Breadth of Biomarker Testing Continues to Inform and Guide Targeted Approaches in Lung Cancer

Balazs Halmos, MD

Advances in the accuracy and array of molecular assays for lung cancer have improved the navigation of immunotherapy and targeted therapy approaches in non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), according to Balazs Halmos, MD. Continued attempts to integrate these approaches into earlier settings will lead to better prediction of patient benefit, faster treatment initiation, and improved patient outcomes in this space.

A caveat to these advances should be noted with liquid circulating tumor DNA (ctDNA) biopsy, which although useful in expediting treatment decisions, is often limited by a low tissue yield and a higher incidence of false positives or negatives. Accordingly, in these cases Halmos stressed the necessity of orthogonal testing to confirm test results and ensure that the correct treatment approach is selected.

“Thoracic oncology has become more and more complicated in terms of navigating individualized treatment for patients, and that’s the beauty of it,” Halmos said. “We [now] have better tools [for] molecular testing, immune biomarker testing, tissue-based testing, and ctDNA-based testing. It really [comes down to] comprehensively applying all this information in a guideline-driven way.”

In an interview with OncLive^®, Halmos discussed factors to consider when selecting a biomarker assay for patients with NSCLC, emphasized the importance of secondary testing, provided recommendations for the treatment of patients with co-mutations, and highlighted ongoing or future areas of interest for research within lung cancer.

Halmos is a professor of medical oncology in the Department of Oncology, a professor of oncology and hematology in the Department of Medicine at the Albert Einstein College of Medicine, and director of the Multidisciplinary Thoracic Oncology Program and Section of Thoracic Medical Oncology for Montefiore Health Systems in New York City, New York.

OncLive: Given the number of available assays in varying practices across academic and community centers, what are your recommendations for biomarker testing in NSCLC?

Halmos: That’s a key question in the practice of thoracic oncology. Medical oncologists are using biomarkers and precision medicine to optimize patient management and the patient journey, maximize outcomes, and minimize adverse effects [AEs] to offer the best treatment to an individual patient. Looking at cancer cell characteristics and using molecular immune biomarker testing [can] guide therapy. This revolutionized the practice of thoracic oncology about 15 years ago, and that revolution continues to expand. Not only in metastatic NSCLC, but also in earlier stages of disease, we have to use biomarker testing to make sure that [we] pick the appropriate treatment approach. Those biomarker tests are critical [for deciding if] a patient with resectable lung cancer [should receive] neoadjuvant chemoimmunotherapy or adjuvant targeted therapy.

What are some basic considerations in terms of choosing the proper biomarker test? In the context of metastatic NSCLC, there’s 2 issues. [The assay] must be comprehensive enough to include NCCN [National Comprehensive Cancer Network] guideline recommended biomarkers and molecular tests. That is currently 9 to 10 [biomarkers] depending on how you count it, so it’s no longer practical to do that based on single-gene testing. We need to utilize next-generation sequencing [NGS] platforms that ideally encompass all these markers. [They should include] fusion genes such as RET, ROS, ALK, and TRK, as well as unique alterations, such as MET exon 14 [skipping mutations].

We are fortunate that many NGS tests that we can order commercially and that have been established in our academic or community hospital labs will [include these markers], but [clinicians] need to make sure that is discussed and appropriately confirmed. This testing can be very comprehensive, but it can also be very time consuming and requires a lot of tissue, which is a basic limitation. The tiny sample that we obtain might not [be] enough tissue for the analysis. Also, patients might need to start treatment within a week or 2, and these NGS tests sometimes take a long time to come back.

This is an area where liquid biopsy ctDNA testing has also helped us take another step forward. Integrating that into upfront testing for patients with metastatic NSCLC in a practical, appropriate way can really expedite [treatment decisions]. [It allows us to] reach a point [where] we feel comfortable about having completed molecular biomarker testing and can go on to start treatment for our patients within the [recommended] maximum of 2 weeks or so.

What scenarios would necessitate orthogonal testing?

Molecular testing is fantastic in many ways, but also poses challenges in terms of potential false negatives and false positives. This can be especially true when we think about ctDNA testing. It’s a great test and is rapidly evolving [to] help us in multiple scenarios. However, it does have a somewhat limited yield, especially as we’re talking about earlier stages of disease, disease without a lot of bulk, and [disease with] limited sites of involvement, such as the CNS [central nervous system] or lung involvement or effusions. The yield of ctDNA [testing] can be more limited, calling for considerations for additional testing. Sometimes we can also face false positives in ctDNA, [including] clonal hematopoiesis with unclear potential or concurrent malignancies. The same applies to tissue-based testing. Whenever we see results that are conflicting, and our confidence levels are not very high, additional confirmation from a different platform can be exceedingly helpful.

For example, what if your tissue-based testing suggests that the patient’s tumor has a particular abnormality, but the pathogenic strength of that mutation is not well known? Maybe there’s an additional test that can look at the expression of that fusion protein [at] the RNA or immunohistochemical level to make sure that we have a full grasp of that molecular alteration. There are some guidelines now that can help the clinician [avoid false results]. [Still], additional testing can be used to corroborate and strengthen confidence in this information, which at the end of the day is so critical for your patients. [You] do not want to miss critical aberrations in the tumor tissue [or] make the wrong treatment decision based on some information about a variant of unclear potential. [With a] confirmatory test, we will be able to prove it one way or the other.

How should clinicians approach treatment in patients with co-mutations?

[Treatment for] co-mutations is a very complicated issue to delve into. It depends on what we’re thinking about. In the case of targeted therapy, if you [have a patient] with a classical EGFR-mutant lung cancer or ALK or ROS1 -translocated lung cancer, in someone whose tumor has more alterations outside of that oncogenic pathway mutation, there could be more chances for resistance to develop, or the primary activity of the drug [could] be more limited. We’re starting to learn a lot more about this. In the coming years, there will be a lot of information perhaps telling us [that a] patient with a co-mutation, [such as] p53 or retinoblastoma, might potentially [require] a more aggressive treatment to achieve the best outcomes. There’s also a secondary question of acquired resistance. Let’s say a patient with one of these tumors responds well to targeted therapies, and then the cancer progresses. By today’s [standards], it’s basically mandatory to think about molecular retesting to see if a secondary alteration might have emerged.

We’re starting to understand and be able to act upon some of those secondary alterations. For example, a patient with an EGFR-mutated lung cancer who, at the time of resistance, is found to have a METamplification; that patient [could receive] combination inhibition with an EGFR and MET-targeting drug. That information is becoming more and more [important] in terms of [helping] the clinician [make informed decisions] and tailoring treatment choices at the time of acquired resistance. Nowadays, the broadening of [testing] platforms allows us to start with ctDNA testing, [which can] make it feasible, easy, and risk-free for patients. If that test is not informative enough, a secondary test will still be important to pursue. This might be a tissue biopsy, [which could identify] molecular alterations. [It could also help] rule out this histological change, because small-cell transformation seems to occur with fair frequency and calls for a different type of treatment decision.

Could you highlight areas for future research regarding the role of molecular testing in lung cancer?

There’s a myriad of research [efforts] trying to expand the horizons of molecular testing and how it affects patient care. [One] area of real interest is expanding ctDNA technology into different settings. We spoke about the use of upfront ctDNA [for] the diagnosis of a patient with metastatic NSCLC [and] at the time of acquired resistance, but how about using ctDNA to look at early responses to treatment? Maybe we can look at ctDNA clearance as an early marker of response. If patients do not respond well enough, that [may] call for treatment intensification. That’s one very intriguing use of ctDNA.

The second one is to look at minimal residual disease [MRD]. We’ll definitely see this emerging more. We’ve seen nice proof of principle in cases of metastatic colorectal cancer, [with] adjuvant therapy. We’ll see the same thing in thoracic oncology as well [for] identifying patients after definitive treatment whether that’s surgical or chemoradiation based. MRD positivity [could] inform clinical trials [by] getting the highest risk patients [enrolled] and inform future treatment [by showing] how a patient with MRD positivity might benefit more from adjuvant therapy, or more intense adjuvant therapy, than a person with MRD-negative disease. Those are going to be rapidly evolving areas of research.

Molecular biomarkers [are also] starting to inform immunotherapy [use]. Immunotherapy has revolutionized [the management of] patients with metastatic [NSCLC], as well as those with locally advanced [or] earlier stage disease. Looking at the molecular complexity [could] inform us as to how our patients might respond to immunotherapy, whether they would be resistant to immunotherapy, and whether we can follow those markers over time to understand [the mechanism of] acquired resistance. We’ve seen a couple of early examples of special markers [such as] STK11, KEAP1, and others. We’ll see more and more emerging signals [showing] that using the molecular complexity of the cancer cell makes sense. [If] we can understand the neoantigenic profile, maybe we can understand the T-cell clones that might be present and could be activated with ongoing immunotherapy. Maybe we can use that neoantigen profile to develop vaccine approaches, for example. We’ve seen a beautiful example [of a cancer vaccine] for melanoma at the 2023 AACR Annual Meeting. We look forward to personalized vaccine approaches of that nature for patients with metastatic NSCLC based on the molecular translation of the cancer genome into active therapy.

Is there anything else you would like to say about the role of immunotherapy going forward?

Over the past 10 years, we’ve seen a transformation in how to manage metastatic NSCLC and extensive-stage SCLC [with] the addition of anti–PD-L1 therapy to standard chemotherapy, and the potential [use of] single-agent immunotherapy approaches to improve upon these outcomes or minimize toxicity. In the past couple of years, we’ve seen immunotherapy [having] an effect on locally advanced lung cancer post-chemoradiation based on the PACIFIC trial [NCT02125461] and now in the early-stage setting [as an] adjuvant [therapy] based on the [phase 3] IMpower010 trial [NCT02486718] and KEYNOTE-091 [NCT02504372] experience. The most robust experience in that context has been the [phase 3] CheckMate 816 study [NCT02998528]. Those data really changed the [treatment] landscape in terms of bringing immunotherapy into the neoadjuvant [space]. [It also emphasized the importance of] precision medicine for patients with earlier stage lung cancer, and of making sure biomarker testing is done [so that] proper patients are guided to a neoadjuvant chemoimmunotherapy approach. In the next couple of years, we’ll learn if we can build upon this foundation. Adding other agents to this approach or using biomarkers to refine who should or should not be receiving a particular regimen will [maximize] patient outcomes further.

Based on this discussion, what would you like oncologists to apply in clinical practice?

The reality is that [oncologists] need to apply all [these practices]. We have excellent NCCN guidelines to help community oncologists make sure that they can follow practical pathways. Ultimately, all of this [contributes to the fact] that patient outcomes are rapidly improving. In fact, improvements in lung cancer outcomes are surpassing practically any other subset in oncology. That shows the incredible [effects] of all the advances that we’ve made. [This positive trend] includes [other improvements like] smoking cessation, lung cancer screening, better surgery, more precise radiation, etc. We have to work together as multidisciplinary teams to bring all of [those developments] to patients in our communities and in our practices. [This will] make sure that they can enjoy the improved outcomes as a result of the great research that we witnessed the past 20 years.