ctDNA Dynamics and Mechanisms of Acquired Resistance in Patients Treated with Osimertinib with or without Bevacizumab from the Randomized Phase II ETOP-BOOSTER Trial

Purpose: The ETOP 10-16 BOOSTER study was a randomized phase II trial of osimertinib and bevacizumab therapy versus osimertinib therapy in patients with an acquired EGFR T790M mutation. The mechanisms of acquired resistance to osimertinib and bevacizumab have not been described previously.Experimental Design: Next-generation sequencing (Guardant360) was conducted in serial plasma samples. The association between ctDNA and efficacy outcomes was explored, and molecular alterations at progression were described.Results: A total of 136 patients (88% of 155 randomized) had plasma samples at baseline (68 per arm), 110 (71%) at week 9, and 65 (42%) at progression. In a multivariable model for progression-free survival (PFS), the treatment effect was found to differ by smoking status (interaction P = 0.046), with the effect of smoking also differing by baseline EGFR T790M (interaction P = 0.033), whereas both TP53 at baseline and the tissue EGFR exon 21 L858R mutation were significantly associated with worse PFS outcome. Smokers (current/former) without baseline EGFR T790M showed a significant improvement in PFS under combination treatment, albeit with small numbers (P = 0.015). Week-9 EGFR T790M clearance was associated with improved PFS in the osimertinib arm (P = 0.0097). Acquired EGFR C797S mutations were detected in 22% and 13% of patients in the combination and osimertinib arms, respectively.Conclusions: The differential effect of treatment by smoking was not explained by TP53 mutations or other molecular alterations examined. Molecular mechanisms of acquired resistance were detected, but no novel molecular alterations were identified in the combination arm.