Selpercatinib doubled progression-free survival, increased response rate, and delayed pulmonary and physical deterioration in RET fusion-positive NSCLC.

RET gene fusions, when present, are potential targets in patients with positive non-small cell lung cancer (NSCLC). Based on the results of KEYNOTE-189 (NCT02578680), the current standard for treatment of patients with RET fusion-positive NSCLC (without EGFR-mutation or ALK-rearrangement) is a platinum, pemetrexed, pembrolizumab combination [1]. Recently, the single-arm phase 1/2 LIBRETTO-001 (NCT03157128) showed strong clinical activity of selpercatinib, a selective RET inhibitor, in patients with RET fusion-positive NSCLC [2].

To further explore the clinical potential of selpercatinib, the randomized phase 3 LIBRETTO-431 (NCT04194944) compared the clinical efficacy and safety of selpercatinib with the standard of care. The study enrolled 261 participants with confirmed RET fusion-positive NSCLC, of whom 159 were assigned to receive selpercatinib and 102 to the standard of care (platinum, pemetrexed, pembrolizumab). Dr. Herbert Ho Fung Loong (Chinese University of Hong Kong, China) presented the interim results for progression-free survival (PFS), as the primary endpoint of the study [3].

At a median follow-up of approximately 19 months, selpercatinib demonstrated superior median PFS versus standard of care: 24.8 months (95% CI, 16.9­-NE) versus 11.2 months (95% CI, 8.8-16.8) (HR, 0.46; 95% CI, 0.31-0.70; P<0.01). The PFS benefit of selpercatinib was observed in all prespecified subgroups. Selpercatinib significantly increased overall response rate (83.7% vs 65.1%), median duration of response (24.2 months vs 11.5 months), intracranial response rate (82.4% vs 58.3%), intracranial complete response rate (35.3% vs 16.7%), and median intracranial PFS (16.1 months vs 10.4%).

Treatment with selpercatinib was relatively well tolerated: median time on selpercatinib was approximately 70% longer than the standard of care (16.7 months vs 9.8 months). Adverse events leading to discontinuation were slightly higher in the selpercatinib arm: 10.1% versus 2.0%. Selpercatinib significantly delayed the time-to-deterioration of pulmonary or physical function (HR, 0.34 for pulmonary function, HR, 0.60 for physical function).

“Selpercatinib should be considered as a first-line standard of care for patients with RET fusion-positive NSCLC,” concluded Dr. Ho Fung Loong. “Furthermore, these data reinforce the importance of genomic testing in NSCLC at the time of diagnosis.”

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