An updated version of this course will be available in summer of 2018. Thoracic malignancies are major, global health problems. Lung cancer is the most common cancer and cause of cancer death in the world, with more than 1.5 million deaths per year. More Americans will die from lung cancer each year (approximately 159,480) than from colon, breast, pancreatic, and prostate cancer combined (approximately 158,630), the next most common causes of cancer death. Esophageal cancer is the 6th most common cause of cancer deaths worldwide, and the 4th most common cause in developing nations. This course will provide a comprehensive, multidisciplinary introduction to state of the art approaches in the care of patients with thoracic malignancies, including various types of lung cancers and esophageal cancers. Didactic material will cover epidemiology, screening and diagnosis, staging, imaging, radiation therapy, systemic therapy, surgery, psychiatry, and patient support topics. This is an on-demand course with integrated learning units that are focused on specific topics. Each unit contains several video lectures with interactive questions and is followed by a short quiz. Prerequisites: None required although basic medical training in some field related to thoracic oncology would be helpful.
Molecularly Targeted Therapy for Non-Small Cell Lung Cancer
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From the course by University of Michigan
Thoracic Oncology
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From the lesson
Non-Small Cell Lung Cancer and Tracheal Cancer: Therapeutics
After reviewing this unit, the learner will understand basic principles regarding:
Meet the Instructors
Dr. Leslie Eisenbud QuintCourse Co-director, Professor of Radiology and Professor of Surgery, Section of Thoracic Surgery
Medical School
Dr. Rishindra ReddyCourse Co-director, Assistant Professor of Surgery, Section of Thoracic Surgery
Medical School
Thoracic Oncology team at the University of Michigan
I'm Greg Ka;emkerian in medical oncologist and
professor of medicine at the University of Michigan Michigan.
The topic of this lecture is going to be molecularly targeted therapy for
non small cell lung cancer.
The objectives of the lecture are to review the appropriate molecular
diagnostic testing for advanced non small cell lung cancer.
To review the role of EGFR and ALK targeted therapy is such patients.
And to review the promising molecular targets in non small cell lung cancer.
About 40% of patients with non small cell will present with and
about 80% will eventually develop stage IV disease with distant metastases.
All treatment for people with stage IV non small cell lung cancer is palliative.
With a 5 year overall survival of less than 5% with currently available therapy.
Molecular diagnostic testing and targeted therapy can improve survival in selected
subsets of patients with advanced disease.
Our pre-lecture question, is that a 48 year old woman presents with cough.
She's a never smoker and has an excellent performance status.
Chest X-ray shows multiple lung opacities.
The chest CT Scan shows bilateral ground-glass nodules up to 3 centimeters
in size.
PET scan shows mild FDG-avidity in the lung lesions with
no other metastatic disease.
Wedge biopsy of two of the lung lesions reading a well differentiated
adenocarcinoma.
What would be the most appropriate next step in her management?
Chemotherapy, chemotherapy plus erlotinib, evaluation for
bilateral lung transplantation, or assay for
EGFR mutations and ALK and ROSI rearrangements?
We'll go through the lecture and come back for the answers for
this at the end of the talk.
There are several different categories of systemic therapy for treatment of cancer.
There's our standard chemotherapy which generally refers to cytotoxic drugs.
Most of which were developed empirically, meaning they were developed without any
knowledge or understanding of the mechanism of action.
Just because they killed cancer cells and were then evaluated in people with cancer.
Where as molecularly targeted therapy are agents that were developed with
specific knowledge of the intended molecular target mechanism of action.
So if you knew that there was specific abnormality driving the growth
of the cancer, you would develop a treatment that specifically affects and
inhibits that particular target.
Similarly with biomarkers there are several types of biomarkers,
there are prognostic biomarkers that are indicators of patient survival
independent of therapy.
These generally reflect the innate tumor aggressiveness or tumor burden.
So an example of this would be LDH, lactate dehydrogenase,
which can be measured in the blood.
Which is a clear indicator of the burden of disease in many different types of
cancers, and correlates with how well the patient might do.
And then there are predictive biomarkers,
these are indicators of outcome with a specific treatment.
So they can either define the sensitivity to a therapy, the chance of response, or
the duration of survival.
Example of this is the EGFR mutations that are found in non small cell lung cancer,
that predict the response to EGFR tyrosine kinase inhibitors, and
we'll discuss that in this talk.
A little over ten years ago, all non-small cell lung cancers were the same.
And then we learned that there were certain differences between different
subtypes of the non small cell lung cancers.
So we had lung adenocarcinoma that were treated a little differently than say,
the squamous-cell carcinoma.
But now in 2016, we can slice that pie even finer and
identify a variety of different molecular classifications of adenocarcinoma based
on driver mutations within those particular individual tumors.
On this slide,
we see that there are a number of driver mutations that have been identified.
Three of which those in red EGFR and ROSI have FDA approved therapies
that can be beneficial in patients who carry these molecular defects.
The genes noted in orange on this slide are ones for
which we do have data that supports therapy.
However, they are not FDA approved for use in lung cancer at this time.
A similar classification scheme exists for squamous-cell carcinoma,
where more and more molecular abnormalities are being identified.
However, in squamous cell carcinoma, we do not yet have any validated markers for
which we have clearly beneficial therapy.
These are all types of treatments that are in clinical trials at this time.
The first target that was identified for non small cell lung cancer, for which we
developed a effective treatment was the epidermal growth factor receptor, or EGFR.
EGFR is a membrane associated growth factor receptor that, when
activated by it's ligand, sends a signal through the signal transduction cascade to
the nucleus of the cell, giving a signal for proliferation and cell division.
And in cancers, in particularly in non small cell lung cancer,
this receptor can be deregulated.
So that it is sending an inappropriate signal through the cells for
proliferation independent of a ligand binding.
A number of strategies have been developed to target and inhibit the EGFR function.
One can do so
with the monoclonal antibody that binds the external ligand binding domain.
And one of these examples would be cetuximab that is used in colon cancer and
neck cancer.
And then we have small molecules such as erlotinib, gefitinib and
afatinib that are all approved for use in lung cancer.
That can enter into the cell as small molecules and
bind to the tyrosine kinase domain of the EGFR gene.
Blocking its enzymatic activity and
blocking it's ability to send signals further down through the cell.
So a number of mutations have been identified within the EGFR gene that
are clustered within the tyrosine kinase domain.
About 80% to 90% of these mutations are either exon 19 deletions or
exon 21 L858R point mutations.
And these mutations predict responsiveness to an EGFR tyrosine kinase inhibitor.
So these are predictive biomarkers.
These mutations are found much more commonly in non smokers,
in adenocarcinomas in women, and in East Asians, meaning Japanese, Chinese,
and Koreans.
When we look at how people do with EGFR inhibitors with nons mall
cell lung cancer, the results are dependent on the population we select.
So if we take unselected patients and give them an EGFR inhibitor,
we'll see a response rate approximately 10%.
If we take ony people with clinical factors which are the factors
that are noted on the top of this slide non smokers and
adenocarcinomas and East Asians and give them EGFR inhibitors.
Then we'll see approximately a 40% responsiveness of their lung cancer.
However, if we enhance the population by selecting only people whose tumors
harbor EGFR gene mutations and treat them with EGFR inhibitors.
Then we'll see response rates upwards of 70% and
over all survivals of about two and a half years.
So clearly we can improve our outcomes by selecting the most appropriate
population of patients to get this treatment.
So one of the obvious strategies to evaluate in this situation would
be to see how well people with EGFR-mutated non-small cell lung
cancer do with a tyrosine kinase inhibitor versus chemotherapy.
And a number of trials have been done looking at this strategy using a variety
of EGFR inhibitors, gefitinib, eriotinib, or afatinib and a number of different
chemotherapy regimens as noted in the second column on this slide.
When we look at the effectiveness of the different treatments in these patients,
we see a very consistent trend of
statistically significant improvements in response rate with
the tyrosine kinase inhibitors compared to chemotherapy in all of these trials.
And an improvement in progression free survival
in all of these trials with the targeted therapy
in a patient population that has the EGFR-mutated tumors.
However, overall survival is not significantly different in these studies,
primarily because there's crossover.
So patients who received chemotherapy initially,
the vast majority of them received an EGFR inhibitor as 2nd-line therapy so
they gained benefit from the treatment at that point.
So what do we know about EGFR inhibition in lung cancer?
We know that patients with EGFR-mutant non-small cell do better with 1st-line
EGFR inhibitor therapy, and that is the best option of treatment.
In unselected patients, where we don't know
what their EGFR status is or if they have EGFR wild type tumors,
then 1st-line chemotherapy is a better option than an EGFR inhibitor.
In unselected patients, however, EGFR inhibitors can improve survival compared
to placebo as 2nd or 3rd line therapy, and we do sometimes use them in that role.
However, there's no proven benefit yet for any EGFR-targeted treatment in stage I,
II or III non-small cell lung cancer.
Unfortunately, tyrosine kinase inhibitors do not work forever in these patients and
they eventually develop resistance with about 50% of people developing a second
mutation within the EGFR gene, the T790M mutation, which predicts
resistance to the first generation EGFR-tyrosine kinase inhibitors.
So that has led to the development of 3rd generation EGFR-tyrosine kinase inhibitors
that are mutation specific.
Meaning they have activity against the common sensitizing mutations,
the L858R and deletion 19,
as well as activity against the resistance mutation, the T790M mutation.
These drugs, primarily osimertinib, which has now been FDA approved for
use against EGFR T790M mutated tumors,
do not have much activity against the EGFR wild type protein, therefore they have
lower rates of the class effects of these drugs, namely diarrhea and rash.
This is an example of a waterfall plot from a trial utilizing rociletinib, which
is one of the 3rd generation tyrosine kinase inhibitors that targets T790M.
Each of the bars, going either up or down on this slide,
represent a patient with a T790M+ non-small cell lung cancer,
who had progressed on prior EGFR-tyrosine kinase inhibition.
If the bar goes down, then that correlates with shrinkage of the tumor, and
the deeper it goes down, that's a higher percentage of shrinkage of the tumors.
And if the bars go up, that's progression of the cancer.
And we see here that the majority of people have bars that go down, meaning
they have had shrinkage of their disease, with a response rate of approximately 60%.
In summary, for EGFR inhibition in non-small cell lung cancer,
erlotinib has now been approved as 1st-line therapy in EGFR-mutated
non-small cell and a 2nd or 3rd line therapy for unselected patients.
Afatinib is approved as 1st-line therapy in EGFR-mutated patients, and
also has some activity against the rare sensitizing mutations and against T790M.
The T790M resistance mutations occurs in about half of people
who progress on the 1st or 2nd-line EGFR inhibitors.
And osimertinib, a mutation-specific EGFR-tyrosine kinase,
has now been approved for use in people with the T790M+ tumors.
These mutation-specific tyrosine kinase inhibitors also appear to have
fewer class-specific toxicities due to their lower effectiveness against
the wild type EGFR protein.
An interim question is
a 43 year-old never-smoker presents with shortness of breath and cough.
He's otherwise in good health and works full-time.
CT scan shows patchy, ground-glass opacities in both lungs.
CT scan of the brain is normal.
A bronchoscopic biopsy shows a well differentiated adenocarcinoma.
And molecular testing shows an EGFR L858R mutation with no ALK or
ROS I rearrangements.
What would be the most appropriate treatment of this patient?
Chemotherapy plus definitive radiation,
chemotherapy plus bevacizumab, erlotinib, or crizotinib?
And the appropriate answer is erlotinib,
because this man has an EGFR-sensitizing mutation, the L858R.
And erlotinib is an EGFR-tyrosine kinase inhibitor that does work better
in this situation, with higher response rates and
progression through survival than standard chemotherapy would.
Crizotinib is an ALK inhibitor, and
the person does not have an ALK rearranged tumor.
So another recent advance in non-small
cell lung cancer has been the identification of ALK rearrangements.
ALK is another receptor tyrosine kinase [COUGH] that can
stimulate proliferation of tumor cells.
It does so when there's a rearrangement on the chromosome that
fuses the ALK gene with a nearby partner, and
thereby creating a fusion protein that has
hyperactive ALK activity leading to cellular proliferation.
These ALK rearrangements, primarily EML4-ALK rearrangements,
occur in approximately 4% of non-small cell lung cancers.
Almost all of these are adenocarcinomas and occur in never/light smokers.
Crizotinib is an FDA-approved inhibitor of ALK, ROSI and cMET.
And when we use crizotinib in people with ALK mutated non-small cell lung cancer,
we see a response rate of approximately 60%.
However, resistance to crizotinib occurs through multiple mechanisms,
including secondary mutations within the ALK gene.
For patients who progress on crizotinib, we now have two FDA-approved drugs
that are potent selective ALK inhibitors, ceritinib and alectinib.
This is another waterfall plot in which each of the bars represents an individual
who had ALK-positive non-small cell lung cancer and was treated with crizotinib.
And we see that the vast majority of these patients had shrinkage of their tumors,
meaning the bars go downward, with a response rate of approximately 60% and
a disease control rate, meaning stable disease or response of 90%.
So crizotinib is very active in people with palp positive non
small cell lung cancer.
So this slide shows an example of a patient who came in with severe
shortness of breath and was found on scans to have a primary tumor.
With tumor invading throughout both lungs.
So this white, hazy snow stormy effect that you see is invasion of
tumor throughout both lungs and her entire CAT scan looked like this.
And biopsy was obtained, and the tumor was an adenocarcinoma.
She was a never smoker.
And mutational analysis revealed an ALK rearrangement.
She was treated with Crizotinib and
within weeks was off of oxygen and up and around, and feeling well.
And then, a scan done six months later shows near complete cavitation,
dissolution of the primary tumor.
And resolution of all of that snow stormy effect throughout the lungs.
This woman is now several years out and is still alive and
doing well on a second generation ALK inhibitor.
Unfortunately, resistance does develop to Crizotinib usually due to
a variety of mechanisms, one of which is the development of secondary mutations
within the ALK gene that can induce resistance to Crizotinib, and two drugs
have been developed that can have activity against some of these secondary mutations.
One of these drugs is Ceritinib.
The other one is Alectinib.
On this side, we see a waterfall plot of patients treated with Ceritinib,
who had ALK positive non small cell lung cancer.
Either treated as first line or treated after a prior Crizotinib therapy.
And we see that they have a response rate of 60% with the vast majority of
patients having shrinkage of their tumors.
So the most remarkable thing about the whole ALK story is that the first report
of an ALK abnormality in non small cell was in 2007.
And it only took four years for Crizotinib to be FDA approved for
use in patients with non small cell lung cancer.
So this is an example of how fast things are moving along now in the oncology
world.
Crizotinib has higher response rates in people with non small cell without
rearrangements.
Resistance does develop.
Due to secondary mutations in other mechanisms.
And now we have two drugs, Ceritinib and Alectinib, that also induce higher
response rates once people develop resistance to Crizotinib.
Another interim question.
A 38 year old woman presents with vague left chest pain.
She is otherwise feeling well and is caring for her two children.
She has never smoked.
CT scan shows multiple lung nodules and a moderate left pleural effusion.
CT scan of the brain is negative.
Cytology on pleural fluid reveals adenocarcinoma.
And molecular diagnostic testing shows an EML4-ALK rearrangement with
wild-type EGFR.
What would be the most appropriate treatment for this woman?
Chemotherapy plus bevacizumab, Crizotinib,
Chemotherapy plus definitive radiation or Hospice care.
Well, she has stage four Non-Small Cell Lung Cancer,
because of the positive pleural effusion and the multiple bilateral lung nodules.
So definitive therapy with chemo and radiation is not feasible and the correct
answer here would be Crizotinib, which has been shown to be better with
regard to response rate and progression free survival than chemotherapy
in patients with EML4-ALK rearranged Non-Small Cell Lung Cancer.
We know that you can have definitive benefit from treatment and
have potential years of survival.
So Hospice care would be inappropriate decision.
Aside from EGFR and ALK, there are number of other
targets that had been identified in Non-Small Cell Lung Cancer.
So ROS one rearrangement are very similar to those that I mentioned for ALK.
And they are occurring a smaller number of people about 2% and
Crizotinib is active against these tumors as well.
And Crizotinib was recently FDA approved for use in ROS1 rearranged Non-Small Cell.
Number of other mutations occur in small numbers of people.
B-RAF mutations, RET rearrangements, HER2 mutations and
MET mutations occur in 1 to 2% of people with Non-Small Cell.
And there are drugs that have been FDA approved for other uses that can
be active in these patients with Non-Small Cell Lung Cancer, and
we do utilize these on various occasions when we identify these abnormalities and
we have all seen people who have benefited from these treatments.
So when we see a person with newly diagnosed Non-Small Cell Lung Cancer,
what do we need to do as far as biomarker testing?
Well, what we definitely need to test is for
EGFR mutations, ALK rearrangements and ROS one rearrangements.
In certain selected situations, when we are looking for people for
clinical trials or when people have relapse disease or
beyond what we have in our arsenal for use against these types of tumors.
At those times, then doing broader molecular testing for
other gene rearrangements or gene mutations would be appropriate.
But for the basic treatment of these patients in a standard clinical setting,
the tests that need to be obtained are the EGFR, ALK, and the ROS one.
Who do we test?
Well, only patients with stage four lung cancer should be tested because there
really is no role for molecular therapy in people at stage I, II, or III testing.
And testing those individuals upfront is only going to waste
resources are rather than benefit the patient.
If those people recur, then at that time,
a biopsy should be obtained in order to test for molecular diagnostics.
Patients with Adenocarcinoma should be tested for these EGFR, ALK, and
ROS one abnormalities.
Also Non-smokers with non-adenocarcinoma should be tested for EGFR mutations
because the smoking status does tramp the histology and we have found
EGFR mutations in people with squamous cell carcinoma who are not smokers.
So coming back to our initial question, a 48 year old woman presents with cough.
She never a smoker and has an excellent functional status.
Chest CT shows bilateral nodules up to 3 cm and
a PET scan shows FDG-avidity in the lung lesions and no other metastases.
Biopsy shows well differentiated adenocarcinoma.
What's the most appropriate next step in her management?
Chemotherapy.
Chemo plus erlotinib.
Bilateral lung transplantation.
Or evaluate for EGFR mutation and ALK rearrangement.
And an obvious answer now from going through this talk is that her tumor should
be tested for specific driver mutations for which we have targeted therapies
that can work far better than chemotherapy for her and improve her longevity.
Take Home Points from this lecture are that Molecular subsets based on predictive
biomarker have been identified for both adenocarcinoma and
squamous cell carcinoma.
First and second line EGFR inhibitors are appropriate treatment for
people harboring EGFR mutations.
First and second line ALK inhibitors are available for
people harboring ALK rearrange tumors.
First line Crizotinib is appropriate treatment for
people harboring tumors with ROS one rearrangements.
And other targets and targeted therapy pairs are showing
promising results in studies on Non-Small Cell Lung Cancer.
>> I want to thank you for taking the time to watch this lecture.
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