Abstract
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).
Keywords
Introduction
Selpercatinib is a highly selective and potent RET inhibitor with central nervous system (CNS) activity. It has a favorable pharmacokinetic profile with activity against diverse activating RET alterations including RET fusions and RET point mutations. 1 Selpercatinib is approved in multiple geographies such as China, the United States, and the European Union for the treatment of RET-driven cancers.2–4
Efficacy and safety of selpercatinib have been established previously in the LIBRETTO-0015,6 with an objective response rate (ORR) of 83% (95% confidence interval (CI), 72, 91) in treatment-naïve patients and 62% (95% CI, 55, 68) in patients previously treated with platinum-based chemotherapy along with a tolerable safety profile. The median duration of response (mDOR) in treatment-naïve and pre-treated patients was 20.3 months (95% CI, 15.4, 29.5; median follow-up: 37.1 months) and 31.6 months (95% CI, 20.4, 42.3; median follow-up: 39.5 months), respectively. 6 In addition, the median progression-free survival (mPFS) was 22.0 months (95% CI: 16.5, 24.9; median follow-up time: 38.9 months) and 26.2 months (95% CI: 19.3, 35.7; median follow-up time: 41.2 months) for treatment-naïve and pre-treated patients, respectively. A total of 26 patients had measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-mDoR of 9.4 months (median follow-up 25.8 months) and CNS-mPFS of 11.0 months. 6
Treatment with selpercatinib in patients with advanced and metastatic RET-fusion-positive non-small-cell lung cancer (NSCLC) has shown durable antitumor activity and a favorable safety profile in global LIBRETTO-001 and LIBRETTO-321 trials.5–7 In China, the National Medical Products Administration’s Center for Drug Evaluation expedited the approval of the New Drug Application (NDA) for selpercatinib in November 2021. 2 This NDA approval was based on data from the global LIBRETTO-001 5 trial and LIBRETTO-321 trial. 7 Furthermore, the LIBRETTO-431 trial is the first phase III study that compared the efficacy of tyrosine kinase inhibitor (TKI) and chemotherapy with or without immunotherapy in patients with advanced RET fusion-positive NSCLC. Selpercatinib demonstrated longer progression-free survival (PFS) than platinum-based chemotherapy with or without pembrolizumab (mPFS was 24.8 months (95% CI, 16.9, not evaluable (NE)) and a median follow-up was 19.4 months (95% CI, 16.7, 19.7) with selpercatinib versus 11.2 months (95% CI, 8.8, 16.8; median duration of follow-up was 18.9 months (95% CI, 14.2, 22.3) with pembrolizumab (hazard ratio for progression or death, 0.46; 95% CI, 0.31, 0.70; p < 0.001)). 8 The mDOR was 24.2 months (95% CI, 17.9, NE; median follow-up, 18.0 months (95% CI, 16.5, 19.5)) with selpercatinib and 11.5 months (95% CI, 9.7, 23.3; median follow-up, 14.6 months (95% CI, 11.2, 19.8)) with pembrolizumab; data for OS were not matured (median duration of follow-up were 21 months). 8
Here we present the long-term efficacy and safety of selpercatinib in Chinese patients with RET-fusion-positive NSCLC with a follow-up of 36 months (approximately 24 months of additional follow-up compared with an 11-month follow-up in the primary analysis) based on the results of phase II LIBRETTO-321 trial. 7 Specifically, we report the PFS and 3-year OS rate in Chinese patients treated with selpercatinib.
Methods
Patient population, study design, and intervention
This was an open-label, multicenter, phase II study (NCT04280081; Trial registration date was November 29, 2019) conducted at 15 institutions in China that enrolled 77 patients (patient enrollment date was March 16, 2020) with locally advanced or metastatic solid tumors, including RET-fusion-positive NSCLC, RET-fusion-positive thyroid cancer (TC), and RET-mutant medullary thyroid cancer (MTC). Patients were categorized into three cohorts based on tumor type and type of RET alteration. The details of three cohorts have been published previously. 7
Selpercatinib was orally administered at a total dose of 160 mg twice daily in a continuous 28-day cycle until disease progression (PD), death, unacceptable toxic effects, or withdrawal of consent. Patients were continuously monitored from the first dose until 28 days (±7 days) after the last dose of selpercatinib. In the opinion of the investigator, patients with documented PD were allowed to continue treatment with selpercatinib if the treatment was tolerable and if the patient was deriving clinical benefit from continuing study treatment. After prior communication with the sponsor, the treatment was approved. The study received approval from the relevant ethics committee(s) and was conducted in accordance with the Good Clinical Practices guidelines, in line with the Declaration of Helsinki of 1964. The sponsor complied with country-specific regulatory requirements relating to safety reporting to the regulatory authority and Institutional Review Boards/Independent Ethics Committees. All patients provided written informed consent for study participation. The reporting of this study conforms to the CONSORT guidelines 9 (Supplemental File).
Inclusion and exclusion criteria
The eligibility criteria (inclusion and exclusion) have been described previously. 7 The key inclusion criteria were locally advanced or metastatic solid tumor and PD on/intolerance to no ongoing standard therapy, or in the opinion of the investigator, likely intolerance or no significant clinical benefit expected from standard therapy, or refusal of standard therapy; evidence of an RET gene alteration in the tumor and/or blood; measurable or non-measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Endpoints and assessments
The primary endpoint was ORR based on RECIST v1.1 as assessed by an independent review committee (IRC). The secondary endpoints included ORR as assessed by the investigator; DOR as assessed by IRC and investigator; CNS ORR, and DOR (by IRC); time to response and time to best response (TTBR) as assessed by IRC and the investigator; and PFS as assessed by IRC and the investigator; overall survival (OS) and safety. 7 Radiologic tumor assessments were performed at baseline, week 4 (±7 days, optional), week 8 (±7 days), and then every 8 weeks (±7 days) until week 48, and every 12 weeks (±7 days) thereafter.
Statistical analysis
Efficacy endpoints were evaluated in all enrolled patients and the primary efficacy analysis population/primary analysis set (PAS) with NSCLC, as well as in the treatment-naïve and pre-treated subgroups within each population. The PAS population included patients enrolled in Cohort 1 and 2 who have confirmed RET-fusion-positive solid tumors confirmed by a central laboratory. The point estimate of ORR, accompanied by a two-sided 95% exact binomial CI using the Clopper-Pearson method, was reported. Time-to-event endpoints (DOR, PFS, and OS) were estimated using the Kaplan–Meier method. Median follow-up for DOR, PFS, and OS was estimated using the Kaplan–Meier method with censored status reversed for each endpoint. CNS efficacy was evaluated in the CNS response analysis population which included all treated patients in Cohort 1 with confirmed RET-fusion-positive solid tumors who had IRC-assessed CNS metastases at baseline.
The safety population consisted of all enrolled patients who received at least one dose of selpercatinib. The severity of AEs was graded as per the CTCAE, version 5.0.
Results
Patient demographics and baseline characteristics
In total, 77 patients were enrolled and 47 patients were diagnosed with RET-fusion-positive NSCLC, 29 with RET-mutant MTC, and 1 with RET-fusion-positive TC. Here we present data from the updated analysis of all enrolled patients with NSCLC (n = 47 (pre-treated, n = 36; treatment-naïve, n = 11)) and NSCLC in the PAS population (n = 26 (pre-treated, n = 18; treatment-naïve, n = 8)). The median age was 54 years; the majority were female (55.3%) among all enrolled patients with NSCLC. Approximately similar characteristics were observed for the PAS population. Eight (30.8%) patients were diagnosed with CNS metastases at baseline, including five with measurable CNS lesions at the time of enrollment. Detailed baseline demographics and clinical characteristics of the patients are presented in the primary analysis. 7 We present the results for the overall NSCLC populations in the main text and the results for the PAS population are presented in the supplemental analysis.
Efficacy outcomes
In all enrolled patients with NSCLC, based on IRC assessment, ORR was 72.3% (95% CI: 57.4, 84.4), with complete response (CR) in 10.6% (95% CI: 3.5, 23.1) and partial response (PR) in 61.7% (95% CI: 46.4, 75.5). Among pre-treated and treatment-naïve patients, ORR was 63.9% (95% CI: 46.2, 79.2) and 100.0% (95% CI: 71.5, 100.0), respectively (Table 1 and Figure 1). Among patients with CR or PR (n = 34), the median TTBR was 1.8 months (Q1–Q3: 1.8–3.7); the mDOR was not reached (median follow-up: 34.2 months; Figure 2(a); and the median PFS was 27.6 months (95% CI: 22.3, NE) with a median follow-up of 35.9 months (Figure 2(b)). The median OS was not reached (median follow-up: 38.1 months; Table 1 and Figure 2(c)). The 1-, 2-, and 3-year DOR rates were 97.1% (95% CI: 80.9, 99.6), 63.1% (95% CI: 44.1, 77.1), and 52.9% (95% CI: 34.3, 68.5), respectively. The 1-, 2-, and 3-year OS rates were 87.2% (95% CI: 73.8, 94.1), 69.8% (95% CI: 54.4, 80.9), 62.0% (95% CI: 45.9, 74.6), respectively (Table 1). Similar efficacy results were observed in the PAS population (Supplemental e-Table 1).
Tumor response to selpercatinib based on IRC assessment (NSCLC population).
Landmark DOR, PFS, and OS rates are not included for pre-treated and treatment-naïve patients due to the small sample size.
All enrolled patients with RET fusion-positive NSCLC.
CI is based on the Clopper–Pearson method.
For DOR, the total number of responders for all enrolled, pre-treated, and treatment-naïve patients was 34, 23, and 11, respectively.
BOR, best overall response; CR, complete response; DOR, duration of response; IRC, Independent Review Committee; n, number of patients in each category; NE, not evaluable; NR, not reached; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival.
Efficacy of selpercatinib in all enrolled patients (pre-treated and treatment naïve) with NSCLC. The Waterfall plot shows the maximum change in tumor size of all target lesions for all enrolled patients with NSCLC (N = 47) as assessed by IRC.
Long-term efficacy of selpercatinib. Kaplan–Meier curves of (a) DOR, (b) PFS, and (c) OS in all enrolled patients with NSCLC.
Among five patients with measurable CNS metastases at enrollment, the IRC-assessed intracranial ORR was 80% (Figure 3). Among the eight patients diagnosed with CNS metastases at baseline, six had CR or PR during treatment. Among these patients, the median DOR was 21.1 months (95% CI: 15.0, NE) and the 1-year DOR rate was 100% (95% CI: 100.0, 100.0).
Antitumor activity of selpercatinib on metastatic CNS lesions in patients with RET-fusion-positive NSCLC. The Waterfall plot shows the percent change in target CNS lesion size in the CNS population as assessed by IRC.
Safety outcomes
A total of 77 enrolled patients with RET-fusion-positive NSCLC and RET-altered TC, who received selpercatinib were included in the safety population. The median number of treatment cycles received was 35 (Q1, Q3: 19.0, 40.0). The median duration of therapy was 32.4 months (140.9 weeks; Q1, Q3: 72.6, 163.9 weeks) and the median relative dose intensity was 97.7% (Q1, Q3: 82.4, 99.8; Supplemental e-Table 2). All patients enrolled in the safety population (N = 77, (100%)) experienced at least one treatment-emergent adverse event (TEAE), 76 (98.7%) of these patients experienced a TEAE related to the study drug (Supplemental e-Table 3). The most common TEAEs were increased aspartate transaminase (AST) (71.4%), increased alanine aminotransferase (ALT) (66.2%), hypoalbuminemia (58.4%), increased blood bilirubin increased (49.4%), diarrhea (46.8%), hypertension (40.3%), and decreased platelet count (40.3%; Table 2). A total of 55 (71.4%) patients experienced at least one grade ⩾3 TEAE. The most common grade ⩾3 TEAEs were hypertension (20.8%), increased AST (16.9%), increased ALT (15.6%), and electrocardiogram QT prolonged (15.6%; Table 2). In total, 5 (6.5%) patients discontinued treatment due to an adverse event (AE) of whom 4 (5.2%) had an AE related to the study drug. TEAEs leading to dose reduction were observed in 38 (49.4%) patients. The most common TEAEs leading to dose reduction were increased AST (n = 7 (9.1%)), hypersensitivity (n = 7 (9.1%)), increased ALT (n = 5, (6.5%)), and electrocardiogram QT prolonged (n = 5, 6.5%). At least one serious AE (SAE) was reported in 31 (40.3%) patients, of whom 24 (31.2%) patients experienced SAEs related to the study drug. Two (2.6%) patients died due to AEs (cardio-respiratory arrest and pancreatitis acute), but no death was related to the study drug (Supplemental e-Table 3).
Summary of TEAEs (⩾20%) in the safety population.
The relationship between the study drug with AEs was assessed by the investigator.
AE, adverse event; ALT, alanine aminotransferase; N, total number of patients; n, number of patients in each category; TEAE, treatment-emergent adverse event; TRAE, treatment-related AE.
The safety profile is also presented separately for the overall NSCLC population. The median duration of treatment was 28.1 months (122.3 weeks; Q1, Q3: 67.7, 164.6 weeks) and the median relative dose intensity was 96.4%. Among enrolled patients (N = 47) with NSCLC, all 47 patients (100.0%) experienced at least one TEAE, and 35 (74.5%) patients experienced grade ⩾3 TEAE. Among them, 30 (63.8%) patients had at least one grade ⩾3 TEAE related to the study drug. The most common grade ⩾3 TEAEs were hypertension (23.4%), increased AST (21.3%), increased ALT (17.0%), and decreased platelet count (17.0%; Supplemental e-Table 4). A total of 3 (6.4%) patients discontinued the study due to an AE and among them 2 (4.3%) patients had an AE related to the study drug. TEAEs leading to dose reduction were observed in 26 (55.3%) patients. The most common reasons for dose reduction were increased AST (n = 6 (12.8%)), hypersensitivity (n = 6 (12.8%)), and decreased platelet count (n = 4 (8.5%)). At least one SAE was observed in 20 (42.6%) patients; 18 (38.3%) of these patients had an SAE related to the study drug. There was 1 (2.1%) death reported due to an AE (cardio-respiratory arrest), not related to the study drug.
Discussion
This phase II, open-label, multicenter study assessed the efficacy and safety of selpercatinib in Chinese patients with RET-altered cancers. This report presents long-term efficacy and safety data focusing on PFS, and 3-year OS rate, in patients with RET-fusion-positive NSCLC, demonstrating durable and robust activity of selpercatinib along with a manageable safety profile. In the present study, a high ORR (IRC assessed) of 64% and 100% was observed in pre-treated and treatment-naïve patients, respectively, in the overall NSCLC population. With the prolonged follow-up period, an increasing trend in ORR was seen in both pre-treated and treatment-naïve patients.
The study outcome was aligned with the global LIBRETTO-001 phase I/II trial, which assessed the long-term efficacy of selpercatinib in patients with RET-altered solid tumors. In LIBRETTO-001 trial, patients with NSCLC who had received prior platinum-based chemotherapy and who were treatment-naïve were included. The study showed a high response rate in both groups, with treatment durability confirmed by prolonged DOR. The median DOR in the overall NSCLC population was not reached and 53% of responses remained ongoing at the data cutoff. 6
Similarly, the efficacy of selpercatinib was further evaluated by PFS. The mPFS in the NSCLC population was 27.6 months with a median follow-up of 35.9 months; the mPFS in pre-treated and treatment-naïve patients were 27.8 months (median follow-up: 35.8 months) and 27.6 months (median follow-up: 38.6 months), respectively. In the LIBRETTO-001 global study, pre-treated patients had a numerically longer PFS compared to treatment-naïve patients. 6
LIBRETTO-431 was the first randomized phase III trial comparing the efficacy of TKIs and chemotherapy with or without immunotherapy in patients with advanced RET-fusion-positive NSCLC. 8 The trial reported that PFS and ORR with selpercatinib were similar 8 to the results observed in the current study. The findings regarding patients with CNS metastases in this study align with those of global LIBRETTO-001 6 and LIBRETTO-431, 8 where four out of five patients with measurable CNS lesions responded. In addition, among the eight patients with CNS lesions in this report, six achieved a response, with an mDOR of 21.1 months (95% CI: 15.0, –).
The efficacy of selpercatinib can be compared to other RET inhibitors that have reported notable efficacy in the treatment of RET-altered cancers.10–12 The efficacy of pralsetinib, another selective RET inhibitor, was evaluated in the ARROW study, a multi-cohort, open-label, phase I/II trial that enrolled 281 patients with RET-fusion-positive NSCLC. 11 Pralsetinib reported an ORR of 72% in treatment-naïve patients and 59% in those previously treated with platinum-based chemotherapy with a median time to first response of 1.8 months. In comparison, selpercatinib has also shown high response rates in similar patient populations, highlighting its potential as a treatment option for RET-fusion-positive NSCLC.
Similar to previous findings, 6 the incidence of some AEs (hypertension (36.4%) and increased ALT (64.9%)/AST (61.0%)) was numerically higher in the Asian population 6 than in the overall global population (hypertension: 41.0%; increased ALT: 35.7%; increased AST: 36.7%). In this study, the incidence rate of certain AEs (hypertension, increased ALT, increased AST) was observed to be numerically higher than that in the global population. 5 However, the overall safety profile was consistent with that observed for the global population. Of note, these AEs were clinically monitorable, manageable, and reversible. The discontinuation rate was 5.2%, and there were no drug-related deaths.
Limitations
This was a single-arm study with an open-label design, which may have resulted in possible bias in the results. At the time of the final data cutoff, median OS was not reached, but the results provide insights into how the results from LIBRETTO-431 may mature. The sample size was limited, specifically for pre-treated and treatment-naïve subgroups, and patients with CNS metastases.
Conclusion
Selpercatinib demonstrated robust and durable responses, prolonged survival, and consistent safety with a longer follow-up of 3 years in Chinese patients with RET-fusion-positive NSCLC. This is the first report of PFS and 3-year OS in the Chinese population. The findings are consistent with those in the overall global population in the global LIBRETTO-001 and LIBRETTO-431 trials. The safety profile was generally consistent with that identified and previously reported across the selpercatinib development program. The key toxicities with selpercatinib such as hypertension, liver enzyme elevation, and hematological toxicities are easily identifiable, monitorable, and manageable with dose modifications or concomitant medication. Overall, the efficacy and safety results suggest a favorable benefit–risk profile of selpercatinib in providing a novel treatment option for Chinese patients with RET-fusion-positive NSCLC. The outcomes of this trial elucidate the need for broad-based genomic profiling to identify Chinese patients with active RET alteration so that a better treatment strategy could be considered in this patient population.
Supplemental Material
sj-docx-1-tam-10.1177_17588359241307199 – Supplemental material for Selpercatinib in Chinese patients with RET-fusion-positive non-small-cell lung cancer: updated efficacy and safety analysis from the randomized LIBRETTO-321 phase II trial
Supplemental material, sj-docx-1-tam-10.1177_17588359241307199 for Selpercatinib in Chinese patients with RET-fusion-positive non-small-cell lung cancer: updated efficacy and safety analysis from the randomized LIBRETTO-321 phase II trial by Shun Lu, Ying Cheng, Dingzhi Huang, Yuping Sun, Lin Wu, Chengzhi Zhou, Jianying Zhou, Ye Guo, Jingxin Shao and Wanli Zhang in Therapeutic Advances in Medical Oncology
Footnotes
Appendix
Acknowledgements
The authors would like to thank all study participants and Jing Jing Li, Jian Kun Zhu from Eli Lilly and Company as reviewers for the manuscript. Medical writing was provided by Zipei Xiao from Eli Lilly and Company and Adrija Tripathy from Syneos Health. This manuscript complied with international guidelines for Good Publication Practice (GPP3).
Declarations
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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