Overcoming Targeted Therapy Resistance in NSCLC

Timothy F. Burns, MD, PhD

Insight into the natural history of EGFR-, ALK-, and ROS1-positive non—small cell lung cancer (NSCLC) has led to the development of novel targeted treatments in the frontline setting as well as expanding options for those with progressive disease, explained Timothy F. Burns, MD, PhD.

“One of the issues of giving osimertinib (Tagrisso) first [in EGFR-mutant NSCLC] is that we didn't have anything to give after,” said Burns. “It’s reassuring to know that we have these targeted drugs that are approved or in development for patients who progress; it will only enhance the fact that osimertinib is the standard of care in the first-line setting.”

In ALK- and ROS1-positive NSCLC, several agents are in the exploratory stages to determine what therapies can be given in later-line settings and in what sequence.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Burns, assistant professor of medicine, Department of Medicine, Division of Hematology/Oncology, at the University of Pittsburgh Cancer Institute, and medical oncologist at University of Pittsburgh Medical Center Hillman Cancer Center, discussed the frontline standards of care in EGFR-, ALK-, and ROS1-positive NSCLC, optimal sequencing strategies, and the nuances of tissue- and plasma-based sequencing.

OncLive: Could you discuss the ongoing research in EGFR-mutant NSCLC?

Burns: The past year has been quite exciting in terms of new treatments in EGFR-mutant NSCLC. In the last year or so, we've moved our best drug, osimertinib, into the first-line setting; this was a controversial move in the EGFR and ALK spaces. Over the past couple of years, we have realized that using our best drug first is the safest way to treat our patients.

However, what happens after those patients progress on osimertinib? The concern with using our best drug first is that we didn't have [another targeted treatment] to offer these patients. At the 2019 AACR Annual Meeting and 2019 ASCO Annual Meeting, we saw several strategies targeting common resistance mechanisms. One of the most common things we see in patients who progress on osimertinib is a MET mutation, upregulation, or amplification. Luckily, compounds that are either FDA approved or in clinical trials are being combined with osimertinib to target this bypass mechanism.

At the 2019 AACR Annual Meeting, Lecia V. Sequist, MD, MPH, of Massachusetts General Hospital, presented the results of the TATTON trial. In the trial, investigators evaluated a newer-generation MET inhibitor in combination with osimertinib and reported impressive results, even in patients who had failed osimertinib. In addition, 2 other drugs have emerged that target this resistance mechanism through MET. Notably, there is JNJ-372, which is a bispecific antibody that targets EGFR and MET.

Moreover, Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, presented data on a HER3-targeted antibody—drug conjugate at the 2019 ASCO Annual Meeting. The drug showed activity in patients who were resistant to osimertinib as well as in patients with EGFR exon 20 insertions, the latter of which we don’t have good targeted treatments for. These patients comprise about 2% of patients whose disease is driven by [EGFR].

You also spoke about the treatment of ALK- and ROS1-positive disease. Could you highlight some of the agents that have emerged in these settings?

ALK-positive lung cancer represents about 7% of lung adenocarcinoma, whereas ROS1-positive lung cancer represents about 2% of lung adenocarcinoma. ALK and ROS occur as translocations. We have known about ALK for a while, and we have had several agents approved for use in this space. We’re at the point now where we’re trying to figure out what the best agent is. ALK has been a success story. We found this translocation in a lung cancer cell line in 2007, and crizotinib (Xalkori) was approved 4 years later. Crizotinib [wasn’t very effective] in this space, and it has since been supplanted by 3 additional drugs which have shown increased activity in the first-line setting; among them is alectinib (Alecensa), which has become our standard [frontline therapy]. Patients can receive alectinib for approximately 3 years before progressing.

When patients progress, we have lorlatinib (Lorbrena), a third-generation TKI, which seems to work in patients who have failed crizotinib, as well as second-generation TKIs like alectinib. It's important to biopsy these patients [at each progression] because we can find second-site mutations in the ALK gene that will determine whether a patient is sensitive to a drug or not.

Regarding ROS1, patients are generally never-smokers and are on the younger side. The histology is predominantly adenocarcinoma. Initially, we treated these patients with crizotinib, which, unlike in the ALK space, was very effective. However, patients do eventually progress. Notably, lorlatinib has shown activity against many [acquired] ROS1 mutations. The majority of patients who progress have secondary-site mutations in ROS1, and lorlatinib has been shown to have high activity in that setting. The issue is what happens after that.

At the 2019 ASCO Annual Meeting, we also saw data from the phase I TRIDENT-1 trial on repotrectinib in patients who had been treated with first-, and in some cases, second-generation ROS1 inhibitors. Repotrectinib has activity after exposure to lorlatinib. The response rate after progression on second-generation TKIs was almost 55% at the recommended phase II dose, both systemically and in the brain. In addition, the safety profile of the agent was remarkable compared with the older-generation inhibitors. [Repotrectinib] also targets a particular mutation that lorlatinib does not. The drug is currently being evaluated in a phase II trial, but we’re expecting an accelerated approval relatively soon.

How can these alterations be detected?

There are multiple ways to look for a translocation. The surest way is to do a tumor biopsy, and there are several methods [to choose from] for ALK, which include immunohistochemistry, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). For ROS1, there is FISH and NGS. If we can't get a good lesion to biopsy, we do blood-based testing, which can be very effective. However, how you interpret blood-based testing is very important. Standard blood-based testing via Guardant360 or FoundationOne sequences the DNA in the blood; it also does fusion capture, which is very inefficient. With a blood-based test, it’s not uncommon to get a report of a mutation in ALK or ROS1, but no report of a fusion. That causes confusion in the community setting.

You can't depend on a blood-based test to tell you if there is an ALK or ROS1 translocation. If you already know [that one exists], [you can rest assured] because they never go away. If it's negative in a blood-based test, you can look for second-site mutations. Both [tissue- and blood-based assays] are useful, but you have to know how to interpret a blood-based test. I've had several patients referred to me who were told that they had lost their ALK or ROS1 translocation, and it's simply a failure of the fusion capture; the sequencing is fine. We’re using those tests to sequence the ALK or ROS1 gene for second-site mutations, so we can identify the right drugs to treat patients with.

What is the key takeaway with regard to EGFR-, ALK-, and ROS1-positive NSCLC?

Osimertinib is the first-line standard of care in EGFR-mutant NSCLC; it should be the backbone of future studies, including studies involving ramucirumab (Cyramza). Additionally, we have therapies that are available off-trial and on-trial to treat patients when they progress. In the ALK space, we’re continuing to [build our arsenal], and we’re getting smarter in how we use these drugs and when. Finally, for ROS1, we have a new FDA approval, so we have 2 good options available in the first-line setting with more in the pipeline.