The Role of RET Rearrangements in Lung Cancer

Understanding a tumor’s genomics is becoming more critical in cancer care. Patients who have a certain mutation or rearrangement may benefit from some of the targeted therapies that the Food and Drug Administration (FDA) approved in recent years.

In lung cancer, approved medications already address EGFR, ALK, ROS1, BRAF and NTRK gene alterations. But experts also anticipate targeted agents to help those with RET rearrangements, which occur in 1% to 2% of patients with lung cancer, mostly non-small cell disease.

In an interview with CURE®, Dr. Justin Gainor, director of the Center for Thoracic Cancers at Massachusetts General Hospital in Boston, discussed the gene rearrangement and treatments in the works.

CURE ®: What is a RET fusion?

Gainor: Genetic changes in RET occur in various malignancies. There are two main types of genetic alterations. There can be RET mutations, which are essentially like a misspelling, and these are most common in a form of thyroid cancer.

Then there are RET fusions or RET rearrangements, which are similar. A RET rearrangement involves basically a piece of DNA breaking off and recombining with a different portion of the genome; hence, they’re fused together.

A RET fusion leads to active kinase enzyme, so it’s always sending growth signals to the cell. So, these are genetic alterations that are transforming and form a cancer.

How does knowing about a RET rearrangement help in determining treatment options?

RET fusions were first described around 2012 in lung cancer. There was a tremendous amount of hope at that time because biologically, they looked very similar to ALK and ROS1 fusions, where we already had this paradigm of developing a test to identify the fusion and then using a targeted therapy to treat it. What happened is that a number of drugs were repurposed.

They weren’t designed as RET inhibitors. They had an incidental RET function. They were repurposed and started being studied in RET fusion-positive lung cancers around 2013. We had a series of small phase 2 studies showing modest activity with these repurposed drugs, but our sense all along was that it wasn’t that the target was off, it was just that our drugs weren’t good enough.

In the past two years, we had two drugs that were specifically designed to target RET enter the clinic: pralsetinib, which is formerly known as BLU-667, and selpercatinib, formerly known as LOXO-292.

We entered with it being investigated in patients specifically with RET alterations, and there we have seen much higher response rates with these agents, including among patients with treatment-naive disease. From my perspective, I think a targeted therapy will become the standard of care for RET fusion-positive lung cancer.

Can you talk a little bit about what those two RET inhibitors have shown in clinical trial?

In the ARROW phase 1 study, we reported a response rate of 58% with pralsetinib. That was in 48 patients, most of whom had previously received chemotherapy and had stage 4 disease.

In terms of selpercatinib, there were 105 patients, and the overall response rate was 68% among those previously treated with chemotherapy and the progression free survival (the time from treatment to disease progression or worsening) was 18.4 months.

Collectively, this is really impressive data. Both drugs have received breakthrough therapy status by the FDA.

What are the implications for patients if these RET inhibitors get approved?

For one, it validates RET as a bona fide targetable oncogenic driver across the paradigm of targeted therapies. Second, we now know that for a given patient found to be RET fusion positive, it adds another layer of therapy. But we also know that these tumors are RET dependent and opens up a whole other area of investigation of developing new RET inhibitors.

We know with targeted therapies that at some point, cancers develop resistance. So, how can we overcome resistance? That strategy has played out for EGFR and ALK, where we now have multiple generations of drugs that were developed to overcome resistance. For patients, this is really important, because we want to keep expanding therapeutic options.

Where do you see the future of non-small cell lung cancer treatment going regarding RET?

I anticipate that we will have the first approved RET inhibitors for RET fusion-positive lung cancer by the end of the year and that these agents will become a standard of care. However, targeted therapies are only effective when we know that there’s an alteration.

This really underscores the need for testing. We absolutely need to be testing for these alterations as part of a broader strategy of doing comprehensive genetic profiling for patients with metastatic non-small cell lung cancer.