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Targeting RET
Targeting RET: Where We Are Today

Released: July 25, 2019

Expiration: July 23, 2020

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I recently saw a 50‑year‑old woman in my clinic. This patient is a never-smoker who was diagnosed with early‑stage non-small-cell lung cancer (NSCLC) approximately 4-5 years ago. At that time, she was treated with a standard surgical resection followed by adjuvant chemotherapy. Unfortunately, her disease recurred approximately 1 year later, at which time a biopsy was sent for molecular testing. Despite the fact that she was a never-smoker, the biopsy tested negative for EGFR mutations and ALK and ROS1 rearrangements. At that time, she started palliative chemotherapy but again experienced progression and, ultimately, received multiple lines of other therapies, including multiple experimental agents on various clinical trials. Then, approximately 1 year ago, because our patient was a never-smoker, her oncologist decided to repeat a biopsy and send it for expanded molecular testing. Fortunately, that expanded testing included RET rearrangements and our patient was found to have a KIF5B RET fusion. Once that fusion was detected, she was referred to our group for participation on a clinical trial of a novel selective RET inhibitor. On the study, she has had a very nice ongoing response to therapy now approaching 1 year.

I think this case highlights a number of important issues about RET genetic alterations as an actionable biomarker, including some of the clinical characteristics of these patients, how long we have known about them, how we test for them, and current treatment options for these patients.

Discovery of RET Fusions and Testing
rearrangements or fusionsRET were first discovered in patients with NSCLC around 2012 and were found to be present in approximately 1% to 2% of patients with advanced disease. Subsequent elegant preclinical work showed that RET rearrangements involve multiple fusion partners that produce constitutively active oncogenic fusion proteins much like the ALK and ROS1 rearrangements do.

Another point that is clear from our patient case example is that finding a RET fusion can have a significant impact for our patients’ care, so it is important to screen for these genetic alterations. Most commonly in the clinic, RET fusions are detected via next-generation sequencing platforms though other forms of testing exist, such as RET FISH and RT-PCR. Although RET fusions are substantially enriched among patients who are never or light smokers, in my opinion, we should not restrict our testing for RET fusions only to this patient population. Instead, we should be testing all of our patients with advanced NSCLC as part of a broader strategy of comprehensive testing. Such an approach can identify molecular alterations for which we have FDA-approved therapies as well as other molecular targets where we have promising early data, such as RET alterations.

Multikinase Inhibitors of RET
In the initial studies that first described RET fusions in NSCLC, the investigators used a variety of multikinase inhibitors—drugs that inhibit multiple kinases including RET—to demonstrate that these genetic alterations were targetable. Early challenges encountered with this strategy were that the multikinase inhibitors (eg., cabozantinib, vandetanib, or lenvatinib) were not very potent inhibitors of RET. Furthermore, full dosing of these agents was limited by toxicity stemming from off‑target effects. A number of phase II studies with these multikinase inhibitors showed response rates of approximately 15% to 30% for patients with advanced NSCLC and RET fusions.

Collectively, these results were a bit underwhelming given the response rates we have become accustomed to when we use targeted therapy for oncogene‑driven NSCLC. Moreover, the rates of dose reduction or drug discontinuation with the multikinase inhibitors were high, and so it was clear that they were not adequately targeting RET.

Selective RET Inhibitors
In the last several years, there have been efforts to develop more selective RET inhibitors. We now have some early clinical data for 2 of these agents specifically designed to target RET: LOXO‑292 and BLU‑667. At the 2018 World Conference on Lung Cancer, we saw updated data from the phase I LIBRETTO-001 trial of LOXO‑292. Among 38 patients with RET fusion‑positive NSCLC evaluated in this study, the investigators reported a confirmed objective response rate of 68%, which are very encouraging data. Similarly, at ASCO 2019, my colleagues and I reported data from the phase I ARROW study that evaluated BLU‑667. Among 48 response‑evaluable patients with RET fusion–positive NSCLC in the ARROW study, we saw an objective response rate of 58% that, again, are very promising data. Of importance, both BLU‑667 and LOXO‑292 have shown significant activity regardless of the specific RET fusion partner and have also shown significant activity in heavily pretreated patients. Moreover, both BLU‑667 and LOXO‑292 have shown evidence of intracranial activity, which is very important when treating NSCLC since we know that the central nervous system can be a sanctuary site of disease for our patients with NSCLC who are treated with some targeted therapies.

Both of these agents appear to be well tolerated based on the currently available evidence. The most common treatment-related adverse events reported with LOXO-292 in the LIBRETTO-001 study were diarrhea (11%), fatigue (17%), and dry mouth (13%). The most common treatment‑related adverse events reported with BLU‑667 in the ARROW study were constipation (17%), neutropenia (26%), liver function test elevations (aspartate aminotransferase, 20%; alanine aminotransferase, 13%), and hypertension (13%).

RET Alterations in Other Cancers
I would also like to highlight that RET gene alterations are not exclusively seen in NSCLC but are actually seen in multiple other solid tumors. RET fusions are also seen in papillary thyroid cancer, with an incidence of approximately 10% to 20% and in a variety of other solid tumors, such as pancreatic cancer and colorectal cancer, although at very low frequencies of generally less than 1%. At ASCO 2019, 2 different presentations from the ARROW study reported that BLU-667 has shown objective responses in patients with RET fusion–positive papillary thyroid cancer and in patients with metastatic pancreatic cancer and intrahepatic bile duct carcinoma harboring RET fusions.

Beyond RET fusions, activating point mutations of RET have also been described. RET point mutations are present in approximately 60% of patients with sporadic medullary thyroid cancer (MTC) and in more than 90% of patients with hereditary MTC. Early evidence indicates that BLU-667 and LOXO-292 are also active in patients with MTC and RET point mutations. For example, in the ARROW study, among 32 patients with RET-mutated MTC, BLU-667 showed an ORR of 56% with many responses ongoing beyond 6 months.

Moving Forward
Going forward, I think we need more data from a larger number of patients, and we need a better sense of the durability of these responses. Currently, we have a relatively limited follow-up for both BLU-667 and LOXO-292 with a median of less than 1 year. The hope is that patients will be on these drugs for a long time with effective disease control, which also underscores the need for good tolerability. Based on the early data, each drug appears to be well tolerated, but we need long-term safety data to get a broader sense of their toxicity profiles and how they compare with each other. Finally, at some point during treatment, patients will likely develop resistance to these 2 selective RET inhibitors. Currently, we lack insights into the molecular mechanisms of resistance to selective RET inhibitors. This speaks to the need to simultaneously conduct translational research aimed at elucidating these mechanisms because that can really help us develop the next generation of RET inhibitors and really build off this initial success.

Your Thoughts
What are your biggest challenges regarding testing for actionable biomarkers in your practice? Please share your thoughts in the comments box below.

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