Turning to Broad Sequencing Panels for Targeted Therapy in Advanced NSCLC

Mohammad Razaq, MD

Targeted therapies have transformed the outlook of EGFR, ALK, and ROS1-driven advanced non—small cell lung cancers (NSCLC), said Mohammad Razaq, MD. Moreover, the availability of broad molecular tissue- and blood-based panels could enable a similar fruition of targeted agents for patients with less common alterations.

Although these targeted therapies are in early stages of development, Razaq stated that every patient with advanced disease should be screened for MET, RET, NTRK, HER2, KRAS, PD-L1 expression, and tumor mutational burden (TMB).

“Targeted therapies are changing the field,” said Razaq. “The majority of them are oral treatments and they are better than the traditional chemotherapies. In the past, we used to say that 5-year survival [rates were low] in stage IV NSCLC. With current treatments, some patients are making it to that 5-year mark.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Razaq, assistant professor, Department of Hematology/Oncology, Stephenson Cancer Center, University of Oklahoma College of Medicine, discussed how the detection of driver mutations has changed the way treatment is approached in advanced NSCLC.

OncLive: Could you discuss the detection of emerging biomarkers in NSCLC?

Razaq: With more testing—especially with next-generation sequencing (NGS)—new driver mutations are being discovered. The whole philosophy of cancer treatment has changed. In the past, we used to direct our treatment based on anatomy. Now that more driver mutations are being diagnosed, cancers are being [treated according to] the driver mutation rather than anatomy, whether it’s lung cancer, breast cancer, or colon cancer. We are classifying most cancers by their driver mutations. Many drug companies are now in the race to develop new targeted therapies.

We have significantly increased 1-year overall survival (OS) and median OS, especially with the targeted therapies and immune checkpoint inhibitors. [In my presentation], I discussed RET-, MET-, TRK-, and HER2-mutated tumors as well as the definition of high TMB and its usage.

How can community oncologists distinguish between the available assays?

I always try to use a tissue-based test; most of us at Stephenson Cancer Center are using FoundationOne. Right now, there is no direct head-to-head comparison among NGS assays, so you cannot say one is better than the other. Your decision is based on what you're comfortable with and what the patient’s insurance prefers. The second emerging method is blood-based testing. My preference is tissue, but if I don't have enough tissue, I'm very comfortable doing a blood panel. Some of the data show that sensitivity [in the blood] is at least 80% as good as tissue testing. There are some data from Guardant Health suggesting that we may be able to detect some mutations via blood that we are not able to find with tissue.

Will TMB assume a greater role in the future?

Down the road, maybe [it will]. I cannot foresee how it will play out in the future. For the time being, it's a practical issue. By the time you're ready to treat patients, you won't have a TMB analysis available. If a TMB analysis becomes available, there may be some people who will choose [immunotherapy], especially in patients who do not express high levels of PD-L1. Some of those patients will be considered candidates for the combination of ipilimumab (Yervoy) and nivolumab (Opdivo).

Could you discuss the progress that has been made with KRAS inhibitors?

KRAS is an important target, as it is one of the most common mutations we find in patients with NSCLC. Small studies have been popping up over the last 5 to 7 years. Unfortunately, nothing has been very promising until now. We are anxiously waiting for something to change the whole scenario.

Can you discuss the HER2 mechanism in NSCLC?

There is a difference between the HER2 alteration that drives breast cancer compared with the HER2 alteration that drives NSCLC. When we say HER2-positive breast cancer, that means HER2-overexpressing breast cancers. In lung cancer, we are talking more about a HER2 mutation. Some studies were done with trastuzumab (Herceptin) in lung cancer; unfortunately, those studies were done in patients with HER2-overexpression. In NSCLC, HER2 is a driver mutation; therefore, those studies were negative.

When trastuzumab was tested in combination with chemotherapy, the response rate was 50%. There was some criticism that those response rates were due to the chemotherapy; however, the response rates were higher than what we’ve seen traditionally. There are some phase II studies with ado-trastuzumab emtansine (T-DM1; Kadcyla). In fact, the National Comprehensive Cancer Network has listed T-DM1 as their preferred choice for patients with HER2-mutated NSCLC. There are some small molecular TKIs that are being evaluated in the field of NSCLC as well.

Could you share some insight on larotrectinib (Vitrakvi) and the impact it has had on patients with NTRK fusions?

It's a very effective drug. The approval is indicated in all solid tumor types in adult and pediatric patients who harbor an NTRK gene rearrangement. The prevalence [of NTRK fusions] in NSCLC is not very high; it ranges from 1% to 2%. However, when we are doing big gene panels and NGS, we will be able to find some of those patients.

What other biomarker-driven trials are you excited about?

The Lung Master Protocol is an exciting trial in the second-line setting. Unfortunately, there are some hiccups in that study. We haven't been able to enroll many patients, but we are evaluating new targets in that trial. That is one of the biggest trials right now that is being done in patients with lung cancer.