More Broad Molecular Tests Are Needed to Accurately Treat Non-Small Cell Lung Cancer


Patients with non-small cell lung cancer driver mutations respond better to targeted treatments compared to chemotherapy, yet less than half of these patients receive next generation sequencing.

Beth Sandy, MSN, CRNP

Beth Sandy, MSN, CRNP

Patients with non-small cell lung cancer (NSCLC) and specific driver mutations respond better to targeted therapy compared with chemotherapy, explained Beth Sandy, MSN, CRNP, Abramson Cancer Center, University of Pennsylvania, during a presentation at the 5th Annual School of Nursing Oncology Meeting.

According to a pooled analysis of patients who received National Comprehensive Cancer Network (NCCN)-guided therapies in accordance with their biomarkers, overall survival (OS) was significantly improved in patients who receive targeted therapy (18.6 months) compared with patients who do not received targeted therapy (11.4 months).

“You can never treat a mutation that you never found,” emphasized Sandy. “We must test and find out what this biomarker is because [their treatment] is going to be better if they get their targeted therapy for that driver mutation.”

Why Perform Molecular/Biomarker Testing?

Current NCCN recommendations for biomarker testing say that, whenever feasible, providers should recommend a broad panel-based, molecular test. Next generation sequencing (NGS) is the most common way to complete this. These can be performed either in-house or through a commercial company. If no biomarkers are uncovered, providers should consider an RNA sequencing panel to detect RNA fusions.

In addition, all patients with metastatic NSCLC with non-squamous histologic subtypes should be tested for biomarkers. Testing should be considered in any patients with squamous histology or with early stage resected NSCLC. The minimum testing recommendations include EGFR, ALK, ROS1, BRAF, MET exon 14 SKIPPING, RET, NTRK, PD-L1, and KRAS; however, testing should be considered for ERBB2/HER2 mutations.

Yet, despite the NCCN guidelines, less than 50% of patients with NSCLC are actually tested for the minimum 5 recommended biomarkers, according to the MYLUNG Consortium Data, presented at the 2021 ASCO annual meeting.

NGS is a broad molecular panel that tests for over 100 gene alterations. While there only 9 necessary tests, each additional test can help guide treatment. Additionally, even the variant of uncertain significance can be useful for future clinical trials, Sandy said.

NGS tests are often more efficient than individual tests for different biomarkers because it requires less tissue. While they may have a reputation for being expensive for the patient, Sandy says that most companies will absorb or reduce the payment.

She also outlined reflex testing, or the testing of all samples of NSCLC that has been identified by pathologists as non-squamous histology. The diagnostician who performs the biopsy suspected to be NSCLC will automatically check a box ordering the molecular test.

It is important to note that the pathologist cannot order the test because it is considered a conflict of interest. This new way of ordering tests is much quicker because now the medical oncologist has the results, or they are being processed by the time they see the patient.

Current challenges for molecular testing include the fact that lung cancer biopsies are less cellular than other solid tumors. Bone biopsies yield poor samples; they need to be decalcified. Furthermore, the tests can take weeks so they can present a logistical challenge. Occasionally, the test can return saying QNS, or quality not sufficient, which means that all the efforts need to be attempted again from square 1. There needs to be 10% to 20% of viable cancer cells in the sample to get a reliable result.

DNA Sequencing vs RNA Sequencing

DNA sequencing scans tissue for an activating somatic mutation, like insertions, point substitutions, and in-frame deletions. This test will detect mutations in EGFR, T790M, KRAS, BRAF, HER2, and MET. DNA sequencing can be performed via PCR, a direct sequencing or NGS. Direct sequencing tends to be the most tedious and time consuming.

RNA fusion panels differ from DNA sequencing because they detect gene rearrangements, not mutations. ALK, ROS1, RET, NTRK, and FGFR are all fusion abnormalities that are through these tests. While these aren’t necessarily clinically useful in NSCLC, they can be helpful for future clinical trials. ALK and ROS1 can both be detected through fluorescence in situ hybridization (FISH) or HCL, although the latter is not considered an acceptable result per NCCN guidelines.

Sandy acknowledged that the results of these tests can be difficult to decipher, “One time my RNA fusion reported an EGFR mutation. And I was like, ‘Oh, they have EGFR,’ I called molecular pathology, and they said, ‘No, no, no, that's a gene rearrangement, not a DNA mutation… So, don't be afraid to call molecular pathology, I have them on speed dial.”

Liquid Biopsies

Liquid biopsies can work great in conjunction with a tissue biopsy, said Sandy. The advantages of the blood test are its minimally invasive nature, and its strong ability to detect any resistance mutations. Unfortunately, the liquid biopsy functions by detecting DNA shedding from the tumor in the bloodstream, and shedding can vary. So, depending on the day, the test’s sensitivity might be different. In addition, these tests cannot detect histology, and cannot therefore determine a “small cell transformation” from EGFR to NSCLC.

The Nile study (NCT03615443) found that performing both tissue and liquid biopsy identifies the highest amount of circulating tumor DNA (ctDNA) and the highest number of mutations. Some institutions, including the Abramson Cancer Center hospital at the University of Pennsylvania in Philadelphia, where Sandy works, perform both the blood and tissue scans on their patients. “Test. Test. Test.” she emphasized.

Approved Targeted Therapies for Different Driver Mutations

Sandy also outlined different approved agents that are preferred to treat common mutations in NSCLC.

Osimertinib (Tagrisso) is the preferred treatment for EGFR exon 19 or 21. These mutations are fairly common: They consist of about 30% of EGFR mutations. Osimertinib demonstrated superiority over erlotinib (Tarceva) and dacomitinib (Visimpro) in the FLAURA trial (NCT02296125) through a clinically significant improvement in progression-free survival (PFS). Patients in the osimertinib arm reported a PFS of 18.9 months, compared with 10.2 months with either erlotinib or dacomitinib. With a hazard ratio (HR) of (95% CI, 0.37-0.57; P < .0001), it was pretty clear evidence, Sandy said.

While some patients reported grade 1 or 2 rash in clinical trial, these symptoms can usually be managed with topicals or doxycycline. About half of trial patients also reported diarrhea, and that is manageable with over-the-counter anti-diarrheal agents. Overall, the drug is fairly tolerable.

Osimertinib is also now approved in the early stage, post-operative setting.

The lesser-known EGFR exon 20 only makes up about 5% of EGFR mutations, however, it is actionable, and it has approved targeted therapy, amavantamab (Rybrevant). Sandy noted that “this is the only target therapy that's IV. It's a monoclonal antibody, and it's got a pretty odd administration, scheduled weekly for 4 weeks and every other week as a high infusion reaction with the first dose… but it's not analyphylactic, it's usually mild, and we can get them through it.”

ALK inhibitors make up about 4% to 6% of NSCLC and their preferred first-line treatment include alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), and alectinib is also recommended for second- andthird-line treatment.

ROS1, though uncommon, makes up to 3% of NSCLC cases, and has 4 approved drugs that are recommended in accordance with NCCN guidelines: crizotinib (Xalkori), entrectinib (Rozlytrek), ceritinib (Zykadia), and lorlatinib. Crizotinib is the most trusted treatment of those 4.

Sotorasib (Lumakras) is the recommended drug for a KRAS G12C mutation. Sandy advised that nurses should “remember that this is more common in smokers. So again, we’ve got to be testing everybody, not just the never-smokers. It's a pill and it's taken in 8 tabs daily, all at once. So, this is a little bit hard for adherence. We have to work with these patients for sure.”

Dabrafenib (Tafinlar) plus trametinib (Mekinist) is recommended for BRAF, which is more common in smokers than non-smokers. MET exon14 skipping has 3 approved agents: capmatinib (Tabrecta), crizotinib, and tepotinib (Tepmetko), while a RET rearrangement can be treated by the any of the following 4: selpercatinib (Retevmo), pralsetinib (Gavreto), cabozantinib (Cabometyx), and vandetanib (Caprelsa).

NTRK, though extremely rare (less than 1 out of 1,000 cases), has 2 approved targeted drugs: entrectinib and larotrectinib (Vitrakvi).

The Take-Away

“Our take home messages here are that the NCCN guidelines recommend testing in these populations of patients, especially the non-squamous [NSCLC], which is [the] majority, and adenocarcinoma. You can never treat a mutation that you never found,” said Sandy.

With so many approved targetable agents available in the metastatic setting, (as well as 1 approved drug in the early-stage setting), each with different dosages, and adverse event profiles, there is a lot more for nurses to keep up with, Sandy concluded. Her best advice? A team-based approach. Diagnosticians, medical oncologists, oncology nurses, and pathology all need to collaborate and communicate in order to ensure that patients are being tested and that the patient has access to the best resources available to treat their disease.


Sandy B. Molecular Testing and Targeted Therapies in NSCLC. Presented at: 5th Annual School of Nursing Oncology; August 6-7, 2021; Virtual.

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