Alexander Drilon, MD
Almost 70% of patients with previously treated RET
-fusion–positive non–small cell lung cancer (NSCLC) had objective responses to the RET inhibitor selpercatinib (LOXO-292), according to data from the phase I/II LIBRETTO-001 trial presented at the 2019 World Conference on Lung Cancer (WCLC).
The median duration of response and median progression free-survival (PFS) exceeded a year and a half. Among patients with no prior treatment, selpercatinib produced an objective response rate of 85%.
Safety data involving more than 500 patients showed that adverse events were primarily low grade and unrelated to the drug.
“Selpercatinib demonstrated robust and durable antitumor activity in a heavily pretreated patient population with RET
fusion–positive non–small cell lung cancer,” said Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York. “The outcomes were consistent with other potent, selective, and CNS-active therapies for genomically driven lung cancer, such as EGFR and ALK.”
A randomized global phase III trial of selpercatinib versus platinum-pemetrexed chemotherapy with or without pembrolizumab (Keytruda) has been planned for patients with newly diagnosed RET
fusion–positive NSCLC, he added. A New Drug Application is expected to be submitted to the FDA for selpercatinib by the end of the year.
Multiple types of malignancies evolve from RET
fusions, which are uncommon (<1%) in most cases. However, about 2% of NSCLC is associated with the gene fusions, as are 10% to 20% of thyroid cancers.RET
fusions are “bonafide” lung cancer drivers, said Drilon. They are mutually exclusive with other driver alterations, transforming and actionable in vitro and in vivo, and associated with brain metastases in as many as half of patients with advanced RET
Multikinase inhibitors have modest clinical benefit in RET
-fusion tumors and carry significant off-target (non-RET
) toxicity, he continued. Some evidence suggests immunotherapy, including PD-1/PD-L1 inhibitors, have reduced efficacy in driver-positive NSCLC, including tumors associated with RET
No RET inhibitor has received regulatory approval for treatment of RET
-dependent tumors. Selpercatinib has exhibited potent and selective RET inhibition in vitro
and in vivo
, providing a rationale for clinical trials of the drug.
Drilon presented primary results from the NSCLC cohort of the LIBRETTO-001 trial of selpercatinib in RET
-altered cancers. Investigators enrolled a total of 531 patients for the phase I dose-escalation study and the phase II open-label evaluation of the 160 mg BID dose of selpercatinib.
The LIBRETTO-001 patient population included 253 patients with RET
-fusion positive NSCLC. Investigators focused on 184 patients with evidence of prior platinum chemotherapy, and whittled the list down to 105 (primary analysis set) after excluding patients who received prior nonplatinum chemotherapy or who had nonmeasurable disease, as well as 39 patients who proved to have treatment-naïve disease. Investigators performed a separate analysis of selpercatinib’s performance in the patients with untreated disease.
The primary endpoint was objective response rate, and secondary endpoints included duration of response, PFS, and safety. Treatment beyond disease progression was allowed for patients who continued to derive benefit.
A review of baseline characteristics showed that the 105 patients previously treated with platinum-based chemotherapy had a median age of 61, that women accounted for 59% of the patients, and that the cohort had received a median of 3 prior systemic regimens (ranging from 1 to 15). Additionally, 55% had been treated with a PD-1/L1 inhibitor (concurrent with or sequential to platinum chemotherapy), and 48% had prior exposure to one or more multikinase inhibitors. Drilon said 35% of the patients had brain metastases.
The 39-patient treatment-naïve cohort had the same median age, a similar female predominance, and a lower prevalence of brain metastases (18%).
For the 2 groups combined, laboratory data showed that the most common RET
fusion partners were KIF5B
(59%) and CCDC6
(22%). A fusion partner was not identified in 11% of the patients.
The efficacy analysis showed an overall response rate of 68%, including complete responses in 2% of patients. An additional 26% of patients had stable disease, resulting in a disease control rate (DCR) of 94%. Only 2% of patients had progressive disease as best response, as the remaining patients were not evaluable for response.
Drilon reported that 11 patients with CNS involvement had a DCR of 100%, including objective responses in 91%.
In 34 treatment-naïve patients evaluable for response, 85% had objective responses and 9% had stable disease, resulting in a DCR of 94%.