The ETOP-BOOSTER study explored the addition of bevacizumab to osimertinib as 2nd line treatment in patients with pathologically confirmed advanced NSCLC harboring common sensitising EGFR (70% Exon 19 deletion; 30% Exon 21 L858R) and acquired EGFR T790M mutations (mt) and reported no difference in progression-free survival (PFS). An interaction of treatment outcomes by smoking status was previously identified. Pre-specified exploratory analysis of serial plasma samples using next generation sequencing (NGS) is reported.
Plasma circulating tumour DNA (ctDNA) analysis was conducted using Guardant360® on samples collected prospectively at baseline (BL), week 9 (w9) and at disease progression (PD). Multivariable Cox models, including interaction of treatment with smoking history, plasma EGFR T790M and TP53 mt at BL and longitudinally, and tumour EGFRmt status were analysed to assess their effect on outcome.
From the 155 randomised patients, 136 (87%) had available blood samples at BL (68 in each arm), 110 (71%) at w9 and 65 (42%) at PD for plasma NGS analysis. EGFR T790M mt was detected in 71% (97/136) of BL samples and was not associated with PFS (Table).
At w9, EGFR T790M mt was undetected in 91% (of 80 available, initially mt, cases), while at PD it was present in 34% (of 47 cases available).
Smoking status was found to be predictive for PFS (interaction p=0.046), however it was not associated with TP53 mt, which was detected in 63% of BL samples. BL TP53 mt and tissue EGFR Exon 21 L858R were each found to be poor prognostic factors for PFS and overall survival independent of treatment.
| Median PFS (95%CI) months, log-rank p | |||
| BEV-OSI | OSI | Whole cohort | |
| BL EGFR T790M mt status (int p=0.29) | |||
| D - 97 ND - 39 | 14.9 (9.1 - 17) 16.5 (8.1 - 26.9) p=0.15 | 9.9 (5.5 - 16.7) 13.4 (4.1 - 18.7) p=0.97 | 12.4 (8.4 - 16.4) 14.4 (8.1 - 20.5) p=0.32 |
| EGFR T790M at BL/w9 (int p=0.037) | |||
| D at BL/9w - 7 D at BL; not at 9w -73 ND at BL/9w - 27 | NR (6.3 - NE) 13.3 (8.3 - 15.9) 7.1 (2.4 -24.5) p=0.39 | 2.1 (0 - 15.1) 9.0 (4.1 - 18.6) 7.5 (0.9 - 12.3) p=0.051 | 3.9 (0 - 15.1) 10.5 (7.8 - 14.6) 7.5 (4.1 - 12.3) p=0.82 |
| BL TP53 mt status (int p=0.67) | |||
| D - 86 ND - 50 | 10.4 (6.2 - 16.4) 20.6 (14.1 - 26.6) p=0.054 | 8.1 (4.2 - 12.4) 18.6 (6.2 - 25.1) p=0.026 | 9.4 (6.2 - 12.4) 18.7 (14.4 - 24.4) p=0.0033 |
D: Detected; ND: Not Detected; Int: Interaction; NR: Not Reached; NE: Not Estimable
The interaction of treatment with smoking, was confirmed for PFS in the current evaluation, and was not found to be driven by the presence of TP53 or EGFR T790M mt. BL TP53 mt and EGFR Exon 21 L858R were associated with poor outcome.
EudraCT number: 2016-002029-12 / ETOP 10-16 BOOSTER