: In terms of clinical presentation and prognosis, what are the key differences between patients with and without driver mutations?

: Over the past 15 years, we&rsquo;ve come to recognize that advanced lung cancer can really be divided and stratified based on patients who have genetic alterations and oncogenic drivers. The first targetable oncogenic driver that was identified was the epidermal growth factor receptor, which was identified in 2004. We&rsquo;ve since learned that these genetic alterations are found in about 10% to 15% of Western patients, and these patients tend to have characteristic clinical and pathologic charac- teristics. Most notably, we know that these genetic alterations confer sensitivity to treatment with targeted therapies or tyrosine kinase inhibitors [TKIs].

mutations in lung cancer, we&rsquo;ve come to recognize this as a paradigm of trying to identify oncogenic drivers that could be targeted with TKIs. Collectively, we know that in the United States, there are 4 different genetic alterations where we have FDA-approved targeted therapies. These are

. And, in general, patients with these specific genetic alterations tend to have pretty characteristic clinical and pathologic characteristics. For example, patients with

these tend to occur in patients who have a never or a very light smoking history. The same can be said for emerging oncogenic drivers such as

rearrangements, which, again, tend to be enriched for patients with a never or light smoking history. One of the outliers of this, though, is

mutations are found in 4% of patients with lung cancer. And in contradistinction to the other targetable alterations,

mutations can also be seen in patients who have a heavy smoking history.

: Are you seeing adequate early testing in patients referred from the community setting? Is the testing strategy changing?

: The current standard of care in the United States is to perform genetic testing on newly diagnosed patients with advanced nonsmall cell lung cancer. We know that among patients with

rearrangements, that these patients derive substantial benefits to treatment with the corresponding targeted therapies. So, one would expect that, based upon these benefits, testing would be 100%. Unfortunately, that still isn&rsquo;t the case in the United states, and that could be for a variety of reasons. In speaking to my colleagues, many times patients who come to academic centers don&rsquo;t have comprehensive genetic profiling and for a variety of reasons. Sometimes it can be because there&rsquo;s no tissue available. Biopsies or fine needle aspirates were performed as the biopsy procedure, and there&rsquo;s limited tissue available to perform the corresponding genetic analysis.

Sometimes patients don&rsquo;t have a disease that&rsquo;s accessible to a core needle biopsy for a variety of reasons. Nonetheless, I do think it should be our goal, and it should be the standard to perform genetic analyses on all newly diagnosed patients and to do so expeditiously. For patients who don&rsquo;t have tissue available to perform genetic analyses, I think one can approach this in 2 different ways. The first is to actually repeat a biopsy. I think if one has sufficient suspicion that a patient may have a targetable genetic alteration, that certainly makes sense, especially if a lesion is amenable to a repeat biopsy.

We know that in patients who are never-smokers, more than 50% of those patients are going to have a genetic altera- tion that can dramatically transform how those patients are managed. For patients who don&rsquo;t have a disease that&rsquo;s amenable to a repeat biopsy, be it because of comorbidities or the location of their tumors, an emerging tool is actually to perform a liquid biopsyso, to look at circulating-tumor DNA as a means to identify targetable genetic alterations. It should be emphasized, though, that liquid biopsies are not a substitute for baseline genetic sequencing if you actually have the tumor material available. Liquid biopsies can be a helpful complement, especially if the baseline tissue has been exhausted. The reason I say this is because circulating-tumor DNA assays are not nearly as sensitive as doing genetic sequencing on a baseline tumor biopsy. A negative CT-DNA assay isn&rsquo;t truly a negative test; it could just be that a patient isn&rsquo;t shedding. And so, negative results on a CT-DNA assay are really nondiagnostic, and you should keep an open mind that that patient may indeed actually still have a targetable genetic alteration.

: What are the emerging predictive driver mutations and how has this evolving identification changed the landscape of mutational testing?

has spurred additional efforts to identify additional oncogenic drivers that can be targeted therapeutically. Over the past several years, there have been several notable examples with very promising clinical data that we&rsquo;ve seen. Important examples of this include

rearrangements as an example: RET rearrangements were first identified in lung cancer in late 2012, early 2013. These were found in about 1% to 2% of patients, and they tended to have characteristic clinical and pathologic characteristics. Like other oncogenic rearrangements,

fusions, and these tended to occur in patients with a light- or never-smoking history.

At the time these were first identified, we didn&rsquo;t really have selective

inhibitors in the clinic, and so investigators relied on multikinase inhibitors that targeted multiple kinases, not just

. And so early on, the response rates that were seen with these multikinase inhibitors were relatively modest compared with other oncogenic drivers in lung cancer. So, we observed response rates in the 20% to 30% range. More recently, there have been 2 selective

inhibitors that have entered clinical testing, and both have shown high response rates, confirming our initial suspicion that

is a bona fide oncogenic driver mutation in nonsmall cell lung cancer.

, another emerging oncogenic driver in lung cancer has been

exon 14 skipping mutations. Here, the pathophysiology is quite distinct, so exon 14 encodes the CBL-binding region in

, which is important in that it targets the protein for ubiquitin-medi- ated proteasomal degradation. In the setting of an absence of exon 14, you get decreased degradation of MET, which results in increased accumulation of

exon 14 skipping is found in about 3% to 5% of patients. And like other oncogenic drivers, it does appear that

exon 14 skipping mutations confer sensitivity to treatment with

-targeted therapies. So, this does appear to be another driver mutation that may be important to test for moving forward.

As the number of targetable genetic alterations increases, it just becomes infeasible to perform single-gene tests one after the other. It really speaks to the need to compre- hensively evaluate the genetic landscape of the tumor and do so while simultaneously using the least amount of tumor tissue available. And to that end, I do think that next-generation sequencing using multiplexed assays is becoming the standard of careif not is already the standard of care at most academic institutions&mdash;which really does speak to the need to rapidly assess the genetic landscape of the tumor and do so while preserving tissue for future clinical trials.

: What is your treatment approach for patients with a new diagnosis? Can you discuss the trial design, results, and practical implications of the FLAURA trial?

: The approach to treatment of patients with advanced

-mutant lung cancer has certainly changed over the past several years. Historically, patients would be treated with either a first- or second-generation EGFR inhibitor. We know that the median progression-free survival with that approach was about a year for first-generation EGFR inhibitors. And at the time of development of resistance, about 50% to 60% of patients would have developed a single gatekeeper resistance mutation,

T790M. Among those patients who developed T790M, we&rsquo;ve recently developed data showing that use of a mutant-selective

-specific inhibitor, such as osimertinib, could induce responses in the vast majority of patients after progression on a first- or second-generation inhibitor.

Over the last year or so, though, that paradigm of start- ing with a first- or second-generation inhibitor and then using a third-generation inhibitor among those who developed

T790M has changed, and it has changed in response to the FLAURA data. So, FLAURA was a randomized phase III study that compared using a first-generation inhibitor, gefitinib or erlotinib, versus osimertinib in newly diagnosed

-mutant patients. In FLAURA, osimertinib led to significant improvements in progression-free survival compared with the first-generation inhibitors. And the median PFS in FLAURA was approximately 19 months for patients receiving osimertinib. Importantly, patients who received osimertinib also had improved control of central nervous system [CNS] metastases. In my clinical experience, I&rsquo;ve also found that osimertinib tends to be quite well tolerated, with a favorable adverse effect profile. And as a result, I believe that osimertinib should be the standard of care for newly diagnosed first-line

An alternative approach that has been put forward after FLAURA has been that clinicians should still continue us- ing a first- or a second-generation inhibitor first followed by a third-generation inhibitor such as osimertinib. In my mind, that approach is flawed, and the reason that that&rsquo;s the case is that among patients who receive first- or second- generation inhibitors, just 50% to 60% will actually develop

and thus be candidates for receiving osimertinib in the second-line setting. Furthermore, we also know that from various clinical trials that not every single patient makes it to the next therapy. Even when patients are eligible for crossover in clinical trials, the numbers of crossover don&rsquo;t reach 100%. And so, I feel that we should use our very best therapy first in order to try to maximize efficacy while also maintaining a favorable safety profile.

: How have the results and implications of the ALEX trial influenced the sequencing of therapies in ALK-rearranged NSCLC?

: The global ALEX study was a randomized phase III study for patients with newly diagnosed

-positive lung cancer, and patients were randomized to receive either crizotinib, the standard ALK inhibitor, prior to the ALEX study, or alectinib, a second-generation ALK inhibitor. And in the ALEX study, alectinib produced significant improvements in progression-free survival compared with crizotinib. Indeed, the median progression-free survival with first-line alectinib was extremely impressive. With the latest ASCO [American Society of Clinical Oncology] update, the median progression-free survival was nearly 3 years, which is quite impressive for newly diagnosed pa- tients with

Importantly, compared with crizotinib, alectinib also resulted in superior control of CNS metastases, with far fewer cumulative incidence of CNS metastases, compared with patients treated with crizotinib. And so, based upon the results of the ALEX studywhich I should also mention confirmed the results of a parallel Japanese study called the J-ALEX study, which had a very comparable design&mdash;together, those 2 phase III studies have really confirmed that alectinib should be the first-line standard of care for patients with newly diagnosed

In July 2018, we had 4 approved ALK inhibitors in the United States: the first-generation inhibitor crizotinib and 3 second-generation ALK inhibitorsceritinib, alectinib, and brigatinib. The historical paradigm was to start with crizotinib, which induced high response rates, followed by use of a second-generation ALK inhibitor such as ceritinib, alectinib, or brigatinib. The second-generation inhibitors are generally characterized by increased potency compared with crizotinib, increased selectivity, and better CNS penetration. All 3 of those second-generation inhibitors are currently approved in the United States for use after crizotinib.

As I mentioned earlier, alectinib is also approved for first- line use based upon the ALEX study, and ceritinib is also approved for first-line use. Together, though, I would consider that alectinib is really the first-line standard of care, putting together the data from the ALEX study with impressive activity combined with CNS penetrability and a favorable safety profile. Nonetheless, there are a number of patients who are currently still on crizotinib in the United States or receiving crizotinib in other areas of the world. And so, it is very much a question of, if patients have started with crizotinib, what should be the preferred next second-generation ALK inhibitor? There are currently no head-to-head comparisons across the second-generation ALK inhibitors, so we&rsquo;re generally left with cross-trial comparisons.

The most recent drug that was approved in this space is brigatinib, another second-generation inhibitor that has shown very high response rates and, in the crizotinib-resistant-setting, has shown impressive progression-free survivalaround 15 to 16 months in the latest update. And so, based upon that impressive data, brigatinib is now being explored in the first-line space with a head-to-head comparison against crizotinib, and I think we&rsquo;ll eagerly await that data.

The the question is, what do we do for patients who are pro- gressing on first-line alectinib, which I argued was the new standard of care? The agent that has the most data in that set- ting is still an experimental agent. This is a so-called third- generation ALK inhibitor, lorlatinib, which was a granted breakthrough therapy designation by the FDA. And that was based upon encouraging response rates among patients who were treated with 1, 2, and even 3 prior ALK inhibitors. And so, that&rsquo;s an agent that has shown activity in the postalectinib setting and, if approved, would be an option in that setting.

: Can you review the use of combination BRAF- and MEK-targeted agents?

mutations are found in about 4% of patients with nonsmall cell lung cancer. One important point to draw contrast with melanoma, where

mutations are found in about 50% of patients, is that not all

mutations in lung cancer are V600E. In fact, only about 50% of lung cancers with

mutations will actually have the canonical V600E mutation. So, that really brings down the frequency to about 2% of patients who will have

V600E. In general, these patients tend to have clinical characteristics in contrast with

mutations in patients with a history of smoking. But we also know that

mutations do confer sensitivity to treatment with targeted therapiesspecifically, BRAF inhibitors, as well as MEK inhibitors.

We have learned early on from our colleagues treating melanoma, that

inhibitors can induce responses to tumors harboring V600E mutationsmost notably in mela- noma and nonsmall cell lung cancer. Actually, the combination of BRAF plus MEK inhibition can result in improved activity and tolerability. We know from single-arm studies that the combination of BRAF plus MEK [inhibition] leads to high response rates in the 60% range and favorable progression- free survivals.

We&rsquo;ve seen in nonsmall cell lung cancer, as well as in melanoma, that the combination of BRAF plus MEK inhibition results in better activity, as well as better tolerability. And this results from blocking downstream of the mutant

with a MEK inhibitor. So, in the United States, the combination of dabrafenib and trametinib is currently approved for patients with

V600E nonsmall cell lung cancer. I should note that this is different from the experience in colon cancer. I think

is a helpful lesson for targeted therapies more broadly because we know that the same genetic alteration can behave very differently depending upon the tumor in which it occurs in. So,

V600E in melanoma and in nonsmall cell lung cancer is very sensitive to treatment with BRAF plus MEK. By contrast, the same mutation in colorectal cancer is far less sensitive to targeted therapies. And so, I do think that it&rsquo;s an important reminder that we need to actually do clinical trials of genetic alterations across different diseases, because they may behave quite differently.

For non-V600E mutations, currently, the standard of care would be the default: chemotherapy, immunotherapy, or a combination of the 2. There are actually many different types of non-V600E mutations. They generally fall into 3 different classes, and the approaches to each of those classes are different. But right now, there&rsquo;s no currently FDA-approved therapy for non-V600E mutations. And so, if I were to encounter one of those patients, I would actually direct them to a clinical trial, but the standard of care to start would be as if I were approaching that type of patient.

: What is the evolving role of immuno-oncology (I-O) therapy for patients with newly diagnosed NSCLC?

: Over the past 6 months, we&rsquo;ve had some really exciting data emerge on the role of chemotherapy-plus- immunotherapy combinations. And we&rsquo;ve seen now 3 randomized controlled studies showing overall survival improvements with the addition of PD-1 or PD-L1 inhibition to standard chemotherapy in nonsmall cell lung cancer. I think the most important of these studies was KEYNOTE-189. This was a randomized phase III study that compared platinum/pemetrexed versus platinum/ pemetrexed plus pembrolizumab. And in the study, the triplet combination resulted in improvement in both progression-free survival as well as overall survival. And an important part of that study is that with respect to overall survival, there was an improvement in every strata of PD-L1 expression, so greater than 50%, 1% to 49%, as well as in less than 1%.

We&rsquo;ve recently had data from the IMpower150 study. This also focused on nonsquamous patients, and here it is a bit of a more complicated study in that there are 3 different arms to the study: arms A, B, and C. Control group was arm C. This was carboplatin/paclitaxel/bevaci- zumab, and this was compared against either carboplatin/ Taxol, or carboplatin/paclitaxel, and bevacizumab plus atezolizumab or carboplatin/paclitaxel/atezolizumab, so removing the bevacizumab from that arm. At both AACR and ASCO, we saw data from this study, and it did look like the quadruplet regimen of carboplatin/paclitaxel/ bevacizumab/atezolizumab resulted in improvements in both progression-free survival as well as overall survival compared [with] the control arm of carboplatin/paclitaxel/ bevacizumab. So, overall, we have another positive study for patients with nonsquamous histology.

: Can you describe the PFS of the patients who had

-rearranged NSCLC? What is the potential explanation for this finding? For which patients would this regimen be most beneficial?

: One key distinction between KEYNOTE-189 and IMpower150 is that KEYNOTE-189 excluded patients with sensitizing

rearrangements. By contrast, those patients were allowed into IMpower150 provided they received the relevant targeted therapy. It was a bit surprising to all of us to see that the benefits to adding atezolizumab to carboplatin/paclitaxel/bevacizumab even extended to the

-positive subgroups compared with the control arm. The reason this was surprising is because in earlier studies of just using single-agent checkpoint inhibitors, the benefits among

- positive patients were quite minimal with just single-agent checkpoint inhibitors. We saw response rates among

patients were 10% or less, and in meta-analyses, there was no improvement in survival compared [with] single-agent docetaxel. And among

-positive patients, really the re- sponse rates have been 0 in the limited studies to date.

And so, in IMpower150, we saw that now combining chemotherapy with

inhibition and PD-L1 inhibition, it did look like there was an improvement in the

positive patients. So, this really represented the first study where we have an improvement with checkpoint inhibition in those molecular subgroups. And I think that&rsquo;s one of the key take-homes from the IMpower150 data.

What [makes] IMpower150 different [from] other studies of single-agent checkpoint inhibitors among

-positive patients? One potential explanation is that chemotherapy may have led to tumor antigen release, and this may have spurred or resulted in increased sensitivity to the checkpoint inhibition. An alternative hypothesis is that there may have been an interplay between the VEGF inhibition with bevacizumab and PD-L1 inhibition with atezolizumab. That interplay may have been particularly important in patients with

-positive lung cancer. Still, a third hypothesis is that there may have been something unusual about this particular subgroup of patients.

In total, there were a little over 100 patients with

-positive nonsmall cell lung cancer who were treated as part of the IMpower150 study, but there were several things that were a bit unusual about that group. In particular, there were about 6 patients who had both

rearrangements. While that&rsquo;s been reported, it&rsquo;s typically quite rare. It did seem like a disproportionate number of patients in that study had both, which calls into question the molecular testing that was performed and the quality of testing. [This] raises the question [whether] all of these patients [were] truly

-positive. Perhaps that may have explained some of the benefit.

: Should patients with oncogenicdriver positive NSCLC be considered for immunotherapy as first-line therapy? Combination I-O therapy? Could immunotherapy be used after progression in these patients?

: Over the past 15 years, there have been 2 major new paradigms that have transformed the management of non small cell lung cancer: targeted therapy and immunotherapy. I can say that today, they still have very important roles in the management of our patients. Each has been guided by a different biomarker, and the importance of those biomarkers, I would say, are still very important today. So, patients with newly diagnosed advanced non&ndash;small cell lung cancer should still have comprehensive genetic profiling as well as PD-L1 expression scores. I think those are just baseline what we should expect to see in all of our patients.

The question, though, is, what are the roles of immunotherapies in certain genetic subsets of patients with nonsmall cell lung cancer? Early on, there was enthusi- asm for exploring the role of immunotherapies in patients with defined oncogenic drivers. We recognized that the activity of immunotherapy as a single agent really pales in comparison with targeted therapies in patients with

From a retrospective single-institution series performed at my own institution, we&rsquo;ve seen that

-positive patients have about a 3% response rate to single-agent checkpoint inhibitors. More recent meta-analyses have looked at the randomized studies, generally in the second-line setting comparing single-agent checkpoint inhibitors versus docetaxel, and specifically among

-mutant patients, really seeing that single-agent checkpoint inhibitors did not result in an improvement in survival compared with docetaxel.

In addition to that, we&rsquo;ve now gotten some prospective data, and I think the best prospective data with single-agent checkpoint inhibitors came from the ATLANTIC study. And this was evaluating durvalumab in specific subgroups, and that included patients with

rearrangements. Notably, even when that study tried to enrich for responders by focusing on PD-L1 expressionin here, it was 25% or greater&mdash;the response rate among EGFR patients with that degree of PD-L1 expression was only 12%. And there were no responses observed in the ALK subgroup, de- spite having high PD-L1 expression. And I think this speaks to a point that PD-L1 expression is a less reliable predictive biomarker in patients with

-positive disease. This is for several reasons, [the] first [being] that these tend to be low mutation tumors.

tend to occur in never- or light-smokers, and so we would expect them to have a low TMB.

The second [reason] is [that] work from our institution shows that there are multiple different ways to induce PD- L1 expression on the surface of tumor cells. Classically, this would be from infiltrating immune cells, leading to interferon gamma secretion and driving PD-L1 expression on the cell surface. We think that [this] is likely to be the most immunogenic, in that you have preexisting immune cells there together with PD-L1 expression. By contrast, oncogenic signaling [itself] via

can lead to, can result in PD-L1 expression independent [of] the presence of immune cells. The responsiveness to PD-1 inhibition in that setting is likely to be very different because, again, it&rsquo;s not presupposing that there are T cells in the local microenvironment.

I think putting this all together speaks for patients with

. We should really be prioritizing targeted therapies for those patients and really maximizing targeted therapies wherever possible for [them]. Unfortunately, we know that patients will eventually develop resistance to [targeted] therapy and, at some point, need to move on to other forms of therapy. I think the IMpower150 data tells us that one path forward may be exploring chemotherapy plus PD-1 combinations in those patients instead of just single-agent checkpoint inhibitors, which I think right now are not the best [way] forward for those particular patients.

Moving forward, I think we need to also look at other oncogenic drivers and how they respond to immune checkpoint inhibitors. We have to keep in mind that smoking status has been a pretty good surrogate. Patients with oncogenic drivers that are classically defined with those who have minimal smoking history, are probably unlikely to derive significant benefit from single-agent checkpoint inhibitor. A final point is that, even within a specific driver subgroup, there are likely to be co-occurring genetic mutations that may also affect sensitivity to checkpoint inhibitors. Here, the best example would be KRAS. We know that

is the most common oncogenic driver mutation in nonsmall cell lung cancer. But there are important co-occurring mutations with

, and I think the most important co-occurring mutations are tumor protein 53 [TP53], liver kinase B1 [LKB1], and kelch-like ECH-associated protein 1 [KEAP1].

Recently, we participated in a Stand Up to Cancer Lung Cancer Dream Team project and demonstrated that the presence of an LKB1 mutation with

resulted in insensitivity to treatment with checkpoint inhibitors. Response rates to single-agent checkpoint inhibitors among

plus LKB1 were quite low, on the order of 10%. By contrast, among

plus TP53, response rates were much higher in the 40% range. [Therefore], I think the primary driver by itself has to also be taken into account with the co-occurring mutations, and

is one such example. I think we&rsquo;re just right now starting to scratch the surface of that.

: Is there a potential role for sequencing or combining targeted therapy and immunotherapy in NSCLC with actionable mutations?

: The hope had always been to combine targeted therapiestaking an advantage of the high response rates of targeted therapies&mdash;with immunotherapies, with the hopes for durability of responses with a way to get both high re- sponse rates and durable responses. Unfortunately, the approaches of combining targeted therapies with immunotherapies have been fraught with difficulty in nonsmall cell lung cancer. And the principal challenge has been toxicity, and it hasn&rsquo;t been the same toxicity. It&rsquo;s actually varied depending on which combinations have been explored. So, for example, combining an EGFR inhibitor such as osimertinib with checkpoint blockade, in this case durvalumab in the TATTON trial, resulted in very high rates of pneumonitis, prompting discontinuation of that approach.

Similarly, the combination of crizotinib plus nivolumab for patients with

Articles

Clinical Articles

Justin F. Gainor, MD, assistant professor of medicine, Harvard Medical School, Massachusetts General Hospital, discusses the treatment landscape of oncogenic driver-positive NSCLC.

Expert Insights in the Treatment Landscape of Oncogenic Driver-Positive NSCLC

Can you provide a brief overview of the incidence and classification of lung cancer?

: Lung cancer can be broken down into nonsmall cell lung cancer [NSCLC] and small cell lung cancer. Non&ndash;small cell lung cancers are the most common type of lung cancer and occur in about 4 out of 5 patients, and the most common histology for non&ndash;small cell lung cancers is adenocarcinoma. In general, in the United States, about 200,000 cases are diagnosed a year, and so it makes it a very substantial population of patients with this burden of disease.

Can you discuss the importance of molecular testing in patients with stage IV NSCLC and the pros and cons of panel versus single-gene testing?

: Paying attention to selecting the most appropriate test for profiling patients&rsquo; tumors on a molecular level is critical in this day and age, and that&rsquo;s because we&rsquo;ve really moved beyond single-gene testing that we used to do in the early 2000s, when we knew about fewer genes like

for example, in 2003 and 2004&mdash;and then later, the

rearrangement. Now we have a whole slew of other potential drivers like

. And so, it&rsquo;s important to choose a test that&rsquo;s comprehensive and that&rsquo;s able to detect all of these alterations in patients who have nonsmall cell lung cancers. My personal preference is not to practice single-gene testing anymore and to go for a multiplex comprehensive approach.

At our center, we use DNA-based next-generation sequencing [NGS], recognizing that not all NGS assays are the same. And, of course, the caveats are that because it&rsquo;s a big test that looks for hundreds of genes, it can sometimes take a few weeks to come back. And for patients who are sick, it&rsquo;s critical to find out early on, maybe within the first week, whether or not those cancers have a driver. And so, a strategy that we&rsquo;ve adopted at our center is to do rapid-phase testing, where we look for

using mutation-specific immunohistochemical antibodies, and that way you might get an answer within the first 1 to 2 days and be able to institute targeted therapy early. And then the rest of the sample we send for comprehensive NGS. So, I think NGS is the way to go in this day and age.

Can you describe the emerging role of tumor mutational burden as a biomarker in clinical practice and how it may be used alone or in conjunction with programmed death-ligand 1 (PD-L1) testing?

: Tumor mutational burden [TMB] on a very simplistic level is a measure of how complex a cancer is, meaning the number of mutations that occur within the tumor. And we found that depending on the assay that you use, you can measure tumor mutational burden, by counting the number of what we call nonsynonymous mutationsmeaning if you have many more mutations that count as a high score versus if you have much fewer, that would be an intermediate or a lower score. The TMB-high patients, those have been associated with benefit from immune checkpoint inhibition, and, again, this cutoff varies depending on the test that you use. But it seems like there is an association between cancers that are TMB high that have a greater proclivity for response either to single-agent immune checkpoint blockade or to combination immune checkpoint blockade. And so, it&rsquo;s one of the potential biomarkers that we&rsquo;re looking at in the immuno-oncology space.

Now, TMB doesn&rsquo;t always completely coincide with the level of PD-L1 expression on cancers, and so I think the approach that&rsquo;s favored now is to treat these as overlapping but independent biomarkers. And so, if I have a patient who, for example, may have a PD-L1negative tumor but really has a high TMB score, I would think very carefully about whether or not I might get immunotherapy to that patient, even though the PD-L1 status is negative.

How have the results of the FLAURA trial changed the sequencing of EGFR- targeted agents in clinical practice?

: The FLAURA trial is a landmark trial that randomized

-mutant lung cancer patients to osimertinib, which is a third-generation EGFR TKI [tyrosine kinase inhibitor], versus first-generation agents erlotinib or gefitinib, recognizing that osimertinib has several advantages. It&rsquo;s able to target the most common mechanism of resistance with the first-generation agents, vis-à-vis a gate-keeper

mutation. In addition to that, it also has excellent CNS [central nervous system] coverage, especially for patients who have brain metastases. And we know that patients who don&rsquo;t have brain metastases, given that they have lung cancer, also have a proclivity or a tendency to develop brain metastases in certain situations.

It's not a surprise the results of the FLAURA trial were positive for an improved benefit in terms of survival with osimertinib versus erlotinib and gefitinib, and that&rsquo;s with progression-free survival. It really changed the standard of care. And now there&rsquo;s FDA approval for osimertinib as the first-line therapy of choice for EGFR-mutant lung cancer cases. And I think this really underscores the paradigm of using your best drug first, knowing that osimertinib was previously approved for patients who have progression on a first-generation or second-generation TKI that then develop a

mutation. Now we&rsquo;re moving that to the frontline setting and using it for everybody.

: What is the best approach for the treatment of patients with brain metastases?

: Fortunately, many of the tyrosine kinase inhibitors that are available for ALK-rearranged lung cancers have good CNS coverage. And I&rsquo;m speaking specifically about alectinib, ceritinib, and brigatinib, which are next-generation agents, compared with crizotinib, which was the former standard of care and is a first-generation ALK TKI. Now, similar to the EGFR space, where the FLAURA trial was positive for osimertinib in terms of progression-free survival over earlier-generation TKIs, there&rsquo;s the ALEX trial that randomized patients to alectinib versus crizotinib. Those are patients with

-rearranged disease. And no surprise, because alectinib targets potential mechanisms of resistance to earlier generation therapy with crizotinib and has better CNS penetration, alectinib won in terms of progression-free survival and is now the new standard of care for

-rearranged lung cancers also have a proclivity for metastases to the brain, although there are reports of the

-rearranged population potentially having a lower level of brain metastases. Crizotinib is FDA approved for this population, and it can have activity in the CNS. However, there are other drugs that are currently being developed that may have better CNS penetration. An example of 1 drug that&rsquo;s currently in clinic trials is entrectinib, which has been looked at in ROS1-rearranged lung cancer patients, and that drug is known to effectively cross the blood-brain barrier and address CNS disease.

: What were the key findings of the phase II ALTA trial leading to the FDA approval of brigatinib in relapsed/refractory

: The phase II ALTA trial looked at the utility of brigatinib in

-directed TKI therapy. Brigatinib is a later-generation TKI that targets many mechanisms of acquired resistance to earlier generation therapy with crizotinib, meaning on-target mutations that might emerge with treatment. It&rsquo;s no surprise that this drug was active in this trial, with a response rate that exceeded 40% and really good progression-free survival compared with some of the other TKIs. And so, because of this, brigatinib is cur- rently approved by the FDA as a second-line therapy for patients with

-rearranged lung cancers who previously received crizotinib.

What is your approach to treatment sequencing in

: Alectinib is currently the standard of care for

-rearranged [nonsmall cell] lung cancers. Because [we have] moved one of our better drugs into the first-line setting, the question becomes what [drug should be used] after that. I think there are 2 potential options in terms of TKI therapy, like brigatinib and lorlatinib, that do have very broad coverage against possible on-target resistance mechanisms. [It is] still not very clear what the response rate is going to be like when we treat more patients. Although, with the lorlatinib data, we have seen that patients have responded after several prior TKIs. It&rsquo;s encouraging. Until we have definite FDA approval for another TKI after alectinib beyond exploring one of [the] TKIs on clinical trials or [prescribing] it for patients, a very viable option is [to] consider giving patients chemotherapy plus/minus immunotherapy [after alectinib].

-mutant lung cancers include a proportion of patients that have

V600E mutations in their tumors, and this has been well known to be a target in the melanoma world. We found that these mutations can occur in nonsmall cell lung cancers, up to a frequency of about 2%, depending on the series that you look at. We know that these are highly actionable, and if you give a single-agent

nhibitor like vemurafenib or dabrafenib, you might achieve response rates of approximately 30%. However, following the lead again of what we&rsquo;ve seen in the melanoma world, when you give a combination of a

inhibitorspecifically, dabrafenib and trametinib&mdash;we know that the response rate more than doubles to 63% with that combination in the phase II setting. And so, that&rsquo;s currently approved by the FDA for the treatment of

V600Emutant lung cancer patients and would be my first choice for someone that&rsquo;s stage IV and treatment naïve, knowing that the outcomes we&rsquo;re seeing with the combination paralleled the outcomes that we&rsquo;ve seen with tyrosine kinase inhibitor therapy for the

What is the rationale for combining PD-1/PD-L1targeted agents with chemotherapy?

: The rationale for adding chemotherapy to immune therapy is complex but can basically be broken down to the fact that chemotherapy drugs can, in a way, modulate the immune system. And so, the purpose of adding chemotherapy to immune therapy is to hopefully boost the likelihood of immune therapy acting to augment the immune system, making tumors visible to the immune system and the immune system attacking these cancers and getting rid of them.

What is the rationale for combining a PD-L1targeted antibody and chemotherapy with a VEGF-targeted antibody?

: The purpose behind adding bevacizumab, which is an antiangiogenic agent, to immune therapy is in the same way that chemotherapy may modulate the immune system. There are data for antiangiogenic therapy with a monoclonal antibody added to VEGF for also modulating immune effec- tor cells, which may then help the immune therapeutic do its job, so to speak, when administered in combination.

What are the implications of using the effector T-cellshigh population as a predictive biomarker, like within the IMpower150 trial, to predict efficacy of the atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) regimen?

: I think we should be very careful when we look at new potential biomarkers. IMpower150 was a randomized trial that looked at patients in the first-line setting with stage IV advanced NSCLC. Patients were randomized to carbopla- tin/paclitaxel and bevacizumab, a well-recognized regimen based on previous testing, with or without atezolizumab, an immune checkpoint inhibitor. In this trial, the investigators looked at the T-effector signature, which seemed like there may be a signal for increased benefit in those that fell into the highT-effector category. However, we know that even PD- L1 and TMB, which one can argue are much more vetted in terms of biomarkers, aren&rsquo;t perfect in their ability to predict the likelihood of response to immune therapy. I think that looking at this T-effector signature is much more in its infan- cy compared [with] other biomarkers. So, it&rsquo;s something that I think we should continue to look at on an investigational level. But on a clinical level, I wouldn&rsquo;t yet jump to rely on this as a potential signature for giving this combination until we see further data come out.

In your opinion, which NSCLC population would benefit most from the ABCP regimen?

: The combination of ABCP parallels the combina- tion of carboplatin/pemetrexed and pembrolizumab. The hope is that for [patients with] stage IV advanced nonsmall- cell lung cancer...(nonsquamous), the combination of chemo and immune therapy with bevacizumab might result in [a] response not just in tumors [that are] much more sensitive to immune therapy, but also in cancers that maybe fall below that cutoff like PD-L1.

How would you characterize the utility of dual checkpoint inhibition in patients with metastatic NSCLC?

: Recently there has been a trial examining the utility of giving the combina- tion of antiPD-1 and cytotoxic T-lymphocyte&ndash;associated antigen 4 [CTLA4] therapy specifically with nivolumab and ipilimumab. This was [administered] in patients that, in a certain subpopulation, had higher levels of TMB. [The] take-home point is [that] the combination does seem to work, and [it is] something that we can look forward to as a potential strategy for treating NSCLC, knowing that activity has also been demonstrated for [patients with] small cell lung cancer.

As clinicians, whenever we give several drugs in combination, one thing that we need to be cognizant about is the additional toxicity of adding a second agent. CTLA4-directed therapy on its own can have a higher [adverse] effect profile compared [with] PD-L1 monoclonal antibody administration. When you give both drugs together, clini- cians need to be very careful to watch for potential immune-related adverse events that might emerge with treatment.

Given the fact that this therapy is a combination and that there is the possibility for increased adverse events, if this treatment does eventually get approved, l think I would personally consider it for patients who are more fit and have less comorbidities, certainly patients who do not have a substantial history of a prior autoimmune disease. Based on the trial design, this would be for the first-line setting for patients with NSCLC.

In what treatment setting and NSCLC subpopulations is the use of immune combination therapy beneficial to patients with NSCLC?

: The question as to whether or not to use immune therapy for patients whose cancer is harboring an actionable driver is really a question of when to use immune therapy. So, it boils down to sequencing, essentially. We know that for patients with

mutations; recurrent gene rearrangements involving

mutations that there are targeted therapies in development, several of which have very high response rates and good progression-free survival. So, when choosing therapies for patients, it&rsquo;s all about the odds of responding to treatment. And you could argue that because for certain subsets of these driver-positive patients, like

, for example, where there are FDA-approved therapies and

, that you should start with a targeted therapeutic because you&rsquo;re seeing response rates in excess of 60% and very good progression-free survival.

Now, what do we know about immune therapy for these driver-positive lung cancers? Well, there have been several reports now, both retrospective and subset analyses of prospective trials, showing that the likelihood of response with single-agent immune checkpoint inhibition is much lower in these populations. So, one example is a retrospective study out of Boston, with

, where the likelihood of response was 3% for

positive lung cancers compared with an historic response rate of 20% in unselected cases.

So, when you see numbers like that and compare them with a response rate of 60% to 80%, you know that you should save these therapies potentially in your back pocket for the future and not use them up front. There are much more recent data, some from our institution on the likelihood of response in

exon 14altered lung cancers and a separate series in

-mutant lung cancers. Again, we&rsquo;re seeing response rates that are less than 15%. And so, I think that if you were to think about a single-agent immune checkpoint inhibitor, this would be given relatively late in the course of therapy. And I would argue that after targeted therapy, if you&rsquo;re going to use chemotherapy alone, then you might use chemotherapy before going to single-agent immune checkpoint inhibitor.

Things are changing now because of the addition of immune therapy to chemotherapy. And beyond platinum/ pemetrexed/pembrolizumab, there were recent data from the IMpower150 study, which randomized patients to carboplatin/paclitaxel/bevacizumab plus or minus atezoli- zumab, showing that there was a signal for benefit in the driver-positive subsets that included

. There may be a potential role for incorporating immune therapy in the treatment paradigm for driver-positive lung cancers after you&rsquo;ve explored targeted therapy either with 1 drug or with a sequence of drugs, if that&rsquo;s available for that subset, where we may then carefully think about the utility of using chemotherapy plus immune checkpoint inhibition therapy for these patients. But it&rsquo;s an evolving question, and I hope that much more data come out supporting the utility of immune checkpoint inhibition and where exactly to include that in the sequence and treatments.

What were the key findings from the recent phase II study investigating pembrolizumab in TKI-naïve, PD-L1positive,

: This was an interesting prospective phase II trial that looked at the utility of single-agent immune checkpoint inhibition for

-mutant lung cancers. And the results were consistent with retrospective analyses of the utility of immunotherapy for these patients and subset analyses of prospective trials. The response rate was low. It was 9% in this phase II study. However, that was in just 1 patient. On subsequent analysis of the tumor, it turns out that it did not harbor an

mutation. So, this really highlights that there are certain therapies that are much more of a fit for particular patients up front in the first-line setting. And this supports the fact that we should look at giving targeted therapy as a standard of care in the treatment-naïve setting for patients with advanced

-mutant lung cancers and not give a single-agent immune checkpoint inhibitor.

-mutant lung cancers, like other driver-positive lung cancers, can express PD-L1, and a certain proportion do have PD-L1 expression of 50% or greater. But even in that situation, I would personally prefer to give targeted therapy rather than considering something like pembrolizumab, recognizing that the trials that showed the activity of pembrolizumab or 50% or higher excluded patients with

What is the role of immunotherapy for patients without driver mutations?

: If we look at patients whose cancers don&rsquo;t harbor a driver, we&rsquo;ll note that a substantial proportion of those cancers are smoking-related cancers, where we&rsquo;ve known that if you look at the number of mutations in those cancers, there tends to be a higher TMB compared with cancers that are driver-positive or those in never-smokers. And so, it seems like this is a subpopulation of patients who don&rsquo;t have a driver, but have a substantial history of prior exposure to carcinogens and may be much more pre- disposed to response to immune therapy versus patients whose cancers have a driver or patients who maybe have never smoked in the past.

What is the potential role for sequencing or combining targeted therapy and immunotherapy in NSCLC with actionable mutations?

: The question of whether or not to add immunotherapy to targeted therapy is an evolving question. There is a likelihood of potentially boosting response when you add an immune therapeutic to a targeted therapeutic. But at the same time, there&rsquo;s also a likelihood of increasing [adverse] effects in patients. We have some examples of

Alexander Drilon, MD, clinical director of Early Drug Development Service at Memorial Sloan Kettering Cancer Center, discusses the evolving role of immune-checkpoint blockade in NSCLC.

Clinical Perspectives in the Evolving Role of Immune-Checkpoint Blockade in Distinct NSCLC Populations

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, comprising approximately 80% to 85% of lung cancer cases.

The 3 main types of NSCLC are large cell carcinoma (10%), squamous cell carcinoma (25%), and adenocarcinoma (40%), with numerous less frequent subtypes.

Approximately 70% of patients with NSCLC are diagnosed with locally advanced or metastatic disease (stage IIIB/IV) at the time of diagnosis, with 40% of these newly diagnosed patients with NSCLC having stage IV disease.

The treatment of advanced, recurrent, and metastatic NSCLC is often associated with poor prognosis, and treatment is aimed to extend survival and provide symptom management.

Recent advances in understanding of distinct tumor biology and immunology have allowed for the development of numerous targeted therapies and immune checkpoint inhibitors, which have improved overall survival (OS) in specific NSCLC populations. Molecular characterization has led to the definition of new subgroups of patients with distinct tumor biology who require specific treatments and strategies.

Prior to the introduction of molecular targeted therapy, first-line treatment for advanced-stage NSCLC was limited to systemic cytotoxic chemotherapy and radiation therapy.

Several factors continue to influence systemic anticancer therapy recommendations for patients with advanced NSCLC, including individual tumor histology, patient performance status, molecular and im-munologic tumor characteristics, and driver oncogene biomarker status. These are evaluated to guide decision making among cytotoxic chemotherapy, targeted agents, and immunotherapy. Approximately 83% to 85% of patients with stage IV NSCLC do not have oncogenic driver biomarker status and require first-line therapy recommendations distinct from those of the biomarker-defined populations.

Updated Recommendations for Molecular Testing in NSCLC

Guideline recommendations across several organizations indicate the need for molecular and biomarker testing of tumor samples as part of the routine diagnosis, prior to initiating therapy in the first-line setting, to guide treatment decisions. At minimum, patients must be tested for the 4 oncogenic driversEGFR mutations, ALK rearrangements, ROS-1 gene rearrangements, and

V600E point mutationsas well as PD-L1 tumor expression level.

, Justin F. Gainor, MD, an attending physician in the Thoracic Oncology Group at Massachusetts General Hospital, emphasized the importance of genetic testing in NSCLC for appropriate treatment selection, &ldquo;Over the past 15 years, there have been 2 major new paradigms that have transformed the management of nonsmall cell lung cancer: targeted therapy and immunotherapy. I can say that today, they still have very important roles in the management of our patients. Each has been guided by a different biomarker, and the importance of those biomarkers, I would say, are still very important today. So, patients with newly diagnosed advanced non&ndash;small cell lung cancer should still have comprehensive genetic profiling as well as PD-L1 expression scores.&rdquo;

, Alexander Drilon, MD, the clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, described the current landscape of genetic testing, &ldquo;Paying attention to selecting the most appropriate test for profiling patients&rsquo; tumors on a molecular level is critical. [We have] really moved beyond single-gene testing that we used to do in the early 2000s when we knew about fewer genes like

rearrangement. Now we have a whole slew of other potential drivers like ROS-1 and rearranged during transfection (RET) fusions, MET exon 14 alterations,

. [It is] important to choose a test [that is] comprehensive and able to detect all of these alterations in patients who have nonsmall cell lung cancers. My personal preference is [to not] practice single- gene testing anymore and to go for a multiplex comprehensive approach.&rdquo;

In the United States, approximately 20% of all NSCLC adenocarcinomas are characterized by the oncogenic

Lung and bronchus cancer are the leading causes of cancer-related deaths in the United States and will be responsible for an estimated 154,050 American deaths in 2018. An estimated 234,030 new cases of lung and bronchus cancer will be diagnosed in 2018, which represents 13.5% of all new cancer diagnoses in the United States.

Role of Immunotherapy in NSCLC | Evolving Paradigms

Expert Insights in the Treatment Landscape of Oncogenic Driver-Positive NSCLC

Clinical Perspectives in the Evolving Role of Immune-Checkpoint Blockade in Distinct NSCLC Populations

Role of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Oncogenic Driver Mutations