Dataset Information

Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations.

ABSTRACT:

Introduction

Savolitinib has been found to have encouraging antitumor activity and a favorable safety profile in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLCs with MET exon 14 skipping alterations (MET ex14 positive) at the primary analysis of a phase 2 study. Here, we present the long-term efficacy and safety data of savolitinib, including subgroup analyses.

Methods

This multicenter, single-arm, open-label, phase 2 study in the People's Republic of China enrolled MET inhibitor-naive adults with locally advanced or metastatic METex14-positive NSCLC (NCT02897479). Oral savolitinib at a dose of 400 or 600 mg was administered once daily (body weight dependent). The primary objectives of the final analysis were long-term overall survival (OS) and subgroup analyses by previous systemic treatment, NSCLC subtypes, and brain metastases.

Results

At the final analysis cutoff date (June 28, 2021), a total of 70 patients were enrolled and receiving savolitinib, and median follow-up was 28.4 (interquartile range: 26.2-36.3) months. The median OS was 12.5 months (95% confidence interval [CI]: 10.5-21.4 [18- and 24-mo OS rates, 42.1% and 31.5%, respectively]). Median OS in pretreated or treatment-naive patients was 19.4 (95% CI: 10.5-31.3) and 10.9 (95% CI: 7.5-14.0) months, respectively; it was 10.6 months (95% CI: 4.6-14.0) in patients with pulmonary sarcomatoid carcinoma, 17.3 months (95% CI: 10.6-23.6) in other NSCLC subtypes, and 17.7 months (95% CI: 10.5-not evaluable) in patients with brain metastases. No new safety signals emerged with prolonged follow-up and exposure.

Conclusions

The updated results further confirm the favorable benefit and acceptable safety of savolitinib in Chinese patients with METex14-positive NSCLC.

SUBMITTER: Lu S

PROVIDER: S-EPMC9547292 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring <i>MET</i> Exon 14 Skipping Alterations.

Lu Shun S Fang Jian J Li Xingya X Cao Lejie L Zhou Jianying J Guo Qisen Q Liang Zongan Z Cheng Ying Y Jiang Liyan L Yang Nong N Han Zhigang Z Shi Jianhua J Chen Yuan Y Xu Hua H Zhang Helong H Chen Gongyan G Ma Rui R Sun Sanyuan S Fan Yun Y Fan Songhua S Yu Jie J Lu Puhan P Luo Xian X Su Weiguo W

JTO clinical and research reports 20220909 10

<h4>Introduction</h4>Savolitinib has been found to have encouraging antitumor activity and a favorable safety profile in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLCs with <i>MET</i> exon 14 skipping alterations (<i>MET</i> ex14 positive) at the primary analysis of a phase 2 study. Here, we present the long-term efficacy and safety data of savolitinib, including subgroup analyses.<h4>Methods</h4>This multicenter, single-arm, open-label, phase 2 study in the People's Repu ...[more]

PMID: 36217329

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Project description:BackgroundCapmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14.MethodsThe inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs.ResultsAll 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models.ConclusionsThe type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.