Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in patients with advanced EGFR‐mutant non‐small cell lung cancer

Abstract

Background: Acquired resistance development is a major challenge in the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR-TKI to overcome acquired resistance. Methods: We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib-resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR-TKI + anlotinib therapy in 24 advanced EGFR-mutant NSCLC patients after EGFR-TKI acquired resistance between January 2018 and August 2020. Results: Anlotinib reversed gefitinib resistance in gefitinib-resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR-TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression-free survival (PFS) was 11.53 AE 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 AE 1.69 months) than in patients with dramatic progression (6.80 AE 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. Conclusions: EGFR-TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR-TKI in advanced EGFR-mutant NSCLC patients.

Efficacy and safety of osimertinib plus anlotinib in advanced non‐small‐cell lung cancer patients after drug resistance

“…Among the 24 NSCLC patients with acquired EGFR‐TKI resistance, the ORR and DCR of EGFR‐TKI combined with anlotinib were 20.8% and 95.8%, respectively. The mPFS was 11.53 ± 2.41 months and mOS was not reached 24 . However, at present, there are few studies on the combination of osimertinib and anlotinib after resistance to osimertinib.…”

“…The mPFS was 11.53 ± 2.41 months and mOS was not reached. 24 However, at present, there are few studies on the combination of osimertinib and anlotinib after resistance to osimertinib. Zhou et al reported a case of a patient with advanced lung adenocarcinoma harboring resistance to Osimertinib who reached PR for 9 months when treated with osimertinib combined with chemotherapy and anlotinib, and was then treated with osimertinib and anlotinib as maintain therapy.…”

Positive response of a recurrent clear cell sarcoma to anlotinib combined with chemotherapy: A case report

“…[25] For example, the literature reported that TKIs can significantly delay disease progression and prolong survival in the treatment of EGFR-positive non-small cell lung cancer patients. [26] Likewise, patients with gastrointestinal stromal tumor caused by activating c-KIT or PDGFR have also responded well to TKIs. [27] More importantly, clinical studies have provided strong evidence that the use of anti-angiogenic agents, and particularly anlotinib, can promote tumor vascular normalization, thereby improving the delivery and efficacy of chemotherapy drugs in many solid tumors.…”

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

“…Preclinical studies have shown that vascular endothelial growth factor (VEGF) and EGFR share a common downstream signaling pathway and acquired EGFR resistance is associated with increased VEGF levels (148). In vivo and in vitro studies have confirmed that anlotinib (a small molecular multitarget tyrosine kinase inhibitor) can overcome acquired resistance to EGFR-TKIs through modulation of the FGFR1 signaling pathway (149,150). Phase II clinical trials have shown that the use of bevacizumab combined with afatinib resulted in an ORR of 22% and a PFS of 7.1 months in T790M-negative patients who developed drug resistance (151).…”