Biomarker Testing Continues to Develop in NSCLC

Kathryn F. Mileham, MD

Osimertinib (Tagrisso) is predicted to have a significant impact in the first-line setting for patients with EGFR T790M-mutated non—small cell lung cancer (NSCLC), explains Kathryn F. Mileham, MD.

According to results from the FLAURA trial, frontline osimertinib was associated with a 54% reduction in the risk of progression or death versus the standard of care of either erlotinib (Tarceva) or gefitinib (Iressa). In the phase III trial, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001). Based on these data, the FDA is currently reviewing an application for frontline osimertinib for patients with EGFR-positive NSCLC.

Biomarkers are necessary to determine which patients should receive osimertinib or other targeted therapies based on their mutations. Currently, there are multiple biomarkers identified within NSCLC, including EGFR, ALK, ROS1, BRAF, and PD-L1.

“We learned that if we have an effective therapy for these mutations, we need to be testing for them,” says Milehan.

OncLive: What biomarkers are currently identified in NSCLC?

In an interview with OncLive during the State of the Science Summit^TM on Non—Small Cell Lung Cancer, Mileham, a medical oncologist at Carolina HealthCare System, discussed the development of biomarker testing for patients with mutated NSCLC.Mileham: The landscape of lung cancer has changed so much over the past 20 years. We used to look at lung cancer as small cell lung cancer versus NSCLC. Then we got more specific with the histologic subtypes for treatment purposes that, now, with the discovery of numerous mutations within adenocarcinoma or nonsquamous NSCLC, we have learned much more about biomarkers and biomarker testing in NSCLC.

There are multiple biomarkers within metastatic NSCLC. The most important ones that we are utilizing right now are EGFR, ALK, ROS1, BRAF, and PD-L1. Each one of these biomarkers are predicting a response to an oral therapy for EGFR, ALK, ROS1, and BRAF inhibitors. Although PD-L1 may not be our best biomarker for response to immunotherapy, PD-L1 expression is predictive of response specifically to pembrolizumab (Keytruda). We can check these in the tissue or plasma. We are still utilizing tissue as our best way to test for biomarkers. Sometimes that may be in a single FDA-approved or companion diagnostic test, whereas other times we may use multiplex sequencing or larger next-generation sequencing.

What are the big questions that community oncologists have regarding biomarker testing?

What advice do you have for physicians to better understand which biomarker to test for or what to do following a biomarker test?

The advantage of using a broader molecular panel is that we are identifying other biomarkers all identified within NSCLC. They may not have an FDA-approved targeted therapy, but there are numerous clinical trials that are looking at some of these less common mutations. One of those trials is ASCO’s TAPUR trial. This trial gives a patient an opportunity to receive a therapy that is directed at that mutation, but may not yet be FDA approved in that indication.The biggest challenge for biomarker testing in the community setting is determining which test to give and when. These therapies are giving better responses and better quality of life in improving cancer-related symptoms than their alternative therapy, which is often chemotherapy. If we are in that setting, we need to be testing for them. Currently, every patient with metastatic nonsquamous NSCLC should be checked for mutations in EGFR, ALK, ROS1, and BRAF, as well as PD-L1. One of the challenges with biomarker testing in the community setting is not only determining which tests, but how to use the tissue from the sample that was obtained from the tumor. It is important for us to think about this because we need this information and, if tumor samples are not sufficient, we may not be able to get all the information that we need. We must make sure that our patients are getting large tissue samples and that we are communicating with our pathologist so that they are not misutilizing the tissue that we are collecting.

Can you discuss the role of osimertinib (Tagrisso) in EGFR-positive NSCLC and the impact this has on the treatment landscape?

We do not need a lot of immunohistochemistry testing to tell us more about adenocarcinoma versus squamous cell carcinoma. We need to streamline this so that we can move forward and still have the appropriate tissue remaining to get these biomarkers. There have been many advances recently and there are trials investigating targeted therapies in the EGFR setting. We are very excited to see the results of the FLAURA trial. That is the first-line utilization of osimertinib in patients with EGFR-mutated metastatic NSCLC. This trial is a phase III randomized trial including patients who had either exon 19 deletion or L858R mutation in EGFR. They had a performance status of 0 or 1 and could have brain metastases, but they needed to have stable disease from that perspective. The patients were randomized 1:1 to receive either osimertinib or another standard agent, erlotinib or gefitinib. They were assessed every 6 weeks with imaging with some crossover for the patients who progressed on the standard-of-care treatment.

We saw an improvement in the primary endpoint, which was PFS. The hazard ratio was 0.46, resulting in a 54% reduction for progression or death when compared with standard of care. This is a tremendous reason to bring osimertinib to the first-line setting because it is currently FDA approved in the second-line setting for patients who developed or acquired the T790M mutation.

What are some forward-looking thoughts on targeted therapies in NSCLC?

In the first-line setting, it was investigated in all patients with sensitizing mutations. Impressively, we could see that PFS was not altered whether the patient had CNS metastases at baseline. The hazard ratios were the same and there was less progression in the CNS for the patients who received osimertinib when compared to those who received erlotinib or gefitinib. I hope that most [physicians] understand that there is a wealth of opportunity to treat patients with targeted therapy. In order to do that, you have to conduct the testing. We do not want to miss opportunities for patients to receive oral therapy that is well tolerated and results in better outcomes. We need to make sure that we are looking at our patients who are going to have these opportunities to receive these therapies.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.