These mutations were found to be much more common in non-smokers,
people with adenocarcinoma, women, and East Asians.
East Asians meaning Japanese, Chinese, and Koreans.
What happens when we target EGFR inhibitors to
different patient populations with non-small cell lung cancer?
If we take an unselected patient population and treat with an EGFR-TKI,
we expect a response rate of around 10 percent,
which is the prevalence of EGFR mutations in the unselected Caucasian population.
If we select for the clinical factors,
these factors up above here,
then we can see a response rate of 40 percent because we're
enhancing the population for people who have an EGFR mutation.
If, however, we look at sequencing to find
the mutation and we only treat people who have an EGFR sensitizing mutation,
then we will see a response rate of 70 percent.
So, by augmenting the particular patient population being treated,
we can enhance the potential benefits of therapy.
So, a rational question would be, well,
if we have someone with an EGFR mutation,
is it better to treat them with
an EGFR inhibitor or with chemotherapy as first-line treatment?
A variety of trials have evaluated this strategy looking at a number of EGFR inhibitors,
gefitinib, erlotinib, afatinib, versus a variety of different types of chemotherapy.
All of these studies have found an improvement in response rate,
anywhere from T2 to threefold improvement in response rate,
and about a doubling of progression
free survival in people who received the EGFR inhibitor.
Now, you'll notice over on the right here that the overall survival is not significantly
different in most of these studies because there was clearly a high-level of crossover.
So, people who are getting chemotherapy at progression
would be switched over to receiving an EGFR inhibitor.
So, these studies do clearly demonstrate that the benefits of receiving an EGFR inhibitor
upfront are greater than those of receiving
chemotherapy upfront if you have an EGFR-mutated tumor.
However, these drugs do not last forever.
So, the median duration of response with
first-line therapy is around 12 months with gefitinib or erlotinib,
and those patients will develop resistance and about 50-60 percent of people develop
a T790M mutation in the tyrosine kinase domain as their mechanism of resistance.
Though a smattering of other mechanisms are known to be possible.
These are a listing of the EGFR inhibitors that are currently FDA approved.
With the first-generation gefitinib and erlotinib having
activity against both wild type and the common mutations,
afatinib having activity against the common mutations as well as many
of the rare mutations and it is FDA approved now for rare EGFR mutations,
and also osimertinib, the most recent addition to the list,
not having much activity against wild type.
Which means, it's going to have a lower toxicity with regard to
the class effect toxicities of the drugs including rash and diarrhea,
but does have activity against the mutant forms of
EGFR as well as the T790M resistance mutation.
So, osimertinib is a mutation-specific EGFR inhibitor.
So, what happens when we give osimertinib to people
whose tumors have developed the T790M mutation?
This is a waterfall plot in which each of
the vertical bars represents a patient who is treated with osimertinib.
If the bar goes down,
then there was shrinkage of the tumor,
if it goes up, then there was growth of the tumor.
This line is the response rate line with 30 percent or greater shrinkage of tumor,
and we see that the response rate is 62 percent in people who had previously had
a first-generation EGFR inhibitor and had developed a T7 in their mutation.
So, clear benefit for use of osimertinib and also osimertinib has
good CNS penetration with a similar response rate in those who have brain metastasis.
What happens when we compare osimertinib to
chemotherapy and people who have developed a T790M mutation?
This is our progression-free survival.
We see an improvement in survival with the use of osimertinib versus use of chemotherapy.
Well, if osimertinib is
a mutation-specific EGFR-TKI that
affects the potential resistance mutation
that can arise when you treat with first-generation drugs,
what happens if we utilize osimertinib as first-line therapy?
So, this is the FLAURA trial that
compared first-line EGFR tyrosine kinase inhibitor either gefitinib,
erlotinib to osimertinib in people with common mutations.
With regard to progression-free survival and overall survival,
there was an improvement with osimertinib over first-generation EGFR-TKIs.
Similarly with regard to CNS progression,
there was an improvement with osimertinib.
So, in summary of all of these studies,
what we have found with EGFR inhibition is that erlotinib, gefitinib,
afatinib and also osimertinib approved as
first-line therapy in EGFR-mutated Non-small cell lung cancer.
Afatinib is approved for the rare sensitizing mutations.
T790M resistance mutations do arise within about 50 percent of patients.
Osimertinib is mutation-specific EGFR-TKI that is approved
for T790M+ Non-small cell after first-first line EGFR tyrosine kinase therapy.
Now, osimertinib has been found to improve survival over first-generation EGFR-TKIs,
and it has less toxicity.
So, it appears that osimertinib should be our new first-line therapy,
with an improvement in survival and
lower toxicity for people with EGFR mutated non-small cell lung cancer.
Question? Forty-three year-old never-smoker showed up with shortness of breath and cough.
She's feeling well and is working full time.
CT scan shows ground-glass opacities in both lungs.
Brain scan is negative.
Bronchoscopy with biopsy shows well-differentiated adenocarcinoma,
and testing reveals an EGFR L858R mutation.
What's the most appropriate further management: chemo plus radiation,
chemotherapy plus bevacizumab, osimertinib, or crizotinib?
Correct answer is osimertinib based on the data we showed that shows
improved survival with the use of osimertinib and
people with a sensitizing EGFR mutation.
So, the second target that had been identified in
lung cancer for which we have a targeted treatment is ALK.
ALK is also a membrane-associated growth factor receptor.
However, in this situation,
ALK becomes oncogenic through
a rearrangement on the second chromosome in which it is paired with
a aberrant promoter such as with the EML4 gene to create
a fusion protein that has hyperactive kinase activity to signal down through the cell.
ALK rearrangements occur in
approximately four percent of people with non-small cell lung cancer.
Almost all have adenocarcinoma and are never or light former smokers.
Crizotinib, ceritinib and alectinib are now FDA approved as
first-line therapy for people without mutant non-small cell lung cancer.
However, resistance also can occur through multiple mechanisms including
secondary out point mutations in
tyrosine kinase domain that inhibit binding of the inhibitors.
Ceritinib, alectinib and brigatinib had been approved as
subsequent therapy for people who have had progression on crizotinib.
This was the first data that came out looking at
ALK inhibition in an expanded phase one study of crizotinib.
Again, a waterfall plot where all of the vertical bars are
patients who received crizotinib in ALK-positive non-small cell,
and we see that the majority of people
64 percent had a response and the vast majority of people,
90 percent of disease control,
with some shrinkage of tumor.
This is an example of a CT scan showing us what can be
achieved with ALK inhibitors and people with ALK non-small cell lung cancer.
This is a woman who came in extremely short of breath with a primary tumor
here and her lungs filled with innumerable small pulmonary nodules.
She was found to have an ALK mutation and treated with crizotinib and six months later,
we see that the primary tumor has cavitated,
a little bit of atelectasis over here and
that blizzard appearance throughout her lungs has been cleared.
This was in 2011,
she subsequently had slow growth of tumor at about one and a half to two years,
and was then subsequently put on a clinical trial with alectinib,
and she continues on alectinib with good control of disease to this day.
Now, almost seven years out from her initial presentation.
So, similar to what we saw with EGFR inhibitors,
what happens if we take someone who has
an ALK mutation and give them first-line ALK inhibition versus chemotherapy?
We see that there's a significant improvement in response rate with crizotinib
and in duration of response with crizotinib with better progression-free survival,
and no big difference in overall survival because, again,
there is high level of crossover here with people on
the chemotherapy are getting crizotinib once they progress.
However the response to Crizotinib lasts on
average about one year at which time resistance develops.
The resistance to ALK is not quite as
clean as the resistance to EGFR and that there can be a variety of
different mutations that can lead to resistance as well as
a number of different bypass tracks of
other oncogenic drivers that can lead to resistance.
Alectinib was developed as
a second line alkyne inhibitor with potent activity against a variety
of these resistance mutations and we see in people
who have previously had Crizotinib and develop resistance,
Alectinib can yield a major response in about half of patients.
Importantly, brain metastases are very common in people who have ALK mutated
lung cancer with about 60 percent
developing brain metastases at some point during their disease,
and Alectinib has much better brain penetration and brain response rates than
Crizotinib does as well as you can see here with a 75 percent response rate in the brain.
Well, Alectinib was compared directly to
Crizotinib in the ALK trial as first-line therapy,
and we see that Alectinib had improved progression-free survival and overall survival
versus Crizotinib with a better progression within the brain as well.
So Alectinib appears to be the more active ALK inhibitor and
this study does suggest that it should be utilized as our best first-line therapy.
So what we know regarding ALK inhibition is that
the first ALK mutation was identified in non-small cell lung cancer in 2007,
and only four years later,
we already had an FDA approved ALK inhibitor in Crizotinib.
So it tells you how fast the field is moving from the time of discovery of
a potential biomarker target to the development of a clinically useful drug.
Currently, Alectinib is favored as first-line therapy based on
its activity as well as its relatively tolerable toxicity profile.
Resistance does develop with other secondary ALK mutations in other mechanisms.
Ceritinib, Alectinib and Brigatinib do have high response rates in people who have
previously had Crizotinib therapy and most importantly with improved CNS responses.
Lorlatinib is an investigational drug that has demonstrated
activity in people who have progressed on the other available ALK inhibitors,
however it remains investigational in the United States.
Let's go to another question.
A 38 year-old woman presents with vague left chest pain.
She's otherwise in good health and is caring for her two young children.
She is non-smoker.
Scan reveals multiple lung nodules of left pleural effusion.
Scan of the head is negative.
Cytology on pleural fluid reveals adenocarcinoma.
Molecular testing shows an EML4-ALK rearrangement.
What's the appropriate further management?
Chemotherapy plus bevacizumab, Alectinib,
Crizotinib plus chemotherapy, or hospice care.
Well based on the data we've looked at today,
Alectinib would be the most appropriate treatment for this young woman in
good shape with a EML4-ALK rearranged adenocarcinoma of the lung.
