Q&A: Biomarker testing opens doors for personalized treatment options in lung cancer
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Biomarker testing in patients with lung cancer allows for the potential of personalized therapy options that may be better tolerated and increase overall survival, yet not all patients undergo testing.
“We think about the advances we're making in new drugs, but if we successfully tested all patients with lung cancer for biomarkers and used the drugs that are already available, we could make a big impact on patients' long-term outcomes,” said Julia Rotow, MD, thoracic oncologist at Dana-Farber Cancer Institute.
In an interview with Healio, Rotow spoke about the importance of biomarker testing, the best methods to identify these biomarkers and new advances in personalized treatment options for patients.
Healio: What is the importance of biomarker testing in lung cancer?
Rotow: For lung cancer, we're very fortunate that the field has really moved toward more personalized therapy where possible — trying to match patients with treatments that are most likely to be effective based on what we know about their individual tumor characteristics and their individual demographics.
We also know that appropriate biomarker testing or optimal biomarker testing has improved outcomes. The most dramatic example of this could be for ALK-positive lung cancer, where more than 60% of patients are now living with an overall survival past 5 years. If you compare that with an average overall survival of less than 2 years for patients who get upfront chemo-immunotherapy who don't have an actionable driver, it's important to find these patients who can benefit from these advances in therapy.
Biomarker testing can also get patients access to potentially better-tolerated treatments. For example, oral targeted therapies can often reduce toxicities compared with traditional cytotoxic chemotherapy and give patients a nice potential first option for treatment that may be better tolerated in addition to being more effective.
Healio: What are three most common biomarkers in lung cancer?
Rotow: The two we test for in most, if not all, patients are PD-L1, which gives a PDL-1 tumor proportion score to help us predict efficacy of immunotherapy for our patients, and next generation sequencing (NGS), looking for actionable gene mutations to treat with targeted therapies.
Among NGS, the most commonly found now are EGFR and KRAS G12C, which is a change from even just a year ago where you might not have spoken a lot about KRAS as a target. We find these EGFR-activating mutations in about 15% of the overall U.S. population with lung adenocarcinoma, and if you look overseas, more than half of patients in some countries like China may have an activating EGFR mutation.
KRAS is very exciting because it means we now have another 10% to 12% of patients with a KRAS G12C mutation that is actionable. This is a very different patient population than our EGFR mutant patient population, which is more closely associated with a history of tobacco use, for example. This gives us a fairly high probability of finding an actual biomarker both for patients with minimal or absent history of tobacco use and for our patients with a history of tobacco use.
Healio: What are the best methods to identify these biomarkers?
Rotow: The gold standard to find an actionable mutation in lung cancer remains NGS. This allows the use of broad testing panels that incorporate both all the known current actionable genomic alterations and a number of alterations that might have future relevance as our list of targetable alterations expand. This is currently our preferred and most effective way to get this testing.
Other strategies, like single gene-based testing, can be useful in select situations such as scant tumor tissue or in a setting where NGS is not available or a rapid result is needed. However, NGS is our encouraged strategy for all patients who need biomarker testing.
A few other strategies out there often play a role in clinical practice these days as well. The first is plasma-based testing or liquid biopsy, looking for shed cell-free DNA for molecular testing, which has played an expanding role in lung cancer management.
These sorts of tests are noninvasive and come back more rapidly — in some cases in as little as a week compared with potentially several weeks for full tumor biopsy-based NGS testing. This allows for more frequent testing during treatment if needed and, if positive, gives results faster than traditional NGS testing. The downside is that plasma testing is less sensitive than tissue-based NGS, so it's informative if it finds something actionable, but noninformative if negative and tissue-based testing remains critical.
In my own practice, for patients with a new diagnosis of lung adenocarcinoma, I'll often send both the tissue-based NGS and a liquid biopsy simultaneously to give two chances to find something actionable and potentially a chance to find something faster if there's adequate tumor DNA shed.
An emerging strategy for testing now becoming more clinically available is RNA-based fusion-optimized testing. This testing is a different strategy looking for actionable genomic alterations and is optimized to identify some of the fusions that may be harder to identify on traditional NGS testing. That means that some of these patients can have false-negatives on traditional NGS testing but have something actionable found on an RNA-based assay. I'll often use these assays if I have a young patient or a patient with minimal or no history of tobacco use but their testing for NGS comes up negative. I'll then look to send an RNA-based assay giving another chance to find something actionable for these patients.
Healio: What targeted therapies have made the biggest impact for these biomarkers in the last few years?
Rotow: A few years is actually a long time in oncogene-driven lung cancer these days because the pace of advance has been so fast. We have had new drugs become available which improved upon older drugs in potency, tolerability, or CNS activity, and new targets are now emerging that patients can receive FDA-approved therapies for.
More recently for example we've had the emergence of drugs that can target KRAS G12C mutations. This has been a prototypical undruggable target for decades in lung cancer, and yet it's one of the most common mutations we find when we do NGS testing. The availability of the first-approved KRAS G12C inhibitor, sotorasib, just over a year ago has invigorated research into this field developing new KRAS G12C and non-G12C targeted KRAS therapies.
E GFR exon 20 insertion mutations were a second challenging target for which our traditional EGFR tyrosine kinase inhibitors did not work, for which we now have not one but two drugs (mobocertinib and amivantamab) with FDA approvals. This means that almost any EGFR mutation you find now in lung cancer will likely have a drug that can be used as a targeted option, if not first-line then second-line.
Healio: What factors in addition to biomarkers are important to consider when determining lung cancer treatment options?
Rotow: Biomarkers are not our only consideration in lung cancer, but we're fortunate to have so many to help us guide decision-making. In the targeted therapy space, if we find something actionable in a targeted therapy is going to be a good treatment option in most cases, with exception of a few targets like KRAS and EGFR exon 20 for which the targeted inhibitors are approved second-line.
For immunotherapy, other factors beyond the biomarkers become quite important. When we think about upfront decisions for immunotherapy for lung cancer, we're using PD-L1 as our biomarker, and that has some cut-offs, like positive or negative or more or less than 50%. However, we know that things like patient disease burden, patient demographics, history of tobacco use and risk of autoimmune toxicities based on health history may all play a role in deciding when to best use immunotherapy and if this patient requires chemotherapy upfront as well.
When making those decisions in my own practice, for a patient with a lower disease burden without a lot of symptoms who has a very high PD-L1 score, I lean toward immunotherapy monotherapy. However, for a patient with a more borderline PD-L1 score and a heavy burden of symptomatic disease, I lean more toward chemoimmunotherapy.
I also always pause and think when I'm seeing a new patient with a diagnosis of metastatic lung cancer, is there any chance that this is oligometastatic disease where consolidation radiation or other local ablative therapy could offer a path to more durable disease control?
Healio: Which patients with lung cancer are most likely to benefit from biomarker testing?
Rotow: For lung adenocarcinoma, effectively all patients need broad biomarker testing —both their PD-L1 score and their NGS panels — and in subsets of patients, other things like plasma testing and RNA-based testing. This is important regardless of demographics.
While we may be familiar with the most common demographics associated with an actionable driver, for example a younger, female patient without a history of tobacco use or with Asian ancestry, but we know that all kinds of patients can have these mutations. In fact, if you look at all patients with EGFR mutations in similar clinical trials, about one-third were male and one-third were current or former smokers.
In squamous cell lung cancer, the role of NGS-based testing is a little less well established. The current national guidelines suggest considering it in selected patients, for example in younger patients or those without a significant history of tobacco use. You can also consider this in patients with very small biopsy samples where perhaps the biopsy has just sampled squamous component in a disease that really has a mixed adenosquamous histology. Institutional standards do vary on this and in some settings NGS will be done on all squamous cell lung cancers.
In lung cancer, until now, testing for biomarkers has revolved around metastatic disease. In the last year we've seen this sort of testing becoming important in earlier stage or locally advanced patients as well. Right now standard of care for resectable stage IB or higher lung adenocarcinoma is to do EGFR testing at a minimum because we now have availability of adjuvant EGFR-targeted therapy with osimertinib after disease resection. Now that immunotherapy-based strategies are being also used in resectable stages of disease as neoadjuvant or adjuvant therapy, it has become even more important to understand the full genomic context of the patient’s cancer as the finding of an actionable driver mutation may impact the expected benefit of these immunotherapy strategies. While not yet standard of care, obtaining NGS testing may be helpful in this setting in order to avoid giving immunotherapy to patients less likely to benefit, particularly for those patients with a high probability of an actionable genomic driver.
The other important element of testing is that we still fall short as an oncologic community in obtaining complete biomarker testing all patients who are eligible. Retrospective series suggest that we are getting testing in a minority of patients who are eligible. There are many real-world challenges that impact the ability to do biomarker testing, but when we think about all the advances that are being made with personalized therapy in lung cancer if we could test all our patients successfully and use the drugs that we already have, we could make a big impact on patients' long-term outcomes.
Healio: How often are biomarkers found when testing patients with lung cancer?
Rotow: The fraction of patients who will have an actionable biomarker in lung cancer continues to increase as we add new targets that have available drugs with evidence of clinical activity or clinical benefit.
We're getting close to a situation where more than a third of patients, if you add up all the different biomarkers that have approved drugs, might have something actionable, so it is important to be sure that the testing patients’ receive looking for an actionable driver is comprehensive.
The emerging biomarker that I think is most likely to be added on to our list of targetable therapies in the near future are are the HER2 exon 20 insertion mutations. These are found in analogous patient populations to those with EGFR mutations, and we've seen HER-2 directed antibody drug conjugates, like trastuzumab deruxtecan, showing some great data for clinical activity and now having FDA breakthrough therapy approval.
Some very rare gene fusions may also be emerging that are less likely to be found in routine clinical practice — things like NRG fusions, which may respond to HER-3 directed therapies, or LTK fusions, which may respond to ALK-directed therapy. These are rare but may start being found as NGS testing becomes more comprehensive.
Healio: How does the identification of these biomarkers improve lung cancer treatment?
Rotow: Our patients who have something actionable — and who get appropriate, personalized therapy — can live longer and with better quality of life during that time as well. This makes a real difference for patients who can find new therapies.
Another important element of these biomarker-directed treatments for these targeted therapies is they're often very active in the central nervous system. So, for patients with CNS metastases where maybe their only option might otherwise be radiation or whole-brain radiation, which can carry real toxicities related to treatments, the use of a systemic therapy for CNS control can be very effective.
Lastly, we know that repeat biomarker testing at acquired resistance to some of these targeted therapies may find additional personalized treatment options, like off label targeted therapy options or clinical trials, which can offer patients treatment options beyond standard cytotoxic chemotherapy. We want all our patients to have as many effective therapies as possible, so connecting patients with new clinical trial-based strategies and more personalized strategies is always our goal.
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