Need for Molecular Testing in Lung Cancer Is Underscored as Additional Targets Emerge

Yujie Zhao, MD, PhD

Molecular testing is a critical component of the treatment selection process in lung cancer, as a host of effective drugs have since been developed to target alterations such as ALK, ROS1, and RET, according to Yujie Zhao, MD, PhD, who added that the integration of RNA-based sequencing into these strategies could potentially provide further benefit to patients.

“It’s paramount for patients to undergo molecular testing; this allows us to discover actionable alterations. We also encourage the use of liquid biopsies,” Zhao emphasized. “[Sometimes we are faced with the] issue of tissue availability; sometimes this can be due to limitations of local expertise. If that is the case, I would encourage [that you] consider sending patients to a tertiary center. There, interventional radiologists, or even thoracic surgeons, could help them obtain tissue for testing. I would also encourage the incorporation of RNA-based sequencing into your approach, as well.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Zhao, an internist oncologist at Mayo Clinic, highlighted progress made with actionable alterations in lung cancer, the importance of molecular testing, and efforts needed to overcome resistance mechanisms to available targeted agents.

OncLive®: Several agents have been developed to target ALK alterations in this disease. Of course, there was crizotinib (Xalkori), and agents like alectinib (Alecensa) and brigatinib (Alunbrig) have since joined the treatment arsenal. How do these agents compare?

Zhao: Alectinib has been compared head-to-head with crizotinib and this research showed superiority [with alectinib] in terms of progression-free survival and overall survival. Moreover, alectinib was found to have better central nervous system penetration and intracranial activity, which is a huge advantage.

Similar to alectinib, brigatinib has also demonstrated superior efficacy and excellent intracranial activity; this agent was [also found to] outperform crizotinib. The response rate was high with this drug and the responses appeared to be durable.

Lorlatinib (Lorbrena) has also emerged as an option for use following progression on crizotinib. What is the hope for moving this agent into earlier lines of treatment?

This agent shows great activity in later-line settings and has very promising activity in the first-line setting, [as was seen in the phase 3 CROWN trial]. However, the agent has not been FDA approved [for use] in the frontline setting yet.

Shifting to RET fusions, the field has seen a lot of activity over the past year with drugs that have shown impressive activity. Could you discuss selpercatinib (Retevmo) and the data that have been reported from the first-in-human LIBRETTO-001 trial?

LIBRETTO-001 is a phase 1/2 study that evaluated the role of selpercatinib in patients with RET-altered lung and thyroid cancers. This study had multiple arms. In non–small cell lung cancer, the agent was found to work very well. The response rate was around 85% in the treatment-naïve patients and 64% in those who received prior platinum-based chemotherapy. These response rates were excellent.

Pralsetinib (Gavreto) also obtained regulatory approval in September 2020 based on data from the ARROW trial. What is the efficacy of this agent, particularly in those with brain metastases?

Pralsetinib has demonstrated great activity. The overall response rate in patients [previously treated with platinum chemotherapy] was 55%; [it was 66% in treatment-naïve patients]. Three patients, out of 9, had an intracranial complete response to treatment. Although the number of patients was small, the response rates reported were impressive.

With all of these additional actionable targets, what is your approach for molecular testing?

Molecular testing is very important. When it comes to fusions such as ALK, ROS1, and RET, the treatments available are very effective and well tolerated. The responses [elicited with these agents] are also very durable. It's important that we do not miss any patients who could potentially be candidates for these therapies.

Broad panel DNA-based next-generation sequencing (NGS) is commonly used in this space; however, there are some limitations with this approach. In research published by [investigators from the] Memorial Sloan Kettering Cancer Center, 232 patients did not have any actionable alterations, per DNA-based NGS results. However, when RNA sequencing was performed, it was discovered that 33 patients did have actionable fusions. Among these patients, some had MET exon 14 skipping mutations, 10 patients had ROS1 fusions, 4 patients had ALK alterations, 3 had RET fusions or rearrangements, and a few more had NTRK gene fusions. With this said, I would encourage my colleagues to consider both DNA-based NGS and also RNA-based sequencing. This may be more costly and take more time [for the results] to turnaround, but it will provide great value to our patients.

How are you utilizing liquid biopsies in practice?

Liquid biopsies are important because we can have trouble obtaining tissue. Many times, we send out a test, and we are told that the tissue [sample] is insufficient. As such, liquid biopsies, which utilize circulating DNA in the peripheral blood, have been very helpful.

I once had a patient who harbored a RET fusion and we wanted to put her on trial, but we couldn't find her initial biopsy. We ordered a liquid biopsy, which confirmed that she had a RET fusion and as a result, we were able to enroll this patient to a clinical trial. It’s also important to note that liquid biopsies have a quicker turnaround than tissue biopsies.

What is some of the work that is being done to address resistance to these agents?

We understand that patients will eventually develop resistance to these targeted therapies.

With this said, we must determine which mechanisms need to be overcome and how we can do that.

For all these therapies, [we know of] 2 types of resistance mechanisms. One would be a mechanism that the cancer cell utilizes to bypass the effect of the drug. For example, there can be an activation of additional pathways in the cancer cells. Another mechanism could be a mutation that arose in the target genes, such as ALK, ROS1, or RET. Those mutations will enable the kinase to avoid the interaction or interfere with the interaction of the drug with the target.

These are the types of alterations that can lead to drug resistance. A few ongoing trials are evaluating new agents that could potentially overcome this challenge.