Molecular Testing and Multidisciplinary Care Is A Necessity in Metastatic NSCLC

Lyudmila A. Bazhenova, MD

Although adjuvant targeted therapy options are reserved for patients with EGFR-mutated non–small cell lung cancer (NSCLC), molecular testing is a critical step in the treatment of all patients with metastatic disease, where multiple driver mutations are associated with FDA-approved therapeutics, said Lyudmila A. Bazhenova, MD, who added that concurrent liquid- and tissue-based testing should be considered.

“In the management of stage IV NSCLC, molecular testing is very important because we do not want to miss patients with oncogenic-driven tumors where we have proven multiple times that targeted therapies outperform chemotherapies [in terms of] response rate, progression-free survival, and quality of life,” said Bazhenova, a medical oncologist and a professor of medicine at the Moores Cancer Center at the University of California, San Diego Health.

“[We] need to have a pathway at [all] institutions to make sure whatever works for individual groups [is employed] so patients are tested for those molecular abnormalities. This could be by liquid or tissue [biopsy], as long as one understands the false negative rate [with liquid biopsy],” Bazhenova said.

In an interview with OncLive^®, Bazhenova discussed the nuances of molecular testing in patients with early-stage and metastatic NSCLC, the role of durvalumab (Imfinzi) in the context of unresectable stage III disease, and the importance of multidisciplinary care for patients across the lung cancer paradigm. 

OncLive^®: How has the role of molecular testing been introduced to the early-stage NSCLC setting, and what advances are coming down the pike?

Bazhenova: When I think about what biomarkers to order for my patients with early-stage lung cancer, I have to [rely on] the data. Currently, the only data that allow me to make treatment decisions based on biomarkers is from the ADAURA trial [NCT02511106], where we used osimertinib [Tagrisso] as adjuvant therapy after completion of surgery and adjuvant chemotherapy. In the future, it is possible that we might be using other molecular biomarkers to decide on adjuvant therapy, but currently, that is not standard of care. I only do EGFRtesting for my patients with resected early-stage lung cancer.

Based on [the results of the] IMpower010 trial [NCT02486718] that was presented by Heather Wakelee, MD [of Stanford University] at the 2021 ASCO Annual Meeting, it is possible that we will also be using PD-L1 immunohistochemistry staining to decide which of our patients will get adjuvant immunotherapy. However, since neither treatment nor testing in the adjuvant setting is currently approved, I am not using it in my day-to-day practice.

What are your thoughts on reflexive testing in NSCLC?

Reflexive testing needs to be decided by each institution. It is not right or wrong to do reflexive testing, but it depends on what works for [individual] institutions. It is more important to know what biomarkers to test for and decide as a group whether to test reflexively or allow an oncologist to order that test. For example, in metastatic lung cancer, it is accepted by everybody that we need to do 2 tests: PD-L1 expression and molecular testing.

Currently, we have up to 9 oncogenic-driven targets with FDA-approved therapies. In my practice, I use next-generation sequencing [NGS] because it saves tissue and time compared with me ordering 9 single-gene tests. At my institution, we have decided that PD-L1 testing will be reflexive because it is not as expensive [as it once was] and will most likely be covered by insurers. However, we decided that NGS will have to be ordered by an oncologist because our pathologists do not know the staging of the cancer when they look at [a tissue] specimen. We felt that asking our pathologists to order NGS in case a patient doesn’t have metastatic disease might result in out-of-pocket expenses to our patients.

I’m not saying that this is the right answer and I know of multiple institutions that do reflex testing for NGS. It doesn’t matter if reflex testing is done or not, if [the molecular biomarkers] are tested for. That is the most important thing to do.

How is molecular testing being streamlined in the metastatic setting to incorporate liquid and tissue biopsy? Should the tests be used concurrently?

Both liquid and tissue NGS are appropriate to use in patients with stage IV NSCLC. There are currently 2 schools of thought. Number 1 is that we order the liquid biopsy and if it is negative, we follow that with tissue [biopsy]. The rationale behind that thought is the understanding that 30% of liquid biopsies are falsely negative. However, some physicians prefer liquid biopsy [because], currently, cell-free DNA results come back a bit sooner than tissue results. The typical turnaround time for liquid biopsy is about 7 to 10 days vs about 14 to 21 days for tissue biopsy. Therefore, some physicians feel that doing liquid biopsy might speed up the process of findings molecular abnormalities. We know that if we find an [actionable] abnormality in the liquid biopsy, it is going to be in the tissue, so we don’t have to wait for tissue results, and we can start treatment right away.

I belong to the concurrent camp. In my practice, I use liquid and tissue biopsy simultaneously because we know that tissue can also be falsely negative in about 10% of patients. Doing [liquid and tissue biopsy] simultaneously helps me to not delay first-line therapy for too long because I routinely wait for molecular testing before initiating first-line therapy.

Therefore, I send the tests at the same time. If 7 days pass and the liquid biopsy comes back [without] a targetable abnormality and I think that could be because of a false negative result, I have to wait 2 more weeks before the tissue comes back. This is [better] than waiting for the liquid [biopsy results] and then sending the tissue [biopsy] and waiting [an additional] 3 weeks. That increases the waiting time to up to 4 and a half weeks, which is psychologically hard for our patients.

What does the real-world uptake of molecular testing look like in metastatic NSCLC?

We have always suspected that the penetrance rate of molecular testing in practices outside of academic institutions is not complete. That was supported by a presentation at the 2021 ASCO Annual Meeting, which looked at biomarker testing in the large, community-based US Oncology Group. [The results showed] that testing for ALK, BRAF, EGFR, and ROS1 happens in approximately 60% to 70% of patients. Approximately 80% of patients will get PD-L1 testing. Only about half of patients had testing for all 5 selected biomarkers.

What is the importance of utilizing a multidisciplinary approach to patient care in NSCLC?

Multidisciplinary care is vital in lung cancer, especially in patients with locally advanced NSCLC where treatment sequencing decisions of chemotherapy, surgery, and possibly radiation must be made as a consensus.

Multidisciplinary care is also important [to guide] decisions [regarding] what is the best site for biopsy, for example, if we’ve run out of tissue at the original NGS attempt. At my institution, we have multidisciplinary care. I’m surprised to see that no matter what stage [disease] a patient has, they benefit from multidisciplinary care, especially when it includes interventional pulmonology, pathology, and clinical trial offices. That way we can present the patient to the tumor board and get all our questions answered in the same day, as well as look at clinical trial possibilities.

For in-person multidisciplinary care, many institutions have multidisciplinary clinics where, in the same physical space, there are representatives from interventional pulmonology, surgery, radiation, and medical oncology. This is very convenient for patients because they can see all specialties and have a consensus on management plan in the same day.

For people who are practicing in the community, there are certainly some virtual tumor boards that they can participate in to access multidisciplinary care and present their cases.