Selective RET inhibitor selpercatinib doubles progression-free survival in RET-mutated NSCLC

Compared with the standard of care for patients with RET-fusion-positive metastatic non-small cell lung cancer (mNSCLC), treatment with selpercatinib doubled progression-free survival (PFS), increased response rate (also intracranial) and delayed pulmonary and physical deterioration, results from the LIBRETTO-431 trial showed.

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

To further explore the clinical potential of selpercatinib, the current randomised phase 3 LIBRETTO-431 trial (NCT04194944) compared the clinical efficacy and safety of selpercatinib with the standard of care. The study enrolled 261 participants with confirmed RET-fusion-positive mNSCLC, of whom 159 were assigned to receive selpercatinib and 102 to the standard of care (platinum, pemetrexed, pembrolizumab). Prof. Herbert Ho Fung Loong (Chinese University of Hong Kong, China) presented the interim results for PFS, 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 versus 11.2 months (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 vs 10.4 months).

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). The occurrence of adverse events leading to discontinuation was slightly higher in the selpercatinib arm: 10.1% vs 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 Prof. Ho Fung Loong. “Furthermore, these data reinforce the importance of genomic testing in NCSLC at the time of diagnosis.”

1. 
   
   1. Gandhi L, et al. N Eng J Med. 2018;378:2078–2092.
   2. Drilon A, et al. J Clin Oncol. 2023;41(2):385–394.
   3. Ho Fung Loong H, et al. Randomized phase III study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC. Abstract LBA4, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December, 202315 February, 2024