Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321)

Shun Lu, Ying Cheng, Dingzhi Huang, Yuping Sun, Lin Wu, Chengzhi Zhou, Ye Guo, Jingxin Shao, Wanli Zhang, Jianying Zhou, Shun Lu, Ying Cheng, Dingzhi Huang, Yuping Sun, Lin Wu, Chengzhi Zhou, Ye Guo, Jingxin Shao, Wanli Zhang, Jianying Zhou

Abstract

Introduction: Oncogenic alterations in RET occur in 1-2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with RET fusion-positive NSCLC remains unknown.

Methods: In this open-label, multicenter, phase II study (NCT04280081), patients with advanced RET-altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed RET status) and in all enrolled patients with NSCLC.

Results: Of 77 enrolled patients, 47 had RET fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS (n = 26) was 69.2% [95% confidence interval (CI), 48.2-85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC (n = 47) was 66.0% (95% CI, 50.7-79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population (n = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs.

Conclusion: Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with RET fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).

Keywords: Chinese; RET fusion; non-small-cell lung cancer; selective RET inhibitor; selpercatinib.

Conflict of interest statement

Competing Interests: Jingxin Shao and Wanli Zhang are employees of Eli Lilly and Company. The other authors have no conflicts of interest to declare.

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
Efficacy of selpercatinib in pretreated and treatment-naïve patients withRET fusion-positive NSCLC. Waterfall plots showing the maximum change in tumor size in all target lesions in the PAS (n = 26; a) and in all enrolled patients with NSCLC (n = 47; b) according to IRC assessment. Waterfall plots only show patients with measurable target lesions. One patient in the PAS and two patients of all enrolled patients with NSCLC had nonmeasurable disease. IRC, independent review committee; NSCLC, non-small-cell lung cancer; PAS, primary analysis set.
Figure 2.
Figure 2.
Duration of response. Kaplan–Meier estimates of DOR in patients withRET fusion-positive NSCLC (a) and all patients with NSCLC (b) who had a CR or PR confirmed by IRC. CR, complete response; DOR, duration of response; IQR, interquartile range; IRC, independent review committee; NR, not reached; PR, partial response; TTBR, time to best response; TTR, time to response.
Figure 3.
Figure 3.
Antitumor activity of selpercatinib against metastatic brain lesions in patients with RET fusion-positive NSCLC. Waterfall plot showing the percent change in brain target lesion size in the CNS population according to IRC evaluation. Waterfall plots only show patients with measurable target lesions. Among the eight patients with brain metastases at baseline, three had nonmeasurable disease. CNS, central nervous system; IRC, independent review committee; NSCLC, non-small-cell lung cancer.

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