CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: July 06, 2022
Expiration: July 05, 2023
In this module, Matthew Gubens, MD, MS, a thoracic oncologist, and Craig Mackinnon, MD, PhD, an anatomical and molecular pathologist, discuss current guidelines and recommendations regarding optimal testing approaches for biomarkers in non-small-cell lung cancer (NSCLC) and contextualize the assessment and application of actionable biomarkers to integrate novel and emerging targeted therapies safely and effectively into clinical practice for the personalization of care for patients with NSCLC.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. Several questions will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Craig Mackinnon, MD, PhD:
Our view of lung cancer has evolved over time. Initially, lung cancer was treated as a single disease, but over time, it became clinically relevant to distinguish NSCLC from small-cell lung cancer. Shortly after that, NSCLC was further broken into 3 major histologic subtypes: squamous cell, large cell, and adenocarcinoma.1,2 It later became increasingly apparent that histologic identification of lung cancer is critical for making treatment decisions and improving treatment outcomes.
In the early 2000s, the first clinical trials of small-molecule inhibitors targeting driver mutations demonstrated that these targeted agents were effective at stopping the growth and spread of lung cancer.2 Since that time, therapies targeting these mutations have been in active development, leading to the current era of precision medicine. More recently, a new class of agents that act via immune checkpoint inhibition was discovered, and this has dramatically changed the way in which lung cancer is treated. One of the most important immune checkpoints being targeted in lung cancer is PD-L1. So, in addition to molecular genetic analysis of malignant lung tumor samples, PD-L1 expression levels are measured. Precision medicine using agents that target PD-L1 has significantly improved lung cancer treatment outcomes for patients with NSCLC without an actionable driver mutation.
Craig Mackinnon, MD, PhD:
Approximately 50% of patients with advanced nonsquamous NSCLC have a driver mutation that is either targetable with an FDA-approved agent or can be enrolled on a clinical trial.3 Therefore, biomarker testing of multiple genes is required to identify these mutations, and single‑gene testing is no longer sufficient for most patients. The treatment landscape continues to evolve with new generations of drugs for existing targets, as well as new and emerging targets.
Craig Mackinnon, MD, PhD:
It is recommended that all patients with advanced NSCLC should be tested for EGFR mutations, including EGFR exon 20 insertion mutations, MET exon 14 skipping mutations, ALK, ROS1, BRAF V600E, NTRK, RET, and KRAS mutations.4-6 In fact, current testing guidelines include recommendations for broad testing with DNA-based NGS, which tests many genes simultaneously, to be performed on tumor samples for all patients with advanced NSCLC. Because testing by polymerase chain reaction (PCR) misses approximately 50% of EGFR exon 20 insertion mutations, targeted RNA–based NGS can be used to complement DNA-based NGS to significantly increase the likelihood of detecting oncogenic gene fusions.7 This approach provides the most efficient way to detect gene mutations and gene fusions, as well as known and novel fusion partner genes in tumor samples, which are often limited in quantity in patients with advanced disease. Based on the recent FDA approval of adjuvant osimertinib after resection in EGFR mutation–positive NSCLC, molecular testing also can be performed for patients with early-stage NSCLC.8
In addition to broad NGS testing, IHC is necessary to measure tumor PD‑L1 expression levels in all patients with NSCLC. PD‑L1 IHC testing takes much less time to complete than NGS, but healthcare professionals should wait for the results from NGS testing before giving a patient immunotherapy in case the patient is eligible for targeted therapy due to the detection of an actionable driver mutation.
Craig Mackinnon, MD, PhD:
Most patients with lung cancer present with advanced disease and have a 5‑year relative survival rate of 6% to 7%.9,10 Patients diagnosed with localized disease have a much better 5-year relative survival rate of approximately 60%, but for those with regional disease, the 5-year relative survival rate is approximately 33%.
Craig Mackinnon, MD, PhD:
The phase III IPASS trial randomized patients with newly diagnosed advanced lung adenocarcinoma with and without EGFR mutations to receive the EGFR inhibitor gefitinib vs carboplatin plus paclitaxel.11 Progression-free survival (PFS) with gefitinib was superior to carboplatin plus paclitaxel among patients with EGFR-mutated disease, and standard chemotherapy demonstrated a superior PFS compared with gefitinib among patients with EGFR-negative disease. Because the presence of EGFR mutations was predictive of a better outcome with gefitinib, EGFR testing is now recommended for all patients with advanced NSCLC.
Craig Mackinnon, MD, PhD:
Regardless of the specific driver mutation, all patients who receive appropriate targeted therapy based on their identified driver mutation have a significantly improved median overall survival (OS) compared with patients who do not receive targeted therapy.12
Craig Mackinnon, MD, PhD:
In the neoadjuvant setting for early-stage disease, there is no need for molecular testing or PD‑L1 IHC. Instead, patients with early-stage NSCLC can receive platinum doublet chemotherapy and the immune checkpoint inhibitor nivolumab.
In the adjuvant early-stage NSCLC setting, however, patients need molecular testing for EGFR mutations and IHC testing for PD‑L1 expression levels following surgical resection. Those with stage IB-IIIA disease with a classical EGFR mutation should be considered for osimertinib either immediately or following chemotherapy. Those with stage II-IIIA disease without EGFR mutations with PD-L1 expression levels ≥1% should be considered for atezolizumab following chemotherapy.
As indicated above, patients with advanced NSCLC should undergo broad molecular testing, and the expression level of PD‑L1 should be determined. All patients who have a targetable genetic alteration should receive matched targeted therapy, but patients without actionable targetable alterations should receive immunotherapy if the PD-L1 expression level is ≥1%.
Craig Mackinnon, MD, PhD:
One of the major barriers to universal biomarker testing is an insufficient amount of tissue available for testing.4,13 Patients with advanced disease often do not have enough samples available for testing, making it a challenge to isolate sufficient DNA and RNA for molecular testing. Tumors also may have extensive necrosis, and the cytology test samples obtained may be inadequate and may result in a low yield of high‑quality DNA or RNA.
Another major barrier is that the turnaround time for molecular testing may not be fast enough when a patient needs immediate treatment and delaying treatment for 10‑14 days to obtain the molecular testing results to make a treatment decision is not an option. Once patients start therapy, even if it is a standard treatment regimen including chemotherapy and/or radiation, it is not easy to change treatment to incorporate the molecular testing results.
In addition, test orders may not always be immediately placed, leading to a delay in obtaining molecular testing results. For this reason, many healthcare systems use reflex testing to automatically place orders upon diagnosis of advanced NSCLC without waiting for an order from the treating physician.
Lastly, some hospital systems are reluctant to order biomarker tests for every patient out of concern for the associated costs and the reimbursement issues that may arise. This is particularly true with regard to patients receiving treatment in the inpatient setting because hospitals will have to assume the financial responsibility for the ordered tests.
In later sections of this module, we will discuss more details and practical considerations related to biomarker testing in NSCLC that I have touched on above.
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