Pfizer.
Molecular testing should be standard for patients with lung cancer. The
testing, at minimum, should include testing for EGFR mutation status, ALK
translocation status and KRAS mutation status. Treatments are based on this
information. There really is no one group of patients with NSCLC that you can
avoid testing, because you will find these abnormalities that will guide
In patients with EGFR mutations, starting with a tyrosine kinase
inhibitor (TKI) can improve outcome. If you have an ALK translocation, starting
with an ALK inhibitor can improve outcome. It makes such a difference because
how you treat patients depends on their molecular profile. A study in The
New England Journal of Medicine conducted in Asia showed a clear-cut
benefit to giving an EGFR inhibitor first line compared with chemotherapy.
There also is a big study in The New England Journal of Medicine
that showed giving an ALK inhibitor upfront improves outcomes.
Against activated oncogenic cancers, you want to give a TKI, when it is
effective, as early as you can in the course of treatment. Right now, we use
them as single agents. Down the road, it may make sense to use them in
combination with chemotherapy, an approach that is being studied.
Thomas Lynch, MD, is the Richard Sackler and Jonathan Sackler
Professor of Medicine and director of the Yale Cancer Center. References: Mok
TS. 2009;361:947-957. Kwak EL. 2010;363:1693-1703. Disclosure: Dr. Lynch
reported no relevant financial disclosures.
There is a striking disparity between the NCCN guidelines and ASCO
guidelines because they’re totally different. The NCCN guidelines
recommend EGFR mutation testing upfront in every patient with advanced
nonsquamous NSCLC. ASCO guidelines say all mutation testing remains
investigational, is of unproven benefit, and is not routinely recommended. Any
time there are two disparate recommendations on a complex topic, I think the
optimal answer is in between.
There is a clear incentive to identifying an EGFR mutation or ALK
translocation. However, there are certain populations who are going to be more
or less likely to have a mutation or translocation. The patients who have a
minimal or no history of smoking have a significant chance of having an EGFR
mutation, and I would recommend screening in these patients. Patients with an
adenocarcinoma also have a strikingly higher probability than other
In the other extreme, if patients have a very significant smoking
history, and if they have a squamous or a large-cell carcinoma histology, the
probability is not zero but is exceptionally low. In that setting, you cannot
make a strong argument for testing for an EGFR mutation to determine timing of
erlotinib, which you could give first-, second- or third-line when there is no
clear evidence of a survival benefit if the drug is given immediately.
The ALK story is a little more complex. The only way you can receive the
therapy is if you test positive for the translocation, and you won’t test
positive if you don’t test at all. But if this typically is a $1,500 test,
it’s difficult to decide that society should assume the cost of spending
$60,000 or more to even identify one patient with a positive result — if
the probability is in the 1% to 2% range for a longtime smoking patient with a
squamous NSCLC — just to enable the possibility of receiving a
non-curative therapy that then will cost nearly $10,000 per month.
At the same time, tissue is of limited availability. Many patients would
require an extra biopsy, which is not without risk. It also adds another level
of expense — in the range of thousands of dollars — to obtain more
Society simply doesn’t have infinite resources to do every test,
regardless of cost or probability that the result will impact patient care. We
can no longer practice in a way in which cost of our management is completely
insensitive to magnitude of benefit.
Molecular oncology is the future, and I definitely want to get more
tissue as opposed to less any time the patient is diagnosed, but I would not
want to be so heavy-handed to say it is mandatory to test everybody.
Howard (Jack) West, MD, is a medical oncologist at the Swedish Cancer
Institute in Seattle. Disclosure: Dr. West reports no relevant financial