The Latest Practices for Testing and Treating Lung Adenocarcinoma

Aaron Lisberg, MD

Molecular testing has become an essential part of managing metastatic lung adenocarcinoma as it informs patient treatment decisions, according to Aaron Lisberg, MD.

Mutations such as ALK, ROS1, and EGFR can increase the risk of toxicity with approved immunotherapy approaches and also decrease efficacy. According to Dr. Lisberg, a thoracic oncologist at The University of California, Los Angeles (UCLA), physicians should conduct broad based molecular testing for all patients with lung adenocarcinoma and use test results to help guide treatment decisions.

PD-L1 expression alone should not dictate therapy, as other mutations could be at play, impacting therapy choice, Lisberg explained. However, if immunotherapy has already been started before results are received, therapy should be adjusted accordingly.

In an interview with Targeted Oncology, Lisberg spoke on the importance of molecular testing for patients with lung adenocarcinoma and provided tips for choosing between immunotherapy and a tyrosine kinase inhibitor (TKI) in patients with targetable mutations.

TARGETED ONCOLOGY: Can you summarize the current role of molecular testing in the lung cancer field?

LISBERG: I think molecular testing is critical in the lung cancer field. We've identified a number of emerging targetable oncogenes in non-small cell lung cancer (NSCLC) over the last 10 years or so, which have revolutionized the field and improved patient care. If these targetable mutations are identified oftentimes TKI therapy can be very effective, very well tolerated and can provide great outcomes for patients for extended periods of time. So basically, in any patient with lung adenocarcinoma, we're suggesting broad-based molecular testing, prior to initiation of front-line therapy. That said, if a lung adenocarcinoma patient has rapidly progressive disease, and needs to start therapy immediately, it’s reasonable to start with chemotherapy, but I would not add immunotherapy to the patient’s initial line of therapy until broad based molecular test results are available. If there's no molecular driver found, then adding immunotherapy to chemotherapy during subsequent cycles is very reasonable.

However, if a molecular driver is found you can certainly switch to the targeted therapy at that point, or if the patient is tolerating chemotherapy, you can continue with that therapy and assess the response before switching. The primary concern is in the patients that have oncogene driven tumors, specifically those with EGFR, ALK, and ROS-1, where we have the most data, immunotherapy appears to lead to much poorer outcomes than in patients without these alterations and there is a real potential for significant toxicity. This is especially true if immunotherapy precedes a tyrosine kinase inhibitor. It's something we want to avoid in patients with lung adenocarcinoma.

Conversely, if a patient has squamous cell carcinoma of the lung, and is a heavy smoker, it is reasonable to start an immunotherapy approach. You can get molecular testing at time of diagnosis or potentially iterative times of progression. That's another point. Molecular testing is not only important at the time of diagnosis, it's also very important at each time of progression to evaluate for resistance mechanisms that may have emerged in the tumor and can be targeted. That said, in patients that have squamous cell histology, but are non-smokers, I think they should be treated similar to lung adenocarcinoma patients. Again, molecular testing should be done before the initiation of therapy. If therapy has to be initiated prior to result availability, chemotherapy alone can be done in the same manner that I suggested before.

What are some of the key biomarkers that you're looking for in testing right now? Are there any novel biomarkers that oncologists can expect to see later on?

The answer to the novel biomarkers is there's a long list and there are a lot of things that still need to be worked out. I'll focus on those that have clinically approved therapies because, again, it's always great to know more about patients’ tumors, but especially in a busy practice setting, the question is, what am I going to do with it?

The molecular tests that are most critical in NSCLC are going to be EGFR, ROS-1, ALK, BRAF, METex14 skipping mutation, RET alterations, and NTRK. Those are going to be the molecular alterations that can be targeted with approved tyrosine kinase inhibitor therapy. There are a number of emerging biomarkers such as KRAS G12C, there were some very encouraging data recently presented at World lung and there may be targeted therapies there soon. And then certainly, there's a litany of other potential biomarkers that are emerging.

The other thing to focuse on is with respect to immunotherapy, there's been a lot of different biomarker evaluation. But the best-validated approach at this point is PD-L1 expression of the tumor cell. So that's another biomarker we definitely want to have on all our patients. In patients with oncogene-driven tumors such as EGFR, ALK, and ROS-1, PD-L1 likely does not mean the same thing. It is not as clearly a sign of prediction for immunotherapy efficacy, but in the absence of an oncogene driver, certainly, PD-L1 expression is very important. Patients with high PD-L1 expression, which is defined as greater than 50% are much more likely to respond to immunotherapy-based approaches than patients with low, between 1% and 49% or no PD-L1 expression, defined as less than 1%. And certainly, in patients that have high PD-L1 expression, immunotherapy alone is a reasonable option in those patients that don't have oncogenes.

During the Winter Lung Cancer Conference, you discussed a scenario where a patient is already receiving immunotherapy, but their molecular results are pending. Can you explain how you would handle a case like this?

My initial thought was that hopefully you never end up in this situation, or if you do, hopefully you do not identify a molecular marker that's going to set this patient up for problems. What I mean by that is, as I said, in lung adenocarcinoma patients and those with squamous cell histology that haven't smoked, I would never start an immunotherapy approach prior to having broad base molecular testing results available for review. So hopefully, that scenario would not arise, but I understand in other settings, it may. And if it does, you may be in a difficult situation.

So, I have a number of different items on my checklist in terms of how to approach it. Briefly, if a KRAS mutation is found, that's the oncogene driver that I'd say has not been shown to decrease efficacy and increase toxicity with immune checkpoint inhibitors. If you get the result of the KRAS mutation, I think you're fine. I think it's fine to continue with immunotherapy based on the data we have right now. Like I said, KRAS G12C targeted therapies may come into the field at some point. But right now, if the KRAS mutation comes back, I don't think you need to make any changes.

However, if you identify an EGFR mutation, for example, you're in a bit of a bind. I think the second question there is what kind of immunotherapy approach is the patient on? If the answer is a combination of chemotherapy and immunotherapy, I think that at that point, you'd have basically a number of different options and there is no right answer. The problem is that the increased toxicity that's been seen with the combination of immunotherapy followed by a TKI, and on trials when a TKI was combined with immunotherapy, there's no clear timeframe that a patient can be off immunotherapy where they won't have any increased toxicity on subsequent TKIs. So if the molecular testing comes back and shows an EGFR mutation, but the patient's already on a combination of chemotherapy/immunotherapy, immediately switching to the TKI is a reasonable option. But you do have a significant risk of toxicity. So, I think your options are to (1) continue chemotherapy and immunotherapy and see what the response is with consideration for switching to a TKI at a later time point, (2) you could drop the immunotherapy at that time because you know that it's unlikely that a patient with EGFR, ALK, or ROS-1 is going to respond to immunotherapy and continue chemo alone, or (3) you could immediately switch to a TKI.

The one case where I think that the data would be clearer would be if the patient had a high PD-L1 expression at 90%. You had no molecular testing back, let's say for a lung adenocarcinoma patient, and you started them on a single agent atezolizumab or pembrolizumab, and they were on that therapy and you got EGFR, ALK, or ROS-1 alteration back. I'd be very concerned that there is a low likelihood that the patient is going to benefit from immunotherapy alone. Although you've probably made that decision based on the high PD-L1 expression, in those patients with EGFR, ALK, or ROS-1, it’s not clear that PD-L1 expression is an indicator of likelihood response to immunotherapy, that hasn't been shown. There's also concern that the PD-L1 expression may just be constitutive expression by the tumor, not indicative or predictive of an immune response. So, I'd say that the patient with those alterations on immunotherapy alone likely has a very low likelihood of benefiting from the approach you've chosen. It also has a lot of potential toxicity that can arise.

If the patient is on single-agent immunotherapy and you get EGFR, ALK, or ROS-1 back, I would switch to a TKI, but you're going to have an increased risk of toxicity. I think if you can have a gap in treatment, it's probably a good thing because immunotherapy will decrease in prevalence in the patient system. But I think you're going to have to change at some point and I think that as you make that change, you have to be very careful about potential toxicities arising. I wouldn't want a patient to be on a therapy that's unlikely to work, because the disease will progress significantly, and you're going to need to go to the TKI at some point.

With a surplus of new agents that have entered the lung cancer space in recent years, there's this an unanswered question about sequencing. How do you go about sequencing at your institution?

At my institution, we have rapid results for EGFR, ALK, and R0S-1, and we also get PD-L1 [testing] at that time. We also concurrently send out to a third-party provider to get broad-based molecular testing on the tissue, which usually takes about 10 to 14 business days once the tissue is received. Typically, when I see a patient, there's still some additional testing that needs to be done such as a PET scan. We have to get insurance clearance and things, so, the timeframe typically works.

Many institutions have their own in-house full-broad molecular profiling that they can do, but I think that it's important to be doing that on all of our patients with lung adenocarcinoma and certainly in those with squamous cell disease that have no smoking history.