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Background: Selpercatinib is approved for the treatment of RET -fusion-positive non-small-cell lung cancer (NSCLC). Objective: We present a final update on LIBRETTO-321 to enhance the understanding of long-term efficacy and safety in Chinese patients. Design: This open-label, multicenter, phase II study included patients with advanced RET -altered solid tumors. Methods: The primary endpoint was objective response rate (ORR), and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was assessed by the independent review committee. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), central nervous system (CNS) response, and safety. Results: A total of 47 patients (treatment-naïve ( n = 11); pre-treated ( n = 36)) with NSCLC were enrolled. The ORR in overall NSCLC was 72.3% (95% CI: 57.4, 84.4), treatment-naïve was 100.0% (95% CI: 71.5, 100.0); and pre-treated was 63.9% (95% CI: 46.2, 79.2). Median DOR was not reached for overall NSCLC, with 53% of responses ongoing at the data cutoff (median follow-up: 34.2 months). With a median follow-up of 35.9 months, the median PFS for overall NSCLC was 27.6 months (95% CI: 22.3, not evaluable (NE)), treatment-naïve was 27.6 months (95% CI: 16.4, NE), and pre-treated was 27.8 months (95% CI: 19.29, NE). The 3-year OS rate for overall NSCLC was 62.0% (95% CI: 45.9, 74.6) with a median follow-up of 38.1 months. Among five patients with measurable CNS metastases, four achieved intracranial responses. The safety profile was consistent with previous reports. Conclusion: With additional follow-up, selpercatinib showed durable responses, prolonged survival, and a consistent safety profile in Chinese patients with RET -fusion-positive NSCLC. Trial registration: Clinical Trials.gov identifier (NCT04280081).

Background: Patient-reported outcomes (PROs) are increasingly becoming an important part of clinical trials as they are helpful in analyzing the safety and efficacy of treatment in chronic diseases like cancer. Objectives: We report PROs and health-related quality of life (HRQoL) with selpercatinib treatment among Chinese patients with rearranged in transfection ( RET ) fusion-positive non-small-cell lung cancer (NSCLC), RET fusion-positive thyroid cancer (TC), and RET -mutant medullary TC (MTC) as an exploratory analysis of the LIBRETTO-321 trial. Design: A total of 77 patients (47 RET fusion-positive NSCLC, 1 RET fusion-positive TC, and 29 RET -mutant MTC) were enrolled. Compliance for European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) was 100% at baseline and >90% at each time point. Methods: PROs were assessed using the EORTC QLQ-C30, and a bowel diary assessment for MTC patients with baseline diarrhea using the Systemic Therapy-Induced Diarrhea Assessment Tool. Data were collected at pre-dose; every 8 weeks from cycle 3; and every 12 weeks after cycle 13. A >10-point change from baseline was considered clinically meaningful. PRO changes were summarized through cycle 13. Results: Most patients with NSCLC or MTC showed improvement or remained stable on the global health status and functional subscales. For global health status, 47.4% of NSCLC and MTC patients showed definite improvement with only 19.7% showing definite worsening. For functional subscales, less than 30% of the patients showed definite worsening. For symptom subscales, more than 64% of the patients either improved or remained stable for the symptoms. For MTC patients with bowel diary assessment ( n = 5), there was no severity or worsening from baseline in the diarrheal episodes observed during treatment with selpercatinib. Conclusion: The study demonstrated favorable PROs in Chinese patients with RET fusion-positive NSCLC, TC, and RET -mutant MTC treated with selpercatinib. HRQoL was improved or stable as assessed by EORTC QLQ-30. Trail registration: This study was registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04280081 ) ClinicalTrials.gov Identifier: NCT04280081.

Background: Selpercatinib, a highly selective and potent REarranged during Transfection (RET) kinase inhibitor, is effective in advanced RET -altered thyroid cancer (TC). However, the efficacy and safety in Chinese patients are unknown. Patients and methods: In the open-label, multi-center phase II LIBRETTO-321 (NCT04280081) study, Chinese patients with advanced solid tumors harboring RET alterations received selpercatinib 160 mg twice daily. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DoR) and safety. Efficacy was assessed in the primary analysis set [PAS; treated patients with RET fusion-positive TC or RET- mutant medullary TC (MTC) confirmed by central laboratory] and all enrolled patients with MTC. Results: Of 77 enrolled patients, 29 had RET -mutant MTC and one had RET fusion-positive TC. In the PAS ( n = 26), the ORR by IRC was 57.7% [95% confidence interval (CI), 36.9–76.6]. Median DoR was not reached and 93.3% of responses were ongoing at a median follow-up of 8.7 months. In all enrolled MTC patients ( n = 29), the ORR by IRC was 58.6% (95% CI, 38.9–76.5). One RET fusion-positive TC patient treated for 23.4 weeks achieved a partial response at week 8 that was ongoing at cutoff. In the safety population ( n = 77), 59.7% experienced grade ⩾3 treatment-emergent adverse events (TEAEs). TEAEs led to dose reductions in 32.5% ( n = 25) and discontinuations in 5.2% [ n = 4; 3.9% ( n = 3) considered treatment related] of patients. Conclusions: Selpercatinib showed robust antitumor activity and was well tolerated in Chinese patients with advanced RET -altered TC, consistent with global data from LIBRETTO-001 (NCT04280081). ClinicalTrials.gov Identifier: NCT04280081 (first posted Feb 21, 2020)

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).