Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

Abstract

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

Survival benefit of combinatorial osimertinib rechallenge and entrectinib in an EGFR‐mutant NSCLC patient with acquired LMNA‐NTRK1 fusion following osimertinib resistance

“… 23 Recently, Fuchs et al 19 described a case series of six patients with EGFRm NSCLC resistant to erlotinib, finding that the median duration of treatment was 5.0 months, and the median overall survival (OS) was 45.0 months. In addition, the combination of osimertinib rechallenge and bevacizumab showed benefits and resulted in significantly longer PFS and OS compared to chemotherapy plus bevacizumab in patients with acquired resistance to osimertinib 18 Comparatively, our patient received chemotherapy intervention and was then directed to clinical trials after osimertinib resistance. Moreover, serial next‐generation sequencing testing showed EGFR T790M persistence, and rechallenge with osimertinib at a dosage of 80 mg once daily showed clinical benefits with the addition of entrectinib.…”

“…Rechallenge with osimertinib has been described as an optional treatment for patients with acquired resistance following prior osimertinib therapy. 18 , 19 , 20 , 21 , 22 , 23 Metro et al 21 documented the success of osimertinib rechallenge against EGFR T790M‐positive NSCLC in a patient who progressed after sequenced osimertinib and chemotherapy. A study that included 15 people with EGFRm NSCLC rechallenged with osimertinib after interval therapy, showing a response rate of 33% and a median progression‐free survival (PFS) of 4.1 months.…”

“…Rechallenge with osimertinib has been described as an optional treatment for patients with acquired resistance following prior osimertinib therapy 18–23 . Metro et al 21 documented the success of osimertinib rechallenge against EGFR T790M‐positive NSCLC in a patient who progressed after sequenced osimertinib and chemotherapy.…”

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

“…The study compared the efficacy and safety of Osimertinib combined with bevacizumab against chemotherapy combined with bevacizumab in patients with Osimertinib resistance. The mPFS duration of the two groups was 7.0 vs. 4.9 months, and the mOS was 12.6 vs. 7.1 months, respectively; the difference was statistically significant ( 203 ).…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…[235][236][237][238][239] Lapatinib combined with camrelizumab, erlotinib combined with nivolumab, and osimertinib combined with bevacizumab have been promising in NSCLC. [240][241][242] But nivolumab combined with EGFR-TKIs had a higher incidence of interstitial pneumonia although effectively treated NSCLC. 243 However, despite improving immune function, lenvatinib combined with anti-PD-1 did not lead to durable tumor regression in TC, 244 and these findings need to be validated with further studies.…”