VP3-2021: A randomized phase II study of second-line osimertinib (Osi) and bevacizumab (Bev) versus Osi in advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and T790M mutations (mt): Results from the ETOP BOOSTER trial
Mené sur 155 patients atteints d'un cancer du poumon non à petites cellules de stade avancé avec mutation du récepteur EGFR et mutation T790M (âge médian : 67 ans ; durée médiane de suivi : 34 mois), cet essai randomisé de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout de bévacizumab à l'osimertinib
Background : Whilst Osi is the standard treatment (TX) in patients (pts) with advanced NSCLC with sensitising EGFR-mt and acquired T790M-mt, progression inevitably occurs. Preclinical studies suggest the angiogenic pathway is implicated in EGFR tyrosine kinase inhibitor (TKI) resistance. The study objective was to determine the efficacy and safety of combined Osi/Bev versus Osi in pts with NSCLC with EGFR-mt (exon 19 del or L858R) and T790M-mt at progression on prior EGFR TKI. Methods : BOOSTER is an open-label randomized phase II trial. Eligible pts were equally randomized to Osi (80 mg QD) and Bev (15 mg/kg i.v. Q3W) versus Osi. Primary end point was investigator assessed progression free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events (AEs). The trial was designed to detect an increase in the median PFS from 11 months (m) with Osi to 17.2m with Osi/Bev (HR 0.64, at 5% 1-sided alpha and 80% power, 126 PFS events; 154 pts). Results : Between 05/2017-02/2019, 155 pts were randomized: 78 Osi/ Bev, 77 Osi. The median age was 67 years, 62% females, 40% current-former (c-f) smokers, 30% ECOG PS 0, stage IIIb-c/IVa/IVb: 1%/70%/28%, 59% non-Asians. At a median follow-up of 34m, the median PFS was 15.4m (95% CI 9.2-18.0) and 12.3m (6.2-17.2) (PFS events: 64 & 65) in the Osi/Bev and Osi arm respectively (HR 0.96; 0.68-1.37; p=0.83). Median OS was 24.0m (17.8-32.1) in Osi/Bev and 24.3m (16.9-37.0) in Osi arm (deaths: 46 & 43) (HR 1.03; 0.67-1.56; p=0.91). ORR was 55% in both arms. Smoking history exhibits significant TX interaction for both PFS and OS (adjusted p= 0.0052 & 0.029); PFS HR 0.52/1.47, OS HR 0.59/1.54, for c-f/never smokers, respectively. Median time to TX discontinuation was 12.4m/8.2m in Osi/Bev and 10.8m in Osi. Grade
≥
3 TX-related AEs occurred in 47% pts in Osi/Bev (Grade 5: 0 pt) and 18% in Osi (Grade 5: 3 pts). Conclusions : No difference in PFS was observed between Osi/Bev and Osi. A significant TX interaction with smoking history is identified in subgroup analysis, indicating superiority of Osi/Bev vs. Osi for c/f smokers.