AACR 2021: ctDNA Analysis in the Savolitinib Phase II Study in NSCLC Patients Harboring METex14 Skipping Alterations
Presenter/Authors: 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, Jing Li, Qian Xu, Xian Luo, Weiguo Su, Shun Lu.
Shanghai Chest Hospital, Shanghai JiaoTong University, Shanghai, China, Hutchison MediPharma Limited, Shanghai, China, Peking University Cancer Hospital & Institute, Beijing, China, Anhui Provincial Hospital,The First Affiliated Hospital of USTC, Hefei, China, West China Hospital of Sichuan University, Chengdu, China, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China, The First Affiliated Hospital of Zhengzhou University,, Zhengzhou, China, The Second Affiliated Hospital of Nanchang University, Nanchang, China, The First Affiliated Hospital of Zhejiang University, Hangzhou, China, Shanghai Chest Hospital,Shanghai JiaoTong University, Shanghai, China, Jilin Cancer Hospital, Changchun, China, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China, Linyi Cancer Hospital, Linyi, China, Cancer Hospital of Harbin Medical University, Harbin, China, Liaoning Cancer Hospital, Shenyang, China, Zhejiang Cancer Hospital, Hangzhou, China, Xuzhou Central Hospital, Xuzhou, China
Background: Savolitinib is a potent and selective MET tyrosine kinase inhibitor. It demonstrated clinical efficacy and a manageable safety profile in Chinese NSCLC pts with METex14 alterations in a phase 2 study (NCT028997479). Here, we report the post-hoc ctDNA analysis of METex14 at baseline and clearance upon treatment and the association of these findings with clinical outcome. In addition, concurrent gene alterations in ctDNA samples from the patients treated with savolitinib and impact on clinical efficacy is explored.
Methods: Plasma samples were prospectively collected pre-dose and at tumor assessment visits, until disease progression or end of treatment. MET and other somatic gene alterations in the ctDNA samples were detected by next generation sequencing (425-gene panel, Geneseeq).
Results: Sixty-six pts provided baseline plasma samples, of which METex14 ctDNA was detectable in 46 (70%) and undetectable in the remaining 20 pts (30%). Among the 46 ctDNA detectable pts, 19 were pulmonary sarcomatoid carcinoma (19/22, 86%) and 27 were other NSCLC (27/44, 61%), respectively. Of the 46 baseline-detectable pts, 24 were clearance evaluable and 22 had no qualified post baseline samples for clearance evaluation. Of the 24 clearance evaluable pts, 14 achieved ctDNA clearance (undetectable) with a median time to clearance of 1.4 months of treatment (Min 1.4 m, Max 4.2 m). The PFS and OS were compared for pts based on their METex14 ctDNA status at baseline and upon treatment. As shown in the table, METex14 baseline undetectable or clearance pts demonstrated significantly longer mPFS and mOS. Furthermore, in 21 pts with analyzable ctDNA samples at baseline and at disease progression, additional gene alterations were observed such as KRAS, NRAS, BRAF, PIK3CA as well as secondary MET mutations and FGF19 amplification in 12 pts (57%). These alterations might be associated with treatment resistance.
Conclusions: The results suggest that ctDNA METex14 undetectable at baseline or clearance upon savolitinib treatment may define favorable treatment outcome. Confirmation of this finding and the predictive value of the ctDNA with larger sample size is desirable.
| METex14 ctDNA | mPFS (mon,95% CI) |
HR (95% CI) |
P value | mOS (mon,95% CI) |
HR (95% CI) |
P value |
| Baseline undetectable (n=20) | 13.8 (4.2, 22.1) |
– | – | NC (10.9, NC) |
– | – |
| Baseline detectable (n=46) | 5.6 (4.1, 6.9) |
1.77 (0.88, 3.57) |
0.108 | 10.9 (9.2, 14.0) |
3.26 (1.35, 7.89) |
0.006 |
| – Clearance (n=14) |
30.3 (6.8, NC) |
0.72 (0.28, 1.87) |
0.501 | 35.8 (14, NC) |
0.89 (0.25, 3.18) |
0.835 |
| – Non-clearance (n=10) |
5.5 (0.66, 5.6) |
4.94 (1.83, 13.36) |
0.002 | 8.7 (0.8, 10.6) |
7.06 (2.39, 20.89) |
<0.001 |
| – Non-evaluable (n=22) |
4.1 (4.0, 6.9) |
3.45 (1.48, 8.03) |
0.006 | 10.6 (4.8, 12.0) |
5.88 (2.24, 15.47) |
<0.001 |
CI, confidence interval; HR, hazard ratio; NC, non-calculable
Disclosures:
Y. Yu: None. Y. Ren: ; Hutchison MediPharma Limited.. J. Fang: None. L. Cao: None. Z. Liang: None. Q. Guo: None. S. Han: None. Z. Ji: None. Y. Wang: None. Y. Sun: None. Y. Chen: None. X. Li: None. H. Xu: None. J. Zhou: None. L. Jiang: None. Y. Cheng: None. Z. Han: None. J. Shi: None. G. Chen: None. R. Ma: None. Y. Fan: None. S. Sun: None. L. Jiao: ; Hutchison MediPharma Limited. X. Jia: ; Hutchison MediPharma Limited. L. Wang: ; Hutchison MediPharma Limited. P. Lu: ; Hutchison MediPharma Limited. J. Li: ; Hutchison MediPharma Limited. Q. Xu: ; Hutchison MediPharma Limited. X. Luo: ; Hutchison MediPharma Limited. W. Su: ; Hutchison MediPharma Limited. S. Lu: ; Hutchison MediPharma. ; Astra Zeneca. ; BMS. ; Heng Rui. ; Beigene. ; Hansoh. ; Roche. ; Pfizer. ; BoehringerIngelheim. ; Simcere. ; Zai Lab. ; GenomiCare. ; Yuhan Corporation. ; PrIME Oncology. ; Menarini.