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

Alexander Drilon, MD

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

Drilon: Lung cancer can be broken down into non—small cell lung cancer [NSCLC] and small cell lung cancer. Non–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–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.

TARGETED ONCOLOGY: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?

Drilon: Paying attention to selecting the most appropriate test for profiling patients’ tumors on a molecular level is critical in this day and age, and that’s because we’ve really moved beyond single-gene testing that we used to do in the early 2000s, when we knew about fewer genes likeEGFR—for example, in 2003 and 2004—and then later, theALKrearrangement. Now we have a whole slew of other potential drivers likeROS1andRETfusions,METexon 14 alterations,BRAFV600E, andHER2. And so, it’s important to choose a test that’s comprehensive and that’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’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’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’ve adopted at our center is to do rapid-phase testing, where we look forEGFRandALKusing 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.

TARGETED ONCOLOGY: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?

Drilon: 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’s one of the potential biomarkers that we’re looking at in the immuno-oncology space.

Now, TMB doesn’t always completely coincide with the level of PD-L1 expression on cancers, and so I think the approach that’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.

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

Drilon: The FLAURA trial is a landmark trial that randomizedEGFR-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’s able to target the most common mechanism of resistance with the first-generation agents, vis-à-vis a gate-keeperT790Mmutation. 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’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’s with progression-free survival. It really changed the standard of care. And now there’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 aT790Mmutation. Now we’re moving that to the frontline setting and using it for everybody.

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

Drilon: Fortunately, many of the tyrosine kinase inhibitors that are available for ALK-rearranged lung cancers have good CNS coverage. And I’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’s the ALEX trial that randomized patients to alectinib versus crizotinib. Those are patients withALK-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 forALK-rearranged lung cancers.

ROS-1-rearranged lung cancers also have a proclivity for metastases to the brain, although there are reports of theROS1-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’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.

TARGETED ONCOLOGY: What were the key findings of the phase II ALTA trial leading to the FDA approval of brigatinib in relapsed/refractoryALK- rearranged NSCLC?

Drilon: The phase II ALTA trial looked at the utility of brigatinib inALK-rearranged lung cancers who had priorALK-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’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 withALK-rearranged lung cancers who previously received crizotinib.

TARGETED ONCOLOGY:What is your approach to treatment sequencing inALK-rearranged NSCLC?

Drilon: Alectinib is currently the standard of care forALK-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’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].

TARGETED ONCOLOGY:What is your approach for treatingBRAF-mutated NSCLC?

Drilon:BRAF-mutant lung cancers include a proportion of patients that haveBRAFV600E 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-agentBRAF inhibitor like vemurafenib or dabrafenib, you might achieve response rates of approximately 30%. However, following the lead again of what we’ve seen in the melanoma world, when you give a combination of aBRAFand aMEKinhibitor—specifically, dabrafenib and trametinib—we know that the response rate more than doubles to 63% with that combination in the phase II setting. And so, that’s currently approved by the FDA for the treatment ofBRAFV600E—mutant lung cancer patients and would be my first choice for someone that’s stage IV and treatment naïve, knowing that the outcomes we’re seeing with the combination paralleled the outcomes that we’ve seen with tyrosine kinase inhibitor therapy for theEGFR, andALK, andROS1genes.

TARGETED ONCOLOGY:What is the rationale for combining PD-1/PD-L1—targeted agents with chemotherapy?

Drilon: 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.

TARGETED ONCOLOGY:What is the rationale for combining a PD-L1—targeted antibody and chemotherapy with a VEGF-targeted antibody?

Drilon: 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.

TARGETED ONCOLOGY: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?

Drilon: 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’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’s something that I think we should continue to look at on an investigational level. But on a clinical level, I wouldn’t yet jump to rely on this as a potential signature for giving this combination until we see further data come out.

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

Drilon: 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.

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

Drilon: Recently there has been a trial examining the utility of giving the combina- tion of anti—PD-1 and cytotoxic T-lymphocyte–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.

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

Drilon: 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 withEGFRmutations; recurrent gene rearrangements involvingALK,ROS1, orRET;METexon 14 alterations; HER2 mutations; orBRAFmutations 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’s all about the odds of responding to treatment. And you could argue that because for certain subsets of these driver-positive patients, likeEGFR,ALK,ROS-1, for example, where there are FDA-approved therapies andBRAF, that you should start with a targeted therapeutic because you’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, withEGFRandALK, where the likelihood of response was 3% forEGFR- andALK-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 inMETexon 14—altered lung cancers and a separate series inBRAF-mutant lung cancers. Again, we’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’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 includedEGFR. There may be a potential role for incorporating immune therapy in the treatment paradigm for driver-positive lung cancers after you’ve explored targeted therapy either with 1 drug or with a sequence of drugs, if that’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’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.

TARGETED ONCOLOGY:What were the key findings from the recent phase II study investigating pembrolizumab in TKI-naïve, PD-L1—positive,EGFR-positive, advanced NSCLC (NCT02879994)?

Drilon: This was an interesting prospective phase II trial that looked at the utility of single-agent immune checkpoint inhibition forEGFR-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 anEGFRmutation. 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 advancedEGFR-mutant lung cancers and not give a single-agent immune checkpoint inhibitor.

We know thatEGFR-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 withEGFR-mutant lung cancers.

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

Drilon: If we look at patients whose cancers don’t harbor a driver, we’ll note that a substantial proportion of those cancers are smoking-related cancers, where we’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’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.

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

Drilon: 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’s also a likelihood of increasing [adverse] effects in patients. We have some examples ofEGFR