Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouring MET exon 14 skipping alterations: a post hoc analysis of a pivotal phase 2 study

Yongfeng Yu, Yongxin Ren, Jian Fang, Lejie Cao, Zongan Liang, Qisen Guo, Sen Han, Zimei Ji, Ye Wang, Yulan Sun, Yuan Chen, Xingya Li, Hua Xu, Jianying Zhou, Liyan Jiang, Ying Cheng, Zhigang Han, Jianhua Shi, Gongyan Chen, Rui Ma, Yun Fan, Sanyuan Sun, Longxian Jiao, Xiaoyun Jia, Linfang Wang, Puhan Lu, Qian Xu, Xian Luo, Weiguo Su, Shun Lu, Yongfeng Yu, Yongxin Ren, Jian Fang, Lejie Cao, Zongan Liang, Qisen Guo, Sen Han, Zimei Ji, Ye Wang, Yulan Sun, Yuan Chen, Xingya Li, Hua Xu, Jianying Zhou, Liyan Jiang, Ying Cheng, Zhigang Han, Jianhua Shi, Gongyan Chen, Rui Ma, Yun Fan, Sanyuan Sun, Longxian Jiao, Xiaoyun Jia, Linfang Wang, Puhan Lu, Qian Xu, Xian Luo, Weiguo Su, Shun Lu

Abstract

Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration (METex14).

Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib.

Design: A multicentre, single-arm, open-label phase 2 study.

Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression.

Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88-3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35-7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0-99.8 versus 36.4%; 95% CI, 10.9-69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2-1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1-1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S).

Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib.

Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

Keywords: MET exon 14 skipping; circulating tumour DNA; non-small cell lung cancer; pulmonary sarcomatoid carcinoma; savolitinib.

Conflict of interest statement

SL reports receiving research support from AstraZeneca, HUTCHMED, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche and Hansoh; receiving speaker fees from AstraZeneca, Roche, Hansoh and Hengrui Therapeutics and being an advisor and consultant for AstraZeneca, Pfizer, Boehringer Ingelheim, HUTCHMED, Simcere, Zai Lab, GenomiCare, Yuhan Corporation, prIME Oncology, Menarini, InventisBio Co. Ltd and Roche. No disclosures were reported by the other authors.

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
Patient flow in the post hoc analysis. ctDNA, circulating tumour DNA; FAS, full analysis set;METex14, MET exon 14 skipping alteration; PD, progressive disease.
Figure 2.
Figure 2.
Kaplan–Meier survival curves for (a) PFS and (b) OS byMETex14 ctDNA status at baseline. CI, confidence interval; ctDNA, circulating tumour DNA; HR, hazard ratio;METex14, MET exon 14 skipping alteration; NC, not calculable; NR, not reached; OS, overall survival; PFS, progression-free survival.
Figure 3.
Figure 3.
(a) Best change in target lesions and best overall response byMETex14 post-treatment clearance. (b) Time to firstMETex14 clearance. aOne patient stopped treatment prior to the tumour assessment time point owing to adverse event; the best overall response for this patient was SD since PR was not confirmed. bOne patient’s sample (Pt 04) was collected prior to the tumour assessment time point (before 6 weeks). ctDNA, circulating tumour DNA; METex14,MET exon 14 skipping alteration; NE, not evaluable; PD, progressive disease; PR, partial response; Pt, patient; SD, stable disease.
Figure 4.
Figure 4.
Kaplan–Meier survival curves for (a) PFS and (b) OS byMETex14 post-treatment clearance. CI, confidence interval; ctDNA, circulating tumour DNA; HR, hazard ratio;METex14, MET exon 14 skipping alteration; NC, not calculable; OS, overall survival; PFS, progression-free survival.
Figure 5.
Figure 5.
Association of baseline METex14 and coexisting gene alterations with best overall response. aTwo patients with PSC and three with other NSCLC subtypes did not have best change in target lesions data determined by IRC; they either had no target lesion or no tumour assessment during treatment. IRC, independent review committee; METex14,MET exon 14 skipping alteration; NE, not evaluable; NSCLC, non-small cell lung cancer; PD, progressive disease; PI3K, phosphoinositide 3-kinase; PR, partial response; PSC, pulmonary sarcomatoid carcinoma; RTK, receptor tyrosine kinase; SD, stable disease; SNV, single nucleotide variation.
Figure 6.
Figure 6.
Gene alterations determined from paired ctDNA samples collected at baseline and disease progression (n = 22). METex14, MET exon 14 skipping alteration; NSCLC, non-small cell lung cancer; PD, progressive disease; PI3K, phosphoinositide 3-kinase; PR, partial response; PSC, pulmonary sarcomatoid carcinoma; RTK, receptor tyrosine kinase; SD, stable disease; SNV, single nucleotide variation.

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