Looking Toward the Future of Targeting Gene Fusions

Alexander Drilon, MD

Alexander Drilon, MD

Gene fusions are known cancer drivers found in many different tumor types, most notably non—small cell lung cancer (NSCLC), and can be clinically meaningful in the treatment of disease, according to Alexander Drilon, MD.

Larotrectinib (LOXO-101), an oral and selective inhibitor of tropomyosin receptor kinases (TRK), was granted a priority review by the FDA in May, based on findings from patients with TRK-positive tumors enrolled across phase I or II clinical trials. Drilon noted that these results showed that regardless of histology, tumors could have an equal proclivity for response to therapy if they harbor a TRK fusion, and that targeting gene fusions could elicit better responses than standard of care options like chemotherapy or immunotherapy.

Gene fusions can be detected in a number of tests, including fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) assays have been shown to improve detection of these actionable fusions, but it can take longer to receive results, Drilon says.

In an interview withTargeted Oncology,Drilon, clinical director of the Drug Development Service at Memorial Sloan Kettering Cancer Center, discussed the data currently available on targeting gene fusions, and shared insight into what is on the horizon in this area.

TARGETED ONCOLOGY:What do we know at this point about targeting fusions and what is still unknown?

Drilon:Fusions are found across a variety of many different cancers. The classic example of a cancer type that harbors these fusions is NSCLC, so a lot of the early learnings about the actionability of these agents and the use of targeted therapies has naturally emerged from that field. We know that things like ALK rearrangements, ROS1 rearrangements, and RET rearrangements are clinically actionable gene rearrangements that have matched targeted therapies. Now that we have learned that these fusions can be targetable from a clinical perspective, we're looking to see if these fusions found in tumors beyond lung cancers are equally as targetable. A good example of this would be the NTRK fusion-positive study, where we see these fusions across many different tumors. Thankfully, data on larotrectinib, a first-generation agent that targets TRK, shows that these tumors, regardless of what the histology was, can have an equal proclivity for response to therapy as long as they harbor a TRK fusion.

TARGETED ONCOLOGY:How can fusions be used as a diagnostic and also to guide treatment?

Drilon:From a diagnostic perspective, there are certain tumor types that are highly enriched for particular fusions. For example, mammary analogue secretory carcinomas or secretory breast carcinomas are known to harbor an upwards of 90% of an NTRK fusion. When you find this fusion on a molecular assay and there's a question about the histology of the tumor, this helps direct pathologists towards the appropriate histology. Beyond that, there are certain sarcomas that also have typical fusions, and this helps with diagnosis.

Certainly, from a therapeutic perspective, if you have a particular fusion that is paired with a drug in the clinic, it becomes much more useful because you can then get these patients to a targeted therapy plan, which for the most part, in lung cancer for example, has been shown to work much better than standard of care options like chemotherapy or immunotherapy.

TARGETED ONCOLOGY:What type of testing is used to detect these fusions?

Drilon:There's been a bit of a diagnostic migration in terms of testing for recurrent gene rearrangements. In the past, we had much more heavily relied on single-gene assays, where you might do

FISH testing or, in some centers, RT-PCR, to look for a specific fusion event. However, now that we have better and much more comprehensive tests and know that some tumors might harbor some other actionable drivers beyond these fusions, many centers have migrated towards using comprehensive DNA-based NGS assays. Of course, the drawback with NGS is that it does take some time for the results to come back. What we do at our center is, we have stage testing where there's an early and rapid phase of testing where we might do something like immunohistochemistry for ALK, which can come back in a day or 2. Then, we send the rest of the sample for NGS, knowing that we are not looking for just these fusions that I mentioned, but many other actionable alterations, like mutations or splice site alterations. 

TARGETED ONCOLOGY:Are there certain areas where you think there will be more success in targeting fusions than in others?

Drilon:What we are seeing is that there are 2 different potential outcomes when you look at a targeted therapy. There is what we call possible context specific activity where you might see a difference between the activity of a particular drug against a fusion across different cancers. One example is that we have observed some cases of gastrointestinal tumors that harbor an ALK fusion, for example, that might respond to an ALK TKI like crizotinib (Xalkori), but then might very quickly lose that response. These tumors might have a shorter progression-free survival. That's certainly 1 possibility. However, on the flip side of the coin, there are other fusion events like the NTRK fusions where it doesn't seem to matter what the cancer looks like under the microscope. These tumors seem to have the same likelihood of response to TRK inhibitors, specifically larotrectinib.