Mutation-Specific Response to Ramucirumab in EGFR-Mutated Metastatic NSCLC: Insights From Circulating Cell-Free DNA
Kazuto Nishio1, Kazuko Sakai1, Makoto Nishio2
1Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
Introduction:
A previous analysis of the RELAY phase 3 liquid biopsy addendum demonstrated suppressed EGFR-activating mutation allele count, increased total cell-free DNA (cfDNA) concentration, and shortened cfDNA fragment size with ramucirumab (RAM) plus erlotinib (ERL) versus placebo (PL) plus ERL in patients with EGFR-mutated NSCLC. We report updated data by EGFR mutation subtypes.
Methods:
Patients were randomized 1:1 to RAM plus ERL or PL plus ERL. Liquid biopsy samples were collected at baseline, during treatment, and at post-progression 30-day follow-up. EGFR-activating mutation allele count, plasma cfDNA concentration, cfDNA fragment size, and treatment-emergent T790M were analyzed in patients with a valid baseline sample (N = 131) by EGFR mutation subgroups (ex19del; L858R).
Results:
Within both ex19del and L858R subgroups, EGFR-activating mutation allele count decreased from baseline to cycle 4 in both treatment arms. Total cfDNA concentration significantly increased from baseline to cycle 4 (p < 0.0001) and was sustained to follow-up in the RAM plus ERL arm within the L858R subgroup only. cfDNA fragment size decreased from baseline to cycle 4 in the RAM plus ERL arm within both subgroups. T790M rates in the RAM plus ERL and PL plus ERL arms were 22.2% (four of 18) and 52.9% (nine of 17), respectively, in the ex19del subgroup by cycle less than or equal to 155 and 31.8% (seven of 22) and 18.8% (three of 16), respectively, in the L858R subgroup by cycle less than or equal to 176.
Conclusions:
This updated analysis revealed differences in total cfDNA concentration and T790M mutation rates between ex19del and L858R. RAM plus ERL may exhibit greater antitumor effects on L858R, supporting the favorable survival benefits observed previously in patients with a L858R.
Insights
Updated analysis of the RELAY trial shows ramucirumab plus erlotinib (RAM plus ERL) impacts cell-free DNA (cfDNA) differently in EGFR-mutated NSCLC subtypes. RAM plus ERL demonstrated greater antitumor effects in the L858R mutation subgroup.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Previous analysis of the RELAY phase 3 trial indicated ramucirumab (RAM) plus erlotinib (ERL) suppressed EGFR-activating mutation allele count and altered cell-free DNA (cfDNA) in EGFR-mutated NSCLC.
- Updated data are presented, stratified by specific EGFR mutation subtypes (ex19del and L858R).
Purpose of the Study:
- To report updated liquid biopsy data from the RELAY trial, analyzing the impact of ramucirumab plus erlotinib versus placebo plus erlotinib on specific EGFR mutation subtypes.
- To investigate differences in cfDNA dynamics and T790M mutation rates between ex19del and L858R subgroups.
Main Methods:
- Patients with EGFR-mutated NSCLC were randomized to receive RAM plus ERL or placebo (PL) plus ERL.
- Liquid biopsy samples were analyzed for EGFR-activating mutation allele count, plasma cfDNA concentration, cfDNA fragment size, and treatment-emergent T790M.
- Analyses were performed on 131 patients with valid baseline samples, stratified by EGFR mutation subgroups (ex19del and L858R).
Main Results:
- EGFR-activating mutation allele count decreased in both arms across both subgroups.
- Total cfDNA concentration significantly increased and was sustained in the RAM plus ERL arm for the L858R subgroup.
- RAM plus ERL showed decreased cfDNA fragment size in both subgroups, and T790M mutation rates varied between subgroups and treatment arms.
Conclusions:
- Updated analysis reveals distinct cfDNA concentration and T790M mutation rate patterns between ex19del and L858R EGFR mutation subtypes.
- Ramucirumab plus erlotinib may exert greater antitumor effects in the L858R subgroup, correlating with previously observed survival benefits.
