Investigators in the LIBRETTO-001 phase I/II trial presented new data on the experimental RET inhibitor selpercatinib at the 2019 World Conference on Lung Cancer. The agent produced robust responses in patients with RET-altered non–small cell lung cancer who had already received multiple therapies, raising hopes that it will soon receive FDA approval.

In the phase I/II LIBRETTO-001 trial, the experimental RET inhibitor selpercatinib (LOXO-292; Eli Lilly) elicited high response rates lasting more than a year and a half in patients with RET-altered non–small cell lung cancer (NSCLC) who had already received multiple treatments. The data were presented at the International Association for the Study of Lung Cancer's 2019 World Conference on Lung Cancer in Barcelona, Spain.

Selpercatinib produced an objective response rate (ORR) of 68% in 105 patients who had received a median of three prior treatment regimens, according to findings presented by the trial's lead investigator, Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. Median duration of response and progression-free survival were 20.3 months and 18.4 months, respectively, and side effects were mostly low grade. The ORR was 85% in a group of 34 previously untreated patients.

“It really checks all the boxes of favorable features that we like to see in a targeted therapeutic,” said Drilon.

RET alterations are relatively rare in NSCLC but are common in certain types of thyroid cancer. They have also been identified in colorectal, pancreatic, and breast cancers. In the absence of approved drugs that specifically target RET, patients have been treated with multikinase inhibitors, including cabozantinib (Cabometyx; Exelixis), vandetanib (Caprelsa; Sanofi), lenvatinib (Lenvima; Eisai), and sorafenib (Nexavar; Bayer), which have shown limited efficacy and often high toxicity.

In contrast, selpercatinib selectively blocks RET, avoiding other targets and the associated treatment-limiting side effects. It is one of two RET inhibitors currently in late-stage clinical trials—the other, pralsetinib (BLU-667; Blueprint Medicines), has shown promising activity in patients with advanced RET-altered medullary and papillary thyroid cancers.

“Data from the LIBRETTO study firmly establish RET as a bona fide oncogenic driver,” said Justin Gainor, MD, of Massachusetts General Hospital in Boston. In the field of NSCLC, the response rates we're observing resemble activity that we've seen in other subgroups of oncogene-driven lung cancers, such as ALK and EGFR.”

Notably, selpercatinib showed robust activity in crossing the blood–brain barrier, producing an ORR of 91% among patients with measurable brain metastases. The results suggest that it could treat and potentially prevent brain metastases, said Drilon.

“CNS [central nervous system] activity is critical for patients with lung cancer and, as systemic therapies have gotten better, it has emerged as an important sanctuary of disease,” said Gainor. “Furthermore, the CNS is an important source of morbidity and mortality for our patients, so development of agents with strong CNS activity is very important.”

Eli Lilly has partnered with Thermo Fisher Scientific to use the latter's Oncomine Dx Target Test to find RET alterations in patients with NSCLC. The test screens tumor samples for multiple gene variants associated with NSCLC to identify patients eligible for approved targeted treatments.

Investigators hope that selpercatinib will be approved by the end of the year.

“Prior to selpercatinib, we tried hard to repurpose existing multikinase inhibitors for these patients, but we saw low response rates and substantial toxicities,” said Drilon. “Selpercatinib has dramatically changed these outcomes.” –Janet Colwell

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