Download Best Practices in Treatment Selection for Patients With Advanced

Leading experts discuss treatment
strategies for advanced NSCLC.
Tulip. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com.
Best Practices in Treatment Selection for Patients
With Advanced NSCLC
Mark A. Socinski, MD, and Nathan A. Pennell, MD, PhD
Summary: Worldwide, lung cancer is the most prevalent form of cancer, and its non–small-cell subtype constitutes up to 85% of cases. Overall, lung cancer is the most common cause of cancer-related death in the United
States for both sexes, and its 5-year survival rate is 17%. It is a heterogeneous disease characterized by a variety
of biomarkers and differing histologies. Non–small-cell lung cancer may be squamous or nonsquamous in nature
and fueled by a number of oncodrivers. Obtaining sufficient tissue during biopsy to perform thorough biomarker
testing is a challenge but essential for the modern, targeted therapeutic environment. Although platinum-based
doublets still play a major role in first-line treatment, novel therapeutic agent targeting BRAF, EGFR, ALK, and
ROS1, as well as agents targeting the T790M mutation, may offer options for patients whose disease fails to respond to initial therapy or relapses following an initial response. The emergence of immunotherapy as second-line
standard therapy has changed the treatment paradigm. Some patients will have more favorable outcomes in the
first-line setting with immunotherapy. However, managing lung cancer has become more complex than it was
15 years ago when the challenge of treatment was seen as being only binary, ie, small-cell vs non–small-cell disease.
Introduction
Non–small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies that constitutes
80% to 85% of lung cancers.1 Adenocarcinoma is the
most common subtype of NSCLC and accounts for
nearly 50% of cases.1 Worldwide, lung cancer represents the most common type of cancer: 1.8 million new
From the Florida Hospital Cancer Institute (MAS), Orlando, Florida, and the Cleveland Clinic (NP), Taussig Cancer Institute, Cleveland, Ohio.
Address correspondence to Mark A. Socinski, MD, Florida Hospital Cancer Institute, Executive Offices, 11th Floor, 601 E. Rollins
Street, Orlando, FL 32803. E-mail: [email protected]
Dr Socinski has received grants/research support from BristolMyers Squibb, Clovis, Genentech, Lilly, Pfizer, and Synta, and has
served on the speakers’ bureaus for Bristol-Myers Squibb, Celgene,
and Genentech. Dr Pennell serves as a consultant/independent
contractor for AstraZeneca and Boehringer Ingelheim.
This monograph is supported by independent educational grants
from Boehringer Ingelheim, Genentech, and Lilly.
2 Cancer Control
cases of lung cancer were diagnosed in 2012 alone,
and it is estimated to be responsible for 1 in 5 cancer-related deaths each year.2 It remains the most common cancer in men.2
Death rates from lung cancer in the United States
have declined by 38% in men since 1990 and by 12%
in women since 2002, primarily due to the decrease
in smoking prevalence.3 Nonetheless, lung cancer remains the second most common cancer in both men
and women in the United States, with 117,920 and
106,470 estimated new cases diagnosed in men and
women, respectively, in 2016.3 Lung cancer is the leading cause of cancer-related death in the United States,
with an estimated 85,920 deaths occurring in men and
72,160 deaths among women.4 This is partly because
16% of lung cancers are diagnosed at a localized stage
when the 5-year survival rate is 55%; however, the
overall 1- and 5-year survival rates for lung cancer are
44% and 17%, respectively.3
October 2016, Vol. 23, No. 4 Supplement
The following report presents highlights from a
roundtable discussion between 2 leading medical oncology experts in NSCLC, Mark A. Socinski, MD, and
Nathan A. Pennell, MD, PhD. The panel members
share insights into the validity and clinical implications
of a variety of NSCLC biomarkers, first- and second-line
therapies for NSCLC of squamous or nonsquamous
origin, and promising novel therapies on the horizon.
Case studies are used to demonstrate selected therapeutic strategies in real-world clinical scenarios.
Scope of the Problem
Dr Pennell: Lung cancer is the second most common
cancer in both men and women in the United States,
but more Americans die of lung cancer than the next 4
most common cancers combined.4 Despite the fact that
death rates have been dropping in men for sometime
and, more recently, in women, it is still far and away
the most important cancer from a morbidity and mortality perspective in the United States and worldwide.2,3
Despite excitement over treatment advances and the
onset of screening in lung cancer, the 5-year survival
rate remains at 18%.3,4
Dr Socinski: I might also mention here that, in comparison with breast cancer, we have a different stage
demographic. At the time of diagnosis, most patients
with lung cancer present with stage III/IV disease,
whereas, because of awareness and screening, most
patients with breast cancer present with stage I/II
disease.4 Right out of the gate, we are disadvantaged
with regard to long-term survival. Stage IV disease is
treatable but not curable; with stage III disease, even
though we approach it in some subset as curative, the
majority of patients are not cured.5
Dr Pennell: It is heartening that smoking rates in
American adults overall have dropped below 20%.6 It
will take several decades for this change in behavior
to be reflected in falling death rates from lung cancer.
While we finally have Centers for Medicare & Medicaid
Services coverage for the screening of lung cancer in
high-risk patients, the process has not yet been widely
enough adopted for us to see any real impact on lung
cancer–related deaths.
Clinical Controversies and Challenges
Dr Socinski: One of the challenges we face in this
population is getting an initial diagnosis and all that
entails. Historically, we have approached this disease
as a single entity. About 15 or 20 years ago the distinction we asked pathologists to make was to differentiate between small cell lung cancer and NSCLC, and
that was pretty much it. We believed all NSCLCs were
similar from a treatment perspective. This perspective
changed with bevacizumab and pemetrexed when we
October 2016, Vol. 23, No. 4 Supplement
decided it was important to distinguish between squamous and nonsquamous histologies. With the advent
of modern molecular testing, obtaining adequate tissue
for testing can be a challenge in the individual patient,
particularly as the initial specimen on biopsy is often
acquired before the patient sees an oncologist.
Dr Pennell: I completely agree. The biggest challenge
is obtaining sufficient tissue and having enough institutional expertise in the pathology department where
the biopsy is performed as well as good communication with those performing the biopsy. Going forward,
nonsquamous NSCLC patients will need to have a fairly broad panel of molecular tests performed. This requires far more extensive testing, which represents a
fairly high burden of need for sufficient tissue.7 Now
we may even be talking about biomarkers such as programmed death ligand 1 (PD-L1). Meanwhile, a large
number of individuals are diagnosed based on a brushing from bronchoscopy with a few cells and that is all
you get. In many of these patients, it is fairly high risk
to obtain tissue. This consideration is an issue I think
does not receive nearly enough attention.8
Dr Socinski: This need for tissue is particularly true for
adenocarcinoma patients in whom the number of markers we are testing for seems to be increasing yearly. We
are rapidly entering an era where immunotherapy will
be the preferred first-line treatment for a subset of patients. But you select those patients based on a biomarker performed from core biopsy.7 Most of the decisionmaking is made without consultation from a medical
oncologist. Instead, pulmonologists, thoracic surgeons,
and primary care physicians refer patients to interventional radiology. Those subspecialties may not know or
have an appreciation of all the demands on tissues. The
word needs to spread to these other disciplines.
Therapeutic Targets
What would you say is the standard of care today for the
minimal number of genotypes that we should be testing?
Dr Pennell: We have consensus guidelines from the
International Association for the Study of Lung Cancer and the College of American Pathologists that
have recommended for years that every nonsquamous NSCLC or adenocarcinoma or suspected adenocarcinoma be tested for EGFR mutations as well as for
ALK rearrangements.9
However, most of us recognize that current guidelines require updating. At a minimum, I think that
EGFR mutations and ALK and ROS1 rearrangements
should be tested for in every newly diagnosed patient
with adenocarcinoma or select squamous cell patients
with a minimal smoking history.9,10 However, I would
argue that there are a number of other markers that
Cancer Control 3
should routinely be tested for if those 3 are negative.
At the most recent annual meeting of the American
Society of Clinical Oncology (ASCO), mature data on
the combination of the B-raf proto-oncogene inhibitor
dabrafenib and the mitogen-activated protein kinase
(MEK) inhibitor trametinib were presented that might
argue for the testing of those biomarkers and the
BRAF V600E mutation in NSCLC.10
Table 1. — Select Adverse Events Associated With Crizotinib
or Dabrafenib Plus Trametinib
Adverse Event
Dr Pennell: I think MET is the next big target. Now that
we have recognized the phenomenon of these driver
mutations and have demonstrated, even in relatively
small numbers of patients, that agents targeting these
mutations lead to high response rates with durable disease control, I do not think we need to wait for a major
phase 3 trial to start saying that these are genetic rearrangements for which we need to start testing.
In the past few years, we have also identified the
exon 14–skipping mutation, which appears to be a
real driver mutation present in about 4% of adenocarcinomas.11 These mutations are probably as common
as ALK rearrangements and seem to respond to MET
inhibitors like crizotinib, which is typically used for
ALK and ROS1 rearrangements but also works well as a
MET inhibitor.12
Dr Socinski: I agree. We have evidence in patients
with EGFR mutations and ALK-positive disease that targeted oral tyrosine kinase inhibitors (TKIs) are superior
to chemotherapy on the basis of their rate of progression-free survival (PFS) and their toxicity profile.13-15 We
also have a drug approved by the US Food and Drug Administration (FDA) for ROS1 rearrangements — crizotinib — yet we do not have any randomized data.16
However, I would not be in favor of conducting a
300- to 400-patient randomized trial of dabrafenib plus
trametinib vs a platinum-based doublet as the control
arm to prove that targeting the oncogenic driver is better
than nonspecific cytotoxic chemotherapy.
Dr Pennell: I agree. When you have 2 small phase 2
trials and you show a response rate of 70% and PFS in
the 10- to 12-month range, which is basically double
what we see with chemotherapy, and there is a favorable toxicity profile and enough experience with safety
to know that it is something reasonable for patients,
then I think the FDA needs to be more flexible in how
it is conducting approvals (Table 1).17,18 It can be very
challenging to conduct randomized trials targeting a
mutation present in 1% to 2% of lung-cancer patients.10
Furthermore, it is not ethical to randomly assign a patient to chemotherapy when one knows that there are
other agents that are active against in their disease.
4 Cancer Control
Dabrafenib +
Trametinib, %
All
Grades
Grade
3/4
All
Grades
Grade
3/4
44
0
34
2
Gastrointestinal
Diarrhea
Dr Socinski: What about the clinical significance of
the data presented on MET alteration at ASCO?
Crizotinib, %
Nausea
40
0
40
0
Constipation
34
0
18
0
Vomiting
34
2
35
0
Dysgeusia
18
0
11
0
Dyspepsia/upper
abdominal pain
10
0
12
0
Decreased appetite
—
—
30
0
Hematological
Neutropenia
12
10
20
9
Febrile neutropenia
—
—
2
2
Anemia
—
—
18
6
Thrombocytopenia
—
—
7
2
Leukopenia
—
—
8
4
Neurological
Visual impairment
82
0
4
2
Dizziness/vertigo
16
0
11–14
0
Headache
—
—
11
0
Sinus bradycardia
10
0
—
—
Hypertension
—
—
6
4
Cardiovascular
Change in Laboratory Value
Elevated aspartate
aminotransferase
22
2
7
2
Elevated alanine
transaminase
14
4
6
2
Elevated blood
alkaline phosphatase
—
—
16
0
Peripheral edema
40
0
23
0
Fatigue
20
0
18
2
Decreased
testosterone
14
0
—
—
Other
Hypophosphatemia
14
10
7
2
Asthenia
—
—
32
4
Hypercalcemia
—
—
4
4
Hyponatremia
—
—
11
7
Pyrexia
—
—
46
2
Data from references 17 and 18.
Dr Socinski: What about ERBB2 (formally known as
HER2/neu) mutations?
Dr Pennell: These are present in about 1% to 2% of adOctober 2016, Vol. 23, No. 4 Supplement
enocarcinoma patients.19-21 I do not know why there has
not been more attention given to clinical trials in this
population, because these mutations seem to be as common as others, and there are a lot of agents available that
target ERBB2. Some European cohorts have evaluated
broad genetic testing and off-label use of anti-ERBB2
agents, suggesting that there can be activity with both
TKIs and a monoclonal antibody like trastuzumab.20,22
Dr Socinski: I would not say ERBB2 needs routine testing, but, if it is identified, then I would probably reserve
any off-label use until patients have exhausted proven
therapies. What role does KRAS have currently?
Dr Pennell: We routinely test for KRAS, but it is a bit
of a holdover from our initial approach where we tested for EGFR, ALK, and KRAS. If KRAS tests positive
— which it does in about 15% to 25% of adenocarcinoma patients — we do not feel it is necessary to test for
other potential drivers.23 I think it is still useful in that
setting. It is also useful to know in terms of selecting
patients for clinical trials. However, in terms of determining treatment outside of a clinical trial, testing for
KRAS mutations is not really all that helpful, other than
you no longer have to worry about looking for other
potential drivers.
Dr Socinski: What about RET alterations? We have a
number of small phase 2 trials suggesting that various
ret proto-oncogene (RET) inhibitors have activity.24,25
However, the level of activity in these alterations does
not seem to be as impressive as the other markers we
have discussed. At the ASCO annual meeting, Reckamp et al26 presented data on targeting RET alterations:
response rates were 20% to 40% and the durability of
response was not highly impressive. I might place RET
in the same category as ERBB2.
Dr Pennell: I think we have a little more data with
various available agents for RET than ERBB2.27-31
However, the data are disappointing.27,30-33 It is a proven driver oncogene, but I agree with you. I would not
treat someone with a RET fusion with a RET inhibitor
as first-line therapy.
Dr Socinski: As for DDR2, the data we have are very
immature; however, this is a potentially attractive target in patients with squamous histology.34,35
Dr Pennell: I think we all want to find targets that we
can exploit in squamous cell carcinoma (SCC), and amplifications and mutations of DDR2 or FGFR1 occur in a
significant percentage of patients with SCC.34-36 However, the actionability of those targets and the clinical
activity of the agents that we have targeting them are
unproven at this point.
October 2016, Vol. 23, No. 4 Supplement
I do think we need to support the LUNG-MAP protocol to try to put squamous-cell patients on some of
these targeted agents so that we can actually get a better idea of how active they are.37 I know that DDR2 is
also part of the NCI-MATCH study.38
Practical Considerations in Biomarker Testing
Dr Socinski: If I were advising a large community
hospital in terms of testing practices, I would suggest
being as cost effective as possible and identifying those
patients who would receive a major benefit from targeted therapy. I would test for EGFR, ALK, MET amplification, exon 14 mutation, ROS1, BRAF, and KRAS.
At the University of Pittsburgh Medical Center, 31% of
the population of adenocarcinomas had a KRAS alteration.39 As for other drivers beyond those I just mentioned, you are in the 1% to 2% range, and, for many of
the other alterations, we do not yet have robust clinical
data that indicate a targeted agent has an impact.40
Dr Pennell: I want to address the cost effectiveness
of testing. In the past we would test for EGFR mutations and ALK rearrangements, and we now have
ROS1-approved agents. Although getting insurance
coverage is not difficult for the majority of those individual tests, we now have so many tests that really
should be considered standard of care that it is much
more cost effective to do a single broad test.41 It conserves tissue, gives you information faster, and it is
cheaper to pay for 1 test than it is to pay for 6 individual tests.
Dr Socinski: Yes, I agree. Panels and next-generation
sequencing strategies are probably going to end up being the most cost effective. One of the issues I struggle
with is just how much information is necessary. Sometimes it is confusing to figure out the impact of testing
in an individual patient. We do not know if all of the
targets identified are valid.
Dr Pennell: Extremely broad testing of hundreds of
potential genes does not have much clinical validity. I
think guided molecular testing for proven targets makes
sense. Broader testing from a purely research stand
point makes sense; however, I would not recommend
broader testing be routinely performed for patients who
have no intention of enrolling in a clinical trial.
Case Study: Treatment of Stage IVb
Nonsquamous Disease
A 65-year-old man presents with a good Eastern
Cooperative Oncology Group (ECOG) performance
status (PS; 0–1 and no comorbidities) and a diagnosis
of stage IVb NSCLC. The patient is tested for all common
oncogenic biomarkers, including EGFR, ALK, ROS1,
MEK, MET, BRAF V600E, and KRAS, but no oncogenic
Cancer Control 5
driver is identified. Histological testing reveals adenocarcinoma.
This individual is a healthy patient eligible for anything
that we might want to use. An upfront, targeted agent
would not be appropriate outside of a clinical trial for
this patient, so platinum-combination chemotherapy
would be the standard of care.
There are 2 established regimens in this setting. A
carboplatin and paclitaxel doublet with the anti–vascular endothelial growth factor antibody bevacizumab
has been established for more than 10 years now and is
effective as first-line therapy.42,43 A second regimen that
is becoming more common these days is the combination of a platinum agent with pemetrexed. There are
head-to-head data from a phase 3 trial showing that, in
the nonsquamous NSCLC setting, this regimen is more
effective and tolerable than a platinum doublet-containing regimen.44-46 I am not a fan of adding bevacizumab to pemetrexed. We do not have any randomized
evidence suggesting that adding bevacizumab results
in any meaningful clinical benefit. However, there are
adequate safety data on that combination and it is commonly used.47-49 My personal preference is to use carboplatin and pemetrexed in an otherwise healthy patient
with adenocarcinoma who has no comorbidities.
Dr Socinski: The PointBreak trial showed us that,
whether you use bevacizumab with carboplatin and paclitaxel or carboplatin and pemetrexed, the outcomes
in terms of response and survival are equivalent.45,46 It
makes me uncomfortable that we are accepting that a
2-drug regimen is as good as the 3-drug regimen. The
PRONOUNCE trial did not demonstrate the superiority
of carboplatin and pemetrexed followed by pemetrexed
maintenance vs carboplatin and paclitaxel plus bevacizumab followed by bevacizumab maintenance.50 However, I do not see that as a definitive phase 3 trial.
My tendency is to try to figure out what is the
best doublet for the patient. If carboplatin with pemetrexed is a reasonable choice for the patient — and
there are some clear advantages for pemetrexed51 — I
would use that agent. However, I do not want to portray pemetrexed as being without toxicity. Common
adverse events associated with pemetrexed include
fatigue, nausea, and anorexia.52 When combined with
a platinum agent, vomiting, neutropenia, leukopenia,
anemia, stomatitis/pharyngitis, thrombocytopenia,
and constipation are common.52 The next question is:
Am I going to add a biologic agent to it? There are
phase 3 data from large trials suggesting that, whether you add bevacizumab to pemetrexed or a taxane,
the outcomes are equivalent.45
Dr Pennell: If you are using a taxane, then bevacizumab is necessary. I do not think there is anything wrong
6 Cancer Control
with using bevacizumab in a healthy patient who does
not have any contraindications. However, the field
seems to be moving away from using bevacizumab so
commonly. Perhaps we have better subsequent therapies and maybe we have become a little less concerned
about trying to squeeze every possible ounce of efficacy
out of our first-line regimen. But there is a little more
discomfort now that we have had years of experience
and we have seen some rare, but potentially serious toxicities associated with bevacizumab.53,54 I am surprised,
however, that we have not seen at least 1 small phase 3
trial of a platinum agent plus pemetrexed with or without bevacizumab. That would probably answer most
people’s criticism of that regimen.
Dr Socinski: Once you have decided on a regimen,
how many cycles do you administer?
Dr Pennell: With chemotherapy, the established
standard of care is 4 cycles of platinum-based doublet therapy.7 I almost never give more than 4 cycles
of platinum-based doublet therapy because we have
very good evidence that 3 or 4 cycles vs 6 or continuation to progression does not seem to confer any additional survival benefit.55 Furthermore, after 4 cycles
of therapy, most patients have had enough in terms of
toxicity and could use a treatment break. However, I
have given 6 cycles in patients who have continued to
respond after 4 cycles and who are tolerating therapy
very well. However, I am not sure I am really helping them with that, especially now in an era where I
routinely continue with maintenance therapy when I
use first-line doublet therapy with pemetrexed. I do
not think that continuing the platinum agent beyond
4 cycles adds much benefit.
Dr Socinski: If you were using carboplatin and a taxane with bevacizumab as your choice for this patient,
then it sounds as if you would be in favor of maintenance therapy if a response was evident.
Dr Pennell: I was surprised that the results from the
PointBreak trial — comparing carboplatin, paclitaxel,
and bevacizumab followed by maintenance bevacizumab with carboplatin, pemetrexed, and bevacizumab followed by maintenance bevacizumab and pemetrexed — showed there was no difference in overall
survival (OS).45 I think if you are going to use a taxane,
platinum-based, bevacizumab regimen, continuing the
bevacizumab as maintenance therapy is appropriate.
Dr Socinski: Yes, I agree. If there were contraindications to bevacizumab and the patient was receiving
carboplatin and pemetrexed and was either stable or
responding and tolerating therapy well, would you
continue with pemetrexed maintenance?
October 2016, Vol. 23, No. 4 Supplement
Dr Pennell: Yes, that is the standard of care now. We
have a couple of good phase 3 trials supporting a survival benefit through either continuation or a switch to
maintenance with pemetrexed if you have a non-bevacizumab regimen for first-line therapy.44,45,56
A 65-year-old man presents with a good ECOG PS
(0–1 and no comorbidities) and a diagnosis of stage
IVb NSCLC. The patient is tested for all common
oncogenic biomarkers, including EGFR, ALK, ROS1,
MEK, MET, BRAF V600E, and KRAS, but no oncogenic
driver is identified. Histological testing reveals SCC.
We do not use bevacizumab or pemetrexed in patients
with squamous histology; however, we do have some
evidence for maintenance gemcitabine or maintenance
taxane therapy.63,64 Nonetheless, there is no clear-cut
advantage in that setting, and, in squamous NSCLC, I
generally do not use maintenance therapy. I watch patients closely, and then I think about second-line therapy at the time of disease progression.
We do have data sets in the squamous population
that we should discuss. There is a suggestion relative to
standard taxane therapy that nab-paclitaxel has higher
response rates.65 Response rates are important in the
lung-cancer setting as they correlate with symptom relief. If you shrink the tumor, the patient feels better.
Dr Socinski: I think that the standard of care is again
platinum-based doublet therapy. The choices really reside between platinum-based therapy plus a taxane, including paclitaxel, docetaxel, and nab-paclitaxel, and a
gemcitabine-containing regimen.57-61 However, I think
the evidence suggests that taxane-based therapy is a
better approach than gemcitabine therapy.57-61
Gemcitabine has some side-effect advantages that
the taxanes do not have. When gemcitabine is used as
a single agent, the most common adverse effects are nausea and vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria,
fever, hematuria, rash, thrombocytopenia, dyspnea, and
peripheral edema.62
In elderly patients receiving biweekly carboplatin
plus gemcitabine as first-line therapy for advanced squamous NSCLC, grade 3/4 neutropenia occurred in 12.3%
of patients, grade 3/4 thrombocytopenia occurred in
7.1%, and grade 2/3 fatigue occurred in 17.5%.60
For maintenance therapy, we have fewer options.
Dr Pennell: From the stand point of SCC, I think that the
choice is clearly one of the taxanes — paclitaxel or nabpaclitaxel — vs gemcitabine. I choose based on which
adverse-event profile fits the patient best. Treatment with
nab-paclitaxel plus carboplatin is associated with a higher
incidence of neutropenia and leukocytopenia compared
with gemcitabine plus carboplatin.58 In patients treated
with nab-paclitaxel as monotherapy, anemia occurred in
38%, leukopenia in 48%, neutropenia in 38%, thrombocytopenia in 11%, and febrile neutropenia in 10%.57 Nonhematological adverse events include alopecia (67%), fatigue
(58%), sensory neuropathy (59%), anorexia (29%), nausea
(36%), myalgia (19%), and arthralgia (26%).57 For patients
who do not want to lose their hair, typically I would select
gemcitabine; for patients who live far away and would rather receive treatment every 21 days, I think paclitaxel makes
more sense. I am not sure if I buy into nab-paclitaxel being better because of the response rate being somewhat
higher.66 However, I am a little more impressed with the
data in the elderly population using nab-paclitaxel (Fig).57
Case Study: Treatment of Stage IVb
Squamous Disease
B
100
Median PFS
7.6 mo (95% CI: 6.60–8.60)
4.9 mo (95% CI: 3.92–5.88)
80
60
40
Cycles
≥3
<3
P = .004
20
0
Cumulative Survival, %
Cumulative Survival, %
A
100
Median OS
11.7 mo (95% CI: 10.33–13.07)
8.9 mo (95% CI: 6.94–10.86)
80
60
40
Cycles
≥3
<3
P = .002
20
0
0
2
4
6
PFS, mo
8
10
12
0
5
10
15
20
OS, mo
Fig A–B. — Kaplan–Meier curve for (A) PFS and (B) OS rates according to cycles of nab-paclitaxel monotherapy in elderly patients with relapsed
squamous NSCLC. CI = confidence interval, OS = overall survival, PFS = progression-free survival. Reprinted with permission of Dove Medical Press,
from A retrospective analysis of safety and efficacy of weekly nab-paclitaxel as second-line chemotherapy in elderly patients with advanced squamous
non-small-cell lung carcinoma, Jin F, Zhu H, Shi F, et al., 2016;11, 2016; permission conveyed through Copyright Clearance Center, Inc.
October 2016, Vol. 23, No. 4 Supplement
Cancer Control 7
Dr Socinski: Yes, we have to remember that, even
though a superior overall response to nab-paclitaxel
was demonstrated, this finding did not translate into
differences in PFS or OS.57 However, I do consider
nab-paclitaxel as the treatment of choice in a patient
with heavy-disease burden who is very symptomatic,
because, if you have a higher likelihood of shrinking the tumor, then that patient is probably experience greater clinical benefit. He or she may live better,
though not necessarily longer in that setting.
Dr Pennell: We need to remember that squamous
NSCLC patients are often older, and they often have
more comorbidities than other NSCLC patients. Comorbidity is a big factor in these patients. I often use
gemcitabine for that reason, but I also use nab-paclitaxel in some patients because it is associated with less
neuropathy and you see patients more often so you
can monitor them.57,67 It also has the advantage of not
requiring the use of premedication with steroids. Unfortunately, we do have to think about cost as well.
Dr Socinski: Nab-paclitaxel is FDA approved and has
a weekly schedule.68 However, it should not be administered to patients with a baseline neutrophil count of
less than 1,500 cells/mm3, and it is recommended that
peripheral blood cell counts be monitored frequently
in those receiving the agent.68 Some elderly patients
like coming weekly because they get more attention,
and they can deal with their problems prospectively,
while others have geographical issues that make weekly visits impossible. These needs are why you have to
individualize treatments.
The role of necitumumab in squamous NSCLC has
to be considered as well. The SQUIRE trial is a large,
phase 3 trial of gemcitabine plus cisplatin with or without necitumumab as first-line therapy in patients with
stage IV squamous cell NSCLC.69 The trial demonstrated
an OS advantage, which led to its approval by the FDA
and, although no significant difference in response rate
was seen, a modest benefit in PFS was observed.69 The
primary toxicities of necitumumab include skin rash,
gastrointestinal toxicity, and hypomagnesemia.69
Dr Pennell: I have never used
necitumumab; however, I do
think it is a reasonable choice. It
has a statistically significant survival benefit in squamous NSCLC
patients when added to the platinum-based doublet when compared with the platinum doublet alone (Table 2).69 However,
SQUIRE was a huge trial, and it
reminds me of the FLEX trial of
platinum plus vinorelbine and
8 Cancer Control
cetuximab, which also showed a survival benefit, but
there was less than a 2-month difference in median OS
between the 2 regimens.70,71
Necitumumab adds toxicity with an epidermal
growth factor receptor (EGFR)–type rash and diarrhea,
and there was a lack of improvement in response rate.72
Although there is real activity there, until they can do
a better job of identifying who benefits and who does
not, it is hard to see a clinically meaningful difference
with the addition of necitumumab. I have not started
using it routinely. I am hopeful that some of the work
coming out of the Hirsch Biomarker Analysis Laboratory73 will allow us to see something, perhaps with EGFR
expression on fluorescence in situ hybridization. For
now, it is hard to justify the additional cost and toxicity
with marginal benefit.
Dr Socinski: We are in a time where now we are making judgments about cost and magnitude of benefits. I
agree that it has been frustrating that a biomarker has
been elusive in this setting. What about the LUX-Lung
trial in SCC?
Dr Pennell: LUX-Lung 8 was a trial of afatinib vs erlotinib in SCC of the lung.74 It was a phase 3 trial that
showed longer PFS and OS rates, as well as a slightly
higher response rate for afatinib in patients with stage
IIIb/IV squamous NSCLC who had progressed after at
least 4 cycles of platinum-based chemotherapy.74 However, use of EGFR TKIs has fallen out of favor in EGFR
wild-type patients due to marginal activity.7
Dr Socinski: Yes, afatinib is now indicated for metastatic squamous NSCLC that has progressed after platinum-based chemotherapy.75
Case Study: Second-Line Therapy
A 65-year-old man presents with a good ECOG PS
(0–1 and no comorbidities) and a diagnosis of stage
IVb NSCLC. Second-line therapy is indicated.
A lot has changed in the past year or so and we have a
new standard. We have the results of the CheckMate
Table 2. — Survival Outcomes in Stage IV Squamous NSCLC With Necitumumab Plus
Gemcitabine/Cisplatin vs Gemcitabine/Cisplatin: IHC Evaluable EGFR-Positive Population
Outcome
HR
(95% CI)
P
Value
Median Survival, mo
Overall
0.79 (0.69–0.92)
.002
11.7
10.0
Progression free
0.84 (0.72–0.97)
.018
5.7
5.5
Necitumumab +
Gemcitabine/
Gemcitabine/Cisplatin
Cisplatin
(N = 456)
(N = 468)
CI = confidence interval, HR = hazard ratio, IHC = immunohistochemistry,
NSCLC = non–small-cell lung cancer. Data from reference 69.
October 2016, Vol. 23, No. 4 Supplement
017 trial of squamous NSCLC comparing nivolumab
with docetaxel; it showed a 50% improvement in median survival and a doubling of the response rate.76
This study was an impressive trial that really changed
the second-line standard. We also saw that same effect
— although to a lesser degree — in the nonsquamous
NSCLC CheckMate 057 trial, which led to nivolumab
receiving an indication for the treatment of metastatic NSCLC in patients who have progressed on or after
platinum-based chemotherapy.77,78 KEYNOTE-010
had a similar design to the 2 CheckMate trials, with
docetaxel as the control arm compared with pembrolizumab.79 These trial results have radically transformed
our second-line platform.
Dr Pennell: Within a month or two of the approval of
nivolumab for squamous cell disease, we were routinely
using that in everyone as second-line therapy over chemotherapy. Then we began using nivolumab in adenocarcinoma and nonsquamous disease almost as rapidly.
Dr Socinski: Nivolumab established itself as the standard not only because it was the first to be approved,
but also due to the fact that it was not linked to a biomarker.80,81 By contrast, pembrolizumab approval was
linked to the biomarker PD-L1.80
Dr Pennell: It is important to recognize the different
populations involved in the CheckMate and KEYNOTE
trials. Pembrolizumab was only approved in patients
who were positive for the PD-L1 biomarker, as these
individuals were the only patients enrolled in the trial
to be randomized to pembrolizumab vs chemotherapy.80 By contrast, in the nivolumab trials, the investigators took all comers, and PD-L1 was used to stratify
response based on expression.78,81 The overall intentto-treat population had a big survival benefit without
relying on being PD-L1 positive.78 There is a difference
in efficacy, especially in nonsquamous patients treated
with nivolumab, where higher levels of PD-L1 expression do infer a greater survival benefit and a higher
response rate compared with docetaxel.78 However,
even patients with no PD-L1 expression have OS and
response rates comparable with docetaxel.78
For second-line patients, I would not recommend
routine testing of PD-L1 because the only purpose of testing would be to select an alternate treatment. There really
is no alternate treatment that would be a better choice.
Dr Socinski: I agree, but I think that PD-L1 is going to
play a very important role in the first-line setting. What
is your take on the different adverse-event profiles of
the immunotherapy agents?
Dr Pennell: The majority of patients have very few adverse events — maybe some fatigue, aches, and pains.
October 2016, Vol. 23, No. 4 Supplement
However, these are often associated with having lung
cancer. Nonetheless, up to 10% of patients do have serious adverse events, which are usually related to autoimmune effects secondary to these agents.82 With
nivolumab and pembrolizumab, we do not see nearly
the level of autoimmune-related adverse events seen
with the anti–cytotoxic T-lymphocyte-associated antigen 4 agents such as ipilimumab.83,84 Severe to fatal
immune-mediated adverse reactions have been reported in up to 41% of patients, including 16% who experienced enterocolitis, 11% who experienced hepatitis, 4%
dermatitis, 2% neuropathy, and 7% hypopituitarism.85
Immune-mediated pneumonitis, meningitis, myocarditis, and pericarditis have also been reported.85
However, the adverse events of PD-1 inhibitors
can still be serious. With nivolumab, immune-mediated pneumonitis occurred in 3.4% of NSCLC patients,
immune-mediated colitis occurred in 2.4%, hepatitis
occurred in 0.3%, adrenal insufficiency in 0.3%, hypothyroidism in 7.0%, hyperthyroidism in 1.4%, renal dysfunction in 0.3%, and immune-mediated rash in 6.0%.81
Other immune-related adverse events associated with
nivolumab include encephalitis, pancreatitis, uveitis, iritis, facial and abducens nerve paresis, demyelination,
polymyalgia rheumatica, autoimmune neuropathy,
Guillain–Barre syndrome, hypopituitarism, systemic
inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis.81 Pembrolizumab therapy has been
associated with pneumonitis (3.5%), colitis (0.7%), hyperthyroidism (1.8%), hypothyroidism (6.9%), hypophysitis (0.2%), and type 1 diabetes mellitus (0.1%).80 Other
immune-mediated adverse events associated with pembrolizumab include hepatitis, rash, vasculitis, nephritis, hemolytic anemia, serum sickness, and myasthenia
gravis.80 Patients need to be monitored for events such
as autoimmune colitis, hepatitis, and thyroiditis resulting in hypothyroidism, but this does not necessarily
require altering treatment other than replacing thyroid
hormones. However, everyone worries about pneumonitis, which occurs in 4% of 5% of patients.86-89 It is common enough that you need to watch for it and be ready
to treat it, but it is still relatively uncommon.
Dr Socinski: It really is a small minority of patients —
typically less than 5% who experience the more serious
immune-related events.90 However, once we start using
these agents routinely as first-line therapy — agents
that potentially may be used for years in some patients
who are receiving benefit — then the awareness of
these toxicities will increase. It is going to be important
to understand and be able to treat these immune-related toxicities.
Dr Pennell: As for first-line therapy, KEYNOTE 024
explored pembrolizumab vs platinum-based doublet
chemotherapy in treatment-naive patients with very
Cancer Control 9
high-level PD-L1 expression.91 A press release stated
that pembrolizumab was superior to chemotherapy for
both the primary end point of PFS and the secondary
end point of OS.91 Based on these results, an independent data monitoring committee has recommended
that the trial be stopped and patients receiving chemotherapy be offered the opportunity to receive pembrolizumab.91 Top-line results from CheckMate 026, a
phase 3 study of nivolumab vs platinum-based doublet
chemotherapy in treatment-naive patients with advanced NSCLC that also expressed PD-L1 but at a lower
cutoff level, were also released.92 However, as monotherapy, nivolumab did not meet its primary end point
of improved PFS when compared with platinum-based
doublet chemotherapy in this patient population.92 Results from both trials will be presented at the annual
congress of the European Society for Medical Oncology in early October 2016, but, at the time of press,
these data were not yet available.
I think most of us expected that immunotherapeutic agents were eventually going to have a role
as first-line therapy. We are going to see the need to
routinely test for biomarkers to identify patients who
would benefit from these drugs as initial therapy. We
also have ongoing trials in patients looking at levels of
PD-L1 expression, and combination trials of chemotherapy and immune checkpoint inhibitors as well as
immune checkpoint inhibitor maintenance therapy following chemotherapy (NCT02758314, NCT02382406,
NCT02564380). Testing for the biomarker is going to
become part of our standard of care very soon.
Case Study: Treatment of EGFR MutationPositive Disease
A 65-year-old man presents with a good ECOG PS
(0–1 and no comorbidities) and a diagnosis of stage
IVb NSCLC. Adenocarcinoma is identified as well as a
sensitizing EGFR mutation.
Everyone with NSCLC should be tested first line for
EGFR. If you are identifying an activating EGFR mutation, then in most cases this will be an exon 19 deletion mutation or an exon 21 point mutation. We have
excellent randomized phase 3 data from multiple trials
suggesting that TKIs (eg, gefitinib, erlotinib, afatinib)
are all superior to chemotherapy with probably twice
the response rate, twice the PFS, and a more favorable
tolerability profile.15,93-96 The phase 2 LUX-Lung 7 trial evaluated gefitinib vs afatinib and observed longer
PFS with afatinib and a slightly higher response rate.97
There are also data from the LUX-Lung 3 and 6 trials
suggesting that patients with an exon 19 deletion potentially derived not only a PFS benefit but also an OS
benefit with afatinib.98,99
I think that, in a healthy patient in whom there is
no concern about skin toxicity or other potential tox10 Cancer Control
icities, afatinib is a slightly more effective choice for
first-line therapy. However, afatinib does have a higher
toxicity rate than the first-generation TKIs.100 Diarrhea
occurred in 96% of patients receiving afatinib with 15%
of cases being grade 3 in severity, whereas diarrhea occurred in 62% of patients receiving erlotinib, with 5%
of cases being grade 3/4 in severity (Table 3).75,101,102 In
6.1% of patients receiving afatinib, renal impairment
occurred as a result of diarrhea.75
For many of my frail elderly patients, I still use
erlotinib as first-line therapy. By contrast, afatinib
would probably be my first-line choice for a healthy
young person.
Table 3. — Select Adverse Events (All Grades) in Patients
Receiving Afatinib, Erlotinib, or Gefitinib
Adverse Event
Incidence, %
Afatinib
Erlotinib
Gefitinib
Diarrhea
96.0
62.0
34.9
Skin reactions
90.0
85.0
57.9
Stomatitis
71.0
17.0
11.0
Nail disorder
58.0
14.0
7.9
Anorexia/decreased appetite
29.0
52.0
19.7
Pruritus/dry skin
21.0
16.0–21.0
—
Vascular disorder/
hemorrhage
17.0
—
4.3
Cystitis
13.0
—
1.1
Cheilitis
12.0
—
—
Pyrexia
12.0
36.0
8.7
Ocular disorder
11.8
17.8
7.0
Hepatic disorder
10.1
—
22.0
Renal failure
6.1
0.5
—
Interstitial lung disease
1.5
1.1
1.3
Bullous/exfoliative skin
disorders
0.2
1.2
<0.1
Alopecia
—
—
4.7
Asthenia
—
—
17.7
Cerebrovascular
accident
—
0.6
—
Cough
—
48.0
—
Dyspnea
—
45.0
—
Gastrointestinal
perforation
—
0.2
0.2
Hepatic failure
—
0.4
—
Hepatitis
—
—
0.2
Myocardial infarction/
ischemia
—
0.2
—
Nausea
—
33.0
17.8
Pancreatitis
—
—
0.1
Vomiting
—
—
13.8
Data from references 75, 101, and 102.
October 2016, Vol. 23, No. 4 Supplement
Dr Socinski: What are your expectations when you
start a TKI? What do you tell your patients to expect
in terms of response and PFS? Then, what do you do
when they progress?
Dr Pennell: Well, the good thing about these TKIs and
EGFR mutations is that patients start to see improvements in symptoms within days to weeks. I usually
bring them back 3 to 4 weeks after they start treatment
because that is when you can expect to see the skin rash
emerge and be ready to jump in with antibiotics (eg,
doxycycline, minocycline) or topical agents to help them
manage the skin toxicity. For most patients, supportive
care for skin toxicity or diarrhea or a dose reduction can
allow them to continue treatment. Patients live very active normal lives on these agents. The average or median time to progression is approximately 1 year.15,93-96
Although I have patients who have been on EGFR
TKIs for many years with disease control, inevitably
their disease will progress. In the past, I would usually
switch these patients to chemotherapy if they had previously received first-line treatment with a TKI. However, these days, we have another choice. For the 50%
to 60% of patients who develop acquired resistance
and progression on a first-line TKI, if you test them
you may identify T790M, which is a gatekeeper mutation on exon 20 of EGFR.100 We have an agent that has
been approved to treat this — osimertinib — which is
very effective in patients with confirmed T790M.103 It
requires testing, however, because the agent is only approved if patients are T790M positive.104 In addition,
the data suggest that, if this mutation is not present,
then osimertinib may not be effective and you may be
better off switching to chemotherapy.105
Dr Socinski: Testing upfront is standard. However,
should the testing be performed on plasma, urine, or
tissue?
Dr Pennell: Tissue is the gold standard; however, obtaining tissue for progression from all patients is difficult if not impossible. We have good evidence that the
commercially available blood-based assays are quite
sensitive and reliable.106 If the assay finding is negative
for mutations, then you can perform a tissue biopsy. In
June 2016, the FDA approved the EGFR mutation test
v2, which is a blood-based companion diagnostic tool
for erlotinib that includes T790M.107
Dr Socinski: Assuming then that a patient is T790M
negative, is standard chemotherapy the option you
would recommend?
Dr Pennell: For most patients who have generalized
symptomatic progression, I switch them to chemotherapy. In some patients, the progression can be relatively
October 2016, Vol. 23, No. 4 Supplement
indolent, and you can watch them without changing treatment for awhile. If they are not symptomatic,
then you do not need to rush to change treatment. In
one-fifth of these patients, progression can be localized to maybe a single site or a few sites. We actually
have a clinical trial testing stereotactic radiotherapy
to areas where we have very limited focal progression
(NCT02450591).
We also have some pretty good biopsy data suggesting that not every metastasis develops acquired
resistance at the same time, and that patients may
sometimes remain on treatment for significantly longer if you ablate the areas that are progressing.108,109 In
these cases, patients can remain on their first-line TKI.
However, most patients who progress need to switch
to something else. For me, stopping the TKI and moving on to chemotherapy is the choice for most patients.
Dr Socinski: I would like to talk about ALK-positive
disease, which occurs in up to 5% of patients with
NSCLC.110 In the first-line setting, we have randomized
data suggesting that crizotinib is better than the best
chemotherapy, which is pemetrexed plus a platinumbased agent.110 But, we now have more choices. Crizotinib was initially developed as a MET inhibitor, but it
has ALK activity. Would you say that crizotinib is still
your first-line choice, or are you tempted to use one of
the other agents initially?
Dr Pennell: Crizotinib is typically my first-line choice
for ALK-positive patients, but I go back and forth about
this consideration. A Japanese phase 3 trial of alectinib
vs crizotinib demonstrated a significantly prolonged
PFS for alectinib.111 Alectinib is approved as secondline therapy in patients with locally advanced or metastatic ALK-positive NSCLC after failure of crizotinib.112
What has not been shown is that alectinib results in
improved duration of disease control in patients who
start on crizotinib, then switch to alectinib as secondline therapy at the time of progression. This strategy
sequence is really what we consider the current standard of care. However, I would like to see a trial that
examines the sequencing of the agents to determine
which is better. I would not be surprised if alectinib
becomes a reasonable standard first-line treatment
option. For now, I still use crizotinib.
Dr Socinski: The second-generation TKIs (eg, alectinib, ceritinib, investigational agent brigatinib) have
demonstrated favorable safety and efficacy profiles but
with notable activity in the brain.113
Dr Pennell: The clinical data suggest these secondgeneration agents penetrate the central nervous system.113-117 ALK-positive NSCLC patients commonly
develop brain metastases.118 Crizotinib is not very efCancer Control 11
fective in that setting.118 Some have suggested that
more than one-half of patients with ALK-positive
NSCLC develop brain metastases as the first sign of
progression.118 If we can prevent or delay brain metastases, then that alone might be a good reason to use a
more potent agent as first-line therapy.
however, we must be thoughtful about how we approach our patients. We need to do our due diligence
in molecular testing and we need to understand when
to intervene with immunotherapy and what the benefits of that may be.
References
Dr Socinski: Because we monitor the brain, frequently we find these lesions when they are relatively small
and asymptomatic. TKI therapy can be a more effective alternative for these patients instead of going right
to whole-brain or targeted radiotherapy.119 You may be
able to delay treating the whole brain with the use of
TKIs in this population.
I would also like to point out that the ALK-positive subset of patients seems to be very different than
those with a EGFR mutation. Among patients with
EGFR mutations, a dominant acquired resistant mutation, T790M, affects 50% to 60% of patients.119 The same
phenomenon has not been observed in ALK-resistant
patients. We have acquired mutations in up to 30%
of patients, and 8 different mutations have been described.120-123 Furthermore, the resistance to ALK-TKIs
involves both ALK- and non–ALK-mediated pathways.120
Dr Pennell: It does appear that brigatinib is effective
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their mechanism of resistance.123 ALK-positive NSCLC
presents a different picture than EGFR mutant-disease does.120-123
Conclusions
Dr Socinski: The management of advanced non–
small-cell lung cancer has transitioned in the past decade or so with our increased understanding of the
biology of the different subsets of patients. The emergence of immunotherapy — now our second-line
standard and soon to become our first-line standard
therapy — and the use of biomarkers in this setting are
important developments of which clinicians should be
aware. There will be a subset of patients who better
respond to treatment in the first-line setting with immunotherapy. However, the complexity of the management of lung cancer has become exponentially greater
than it was 10 or 15 years ago when we thought of the
problem as small-cell vs non–small-cell disease. This
evolution in how we manage the disease today puts a
tremendous amount of pressure on our diagnostic colleagues to obtain adequate tissue for molecular testing.
We need new ideas for patients. Likewise, we need
studies to examine the activity of chemotherapy following immunotherapy in patients with non–small-cell
lung cancer. The fact that the number of therapeutic
options has greatly expanded is a source of optimism;
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