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NSCLC Biomarkers
Using Biomarkers to Guide NSCLC Care: An Expert Discussion

Released: May 26, 2022

Expiration: May 25, 2023

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In association with the 2022 American Association for Cancer Research (AACR) Annual Meeting, experts presented a live program titled “Biomarker-Driven NSCLC Care: The Precision Medicine Model for Today and the Future.” Here, Todd M. Bauer, MD; Sandip P. Patel, MD; and Joshua Sabari, MD, address topics that were raised by the audience during the question and answer session of this program.

The biomarker testing paradigm in advanced non-small-cell lung cancer (NSCLC) is continuing to become increasingly complicated. There is a growing list of driver mutations being targeted with novel agents, including various small-molecule tyrosine kinase inhibitors (TKIs). Today, patients with lung cancer must undergo tissue and/or liquid biopsy to assess which therapy will work best for their disease. For example, patients with an EGFR exon 19 or L858 mutation should receive the EGFR TKI osimertinib. On the other hand, those with an EGFR exon 20 insertion mutation may benefit more from amivantamab, an EGFR/MET bispecific antibody, or mobocertinib, a TKI which specifically targets the exon 20 mutation.

Molecular diagnosis is not only important to identify a patient’s optimal therapies, but also can help them avoid expensive, ineffective treatment with associated toxicities. For example, a patient with an activating driver mutation may not benefit from an immune checkpoint inhibitor. Molecular diagnosis for patients with advanced NSCLC is done using both DNA- and RNA-based testing, ideally using a multiplex panel of next-generation sequencing (NGS). DNA-based NGS testing helps us simultaneously identify potential mutations and EGFR exon 20 insertions, while RNA testing can help detect fusions (ALK, ROS2, NTRK) and MET exon 14 skipping events. Testing for levels of proteins such as programmed death-ligand 1 (PD-L1) to guide treatment with checkpoint inhibitors is also very relevant to our patients with NSCLC. Of note, while tissue biopsy is still considered the gold standard for biomarker testing, liquid biopsies have made it possible to perform molecular testing in patients whose tissue biopsy was inadequate or difficult to biopsy and as a complementary approach to tissue testing.

What are the biggest barriers to genetic testing of patients with lung cancer in the community setting?

Todd M. Bauer, MD:
Molecular diagnosis, or genetic testing, is used inconsistently in community cancer clinics. Physicians, including myself, can benefit from a reminder to order these tests; all patients with metastatic cancer should undergo broad-based molecular testing. Physicians may also not understand what to do with a test result showing multiple unfamiliar alterations, which will impact how they counsel patients. For example, getting an NGS report back with 14 different alterations that you are not familiar with makes it hard to talk to patients about their potential treatment decisions. Understanding which alterations are the most important and targetable for patients can help alleviate that uncertainty.

Joshua Sabari, MD:
I agree. Another issue is that these tests can take time. A patient eager to start treatment may be disappointed to wait 7-10 days for plasma testing, and tissue tests can have an even longer turnaround time of approximately 3 weeks. Having that discussion with patients is important to let them know that waiting allows us to see what the best treatment is for their particular disease. Patients who are highly symptomatic and/or who have a high disease burden can be started on systemic chemotherapy while waiting for the NGS results.

Sandip P. Patel, MD:
I think these are all great points. Just like we have personalized medicine and different molecular aberrations for individual patients, the issues for molecular testing differ for individual patients as well. Access to testing has become more complicated in the COVID-19 era. Patients are reluctant to come to the clinic in person, or to have a blood draw at home for cell-free DNA testing. While understandable, patients’ reluctance to see healthcare providers in person can delay diagnoses. Also, in populations that are elderly or historically underserved, there may not be an appreciation of the importance of molecular testing or biomarker testing may not be discussed with patients. It is important for clinicians to take the time to listen to each patient’s concerns, address those concerns as much as possible, and learn how to discuss molecular testing in a way that is approachable and understandable to each patient as an individual. It is helpful that electronic medical records (EMRs) can provide reminders for clinicians to do appropriate testing, whether a tissue or liquid biopsy, but as a community, we need to think through how we can get over some of these communication barriers with our patients.

Cost is, of course, an issue with molecular testing. With pathologic immunohistochemistry testing for breast cancer, for instance, insurance coverage will generally support assessment of certain markers (hormone receptor status and HER2 status) on nearly any specimen. However, for reflex NGS testing, the billing parameters from insurance companies are far more stringent and may require a discussion with the medical oncologist to obtain coverage. Most community cancer centers are not able to use NGS as reflex testing due to costs, although some academic health systems have internalized those costs with in-house assays.

Todd M. Bauer, MD:
My last point on potential barriers is that I consider patients with a long tobacco smoking history to be another underserved population in this regard. While many of these biomarkers have been found more frequently in patients without a long smoking history, smoking does not protect against these molecular alterations. Some physicians skip these tests for lifelong smokers, but these patients deserve molecular testing as well.

Joshua Sabari, MD:
Great point. There are rare alterations that are important to catch, such as the 1% EGFR mutation rate in squamous cell cancer. And up to 50% of MET exon 14 skipping mutations occur in smokers. BRAF V600E mutations are also important to identify in lung cancer patients, including heavy smokers. In short, there really aren’t any good reasons to not sequence every patient with lung cancer.

What molecular tests do you use in your clinic to assess patients with lung cancer?

Joshua Sabari, MD:
In patients with metastatic disease, I order both plasma (liquid biopsy) and tissue NGS at the same time. We use a commercial lab for plasma testing and have a turnaround of 7-10 days, which allows for us to begin therapy more quickly if there is a molecular marker detected. Then, we also do tissue NGS in house, both DNA- and RNA-based NGS. Having both plasma and tissue biopsies tested is important because if plasma testing is negative, this result should be confirmed with tissue testing.

Sandip P. Patel, MD:
I agree. In my clinic, I order testing of both plasma and tissue at the same time. If the liquid biopsy sample is negative, then the tissue biopsy is already being processed and tested. If the liquid biopsy is positive for a biomarker, then the NGS testing for the tissue biopsy can be cancelled.

Joshua Sabari, MD:
Yes, but remember when you order both plasma and tissue biomarker testing that liquid biopsy does not replace a histologic diagnosis. The tissue biopsy is important not only for NGS testing, which can be cancelled if liquid biopsy comes back positive, but also to understand the histology of the disease (eg, whether the cancer is an adenocarcinoma, squamous, or mixed). The absence of histologic diagnosis can make sense in some cases, for example in older, more-frail patients who may not be candidates for a biopsy. If plasma testing identifies an EGFR mutation in these types of patients, they can receive targeted therapy, but in general histologic diagnosis is important.

How do you choose between agents with the same targets, such as selpercatinib vs pralsetinib, or amivantamab vs mobocertinib?

Todd M. Bauer, MD:
There is no right answer to that question, since we do not have head-to-head trials comparing different agents that target the same driver mutation. Physicians must use their best judgment based on the response rates and other efficacy data and then make a decision taking into consideration the patient’s preferences about the side effect profiles and administration considerations of each agent. For example, selpercatinib and pralsetinib are both effective therapies in NSCLC with RET fusions, but selpercatinib can cause QT prolongation, so may not be a good choice for a patient with existing heart failure.

Joshua Sabari, MD:
I agree. Similarly, for amivantamab and mobocertinib, both are very effective for patients with NSCLC and EGFR exon 20 insertion mutations but have differences in side effects and administration. Patients who dislike IV medications or who are reluctant to come to the clinic weekly for 5 weeks—whether it is because they dislike infusions or because they live far from the infusion center or do not have reliable transportation—may want to consider mobocertinib, which is an oral agent they can take at home, instead of amivantamab, a monoclonal antibody that must be infused in the clinic. However, mobocertinib has a high incidence of diarrhea, so a patient may prefer amivantamab to avoid this side effect. I always give patients as much information on these drugs as possible, so they can have as much control over their care as they wish, even if it means different choices than I recommended.

What is the best course of action for patients with NSCLC who progress on targeted therapy but are PD-L1 high?

Todd M. Bauer, MD:
In my experience, most molecularly driven NSCLC tumors do not respond to PD-L1 checkpoint inhibition regardless of their PD-L1 status, so I would not recommend a PD-L1 checkpoint inhibitor. Instead, they should go to the next-generation TKI, potentially with chemotherapy, or switching to chemotherapy.

Joshua Sabari, MD:
I agree. PD-1/PD-L1 inhibitors have considerable toxicity, particularly if used with or in proximity to TKI therapy. Patients with NSCLC positive for a targetable mutation should exhaust all potential targeted therapeutic options and any other standards of care, or be offered the chance to participate in clinical trials, before being offered immunotherapy. However, if immunotherapy is eventually used after other options have not worked, I recommend an 8-week washout period for any targeted therapy before starting.

Sandip P. Patel, MD:
I agree. The discussion you have with patients in these advanced settings can be very complex. Some patients may have heard of immune checkpoint inhibition and request it. I tell patients that not only is there a lack of potential efficacy, but this is somewhat of a one-way street. If they return to TKIs after checkpoint inhibitors they are at a higher risk of toxicities (eg, pneumonitis from EGFR TKIs, immune hepatitis with ALK inhibitors). Having that discussion with patients to come to the best decision for them is so important.

With new biomarkers emerging and targeted agents being approved, are you reexamining patients’ molecular profiles to see if they are candidates for any newer targeted agent?

Sandip P. Patel, MD:
Given the multiple new approvals for NSCLC in both the first-line and refractory settings, deciding how clinicians contextualize their practice to allow for a switch to a new drug, or to transition to it upon progression can be challenging.

Joshua Sabari, MD:
Knowing what genetic drivers the patient has is critical. However, I do not always remember what mutations a patient has if it has been a long time since their test. So, patient records need to be reexamined for genetic alterations of newly approved agents. I think most practices will have patients that can benefit from each new approval. This process should happen every time a new drug is approved, but is dependent on thorough molecular testing of the patients. Additionally, when it seems likely that a new approval may be coming, it can be helpful to note that in advance in patient records; for example, HER2-targeted therapies are expected to be approved in NSCLC soon.

Todd M. Bauer, MD:
I agree. We have talked about the challenges of remembering to test for biomarkers in general, and now remembering that you have tested in the past and what biomarkers were present on those test results, but, because new genetic drivers keep being identified, it may also become important to remember to retest patients occasionally, as some will have these newly identified markers and may benefit from novel treatment approaches.

Sandip P. Patel, MD:
I remember using single-gene testing for neversmokers with adenocarcinoma, and this resulting in targeted treatment for approximately 15% of patients. Today, a broader molecular diagnosis results in targeted therapy for more than half of patients. For me, the way I format my notes for every patient is key to remembering some of this information. In my note, I have a few things right at the top: the name of the patient, their primary contact if something happens, their diagnosis (eg, lung cancer, breast cancer, the stage at diagnosis), and then their molecular phenotyping. I go through these notes to remind myself where we are with each patient and then try to continue them on their journey, given the number of remarkable targeted therapies that we have now.

The key point is that we need to test and not guess, because many of these patients will have these abnormalities and can really benefit.

Final Thoughts
To hear more of this discussion, click here for an on-demand webcast of the live meeting:

To hear the latest information optimizing the care of patients with NSCLC using available biomarkers, sign up here to attend a symposium at ASCO 2022, either in-person or as a live stream on Saturday, June 4, 2022 with experts Todd M. Bauer, MD; Narjust Duma, MD; and Karen L. Reckamp, MD, MS: https://www.clinicaloptions.com/LungBioChicago2022

What challenges have you encountered in treating patients with NSCLC and genetic aberrations? Share your experience in the comment box below.

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Do you use liquid biopsy for broad molecular testing by NGS in patients with newly diagnosed advanced NSCLC in your clinical practice?
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