LIBRETTO-001: RET-Fusion Positive Metastatic NSCLC


Suresh S. Ramalingam, MD, FASCO: Shifting from EGFR to a less common target, 1 for which we have not had an approved agent yet, are patients with a RET fusion gene. Cho, can you talk about how common the RET fusion gene is? How do you test for it? Walk us through some of the exciting data with LOXO-292.

Byoung Chul Cho, MD, PhD: A RET fusion is a rare oncogenic alteration actionable mutation in non—small cell lung cancer. It accounts for only 1% or 2% of all non–small cell lung cancer. LOXO-292 is a very selective RET inhibitor. Based on recent phase I/II studies, among over 100 patients with advanced-stage, RET fusion-positive non—small cell lung cancer, response rate was almost 60%, and response duration was very durable—longer than 20 months. It also showed excellent intracranial response, up to 90% in measurable CNS [central nervous system] metastases. This drug is active. In this rare disease, a treatment as well as a detection of a RET genomic alteration is really important given the rarity of these genomic alterations.

In my clinic, I’ll usually use next-generation sequencing to detect RET fusion-positive non—small cell lung cancer. We haven’t tried immunohistochemistry and FISH [fluorescence in situ hybridization] or CISH [chromogenic in situ hybridization] assay to detect RET fusions, but sensitivity and specificity of immunohistochemistry followed by FISH is not that good as we’ve already seen in ROS1-positive lung cancer. I prefer to use next-generation sequencing to detect RET fusion-positive lung cancer.

Suresh S. Ramalingam, MD, FASCO: One of the pieces of the LOXO-292 data that represented at the [International Association for the Study of Lung Cancer 2019] World Conference on Lung Cancer that really struck me was in patients with RET fusion who were treatment-naïve, the response rate with the drug was greater than 80%, really positioning the drug for frontline therapy. Johan, how do you do that testing in your practice? Are you testing for it now?

Johan F. Vansteenkiste, MD, PhD: Well, I think in our setting and in most European countries, it’s not already common to do NGS [next-generation sequencing] for gene fusions. Often, the RET abnormality is searched by a FISH test. Again, a FISH test is a burden and a cost for the pathologist, and that matters in Europe. At the present time, what we do is we first look for the more common ones like NGS on DNA—so we look for EGFR, HER2. We also look for KRAS and so on. If it’s a patient with a high likelihood of RET fusion abnormalities, if all the rest is negative, then we do a FISH. But we don’t do the FISH test at the present time yet in the reflex setting.

Suresh S. Ramalingam, MD, FASCO: Pasi, how do you view these data, and does this provide sufficient information for you to start treating these patients once the drug is available in clinical practice?

Pasi A. Jänne, MD, PhD: Absolutely. I think the data here are consistent with all the paradigms of oncogene addiction and having a cancer that’s dependent on RET signaling. When you have the highly selective RET inhibitor, you see a dramatic response analogous to what we’re seeing in EGFR, ALK, and ROS1. I think this completely fits that, and the frontline data are also encouraging and consistent with that. It also raises the possibility of ultimately being in that space as yet another testable driver oncogene with a targeted therapy.

Suresh S. Ramalingam, MD, FASCO: That would end up being the sixth target…

Pasi A. Jänne, MD, PhD: Absolutely.

Suresh S. Ramalingam, MD, FASCO: With a targetable agent.

Pasi A. Jänne, MD, PhD: Yeah.

Suresh S. Ramalingam, MD, FASCO: Therefore, the molecular testing that we do in the front end will slowly start moving toward NGS, if it’s not already being done.

Pasi A. Jänne, MD, PhD: You pretty much have to do that now, because these are rare enough that if you’re not having a routine test, it’s hard to find them. Although strategies like the one Johan mentioned are an alternative approach. But even routinely doing comprehensive things, you find the common ones but you also find the rare ones like the RETs.

Johan F. Vansteenkiste, MD, PhD: Without any good restrictions, I would surely favor it looking at it in the reflex setting because it has very strong data compared with other previous data with multikinase inhibitors. It’s much more powerful. It’s much less toxic, so I’m very convinced. But there is a reason; there’s a reality of rigid aspects of molecular testing in Europe.

Transcript Edited for Clarity

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