Osimertinib combined with bevacizumab for leptomeningeal metastasis from <scp><i>EGFR</i>‐mutation non‐small cell</scp> lung cancer: A phase <scp>II single‐arm</scp> prospective clinical trial

Lu, Zhiqin; Cai, Jing; Wang, Xia; Weng, Jianping; Zeng, Zhimin; Huang, Long; Liu, Anwen

doi:10.1111/1759-7714.13738

Cited by 28 publications

(12 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TKIs combined with antiangiogenic drugs such as bevacizumab have shown efficacy in lung cancer [ 12 , 13 ]. A phase II clinical study showed that osimertinib plus bevacizumab is beneficial in the treatment of lung cancer brain metastases [ 14 ], and our previous study indicated that osimertinib plus bevacizumab was safe and effective for the treatment of LM in EGFR-mutant lung cancer [NCT04148898] [ 15 ]. LM is different from brain parenchymal metastasis, and its mechanism and treatment are complicated issues in current clinical treatment.…”

Section: Introductionmentioning

confidence: 99%

Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer

Cai

et al. 2022

J Transl Med

Self Cite

View full text Add to dashboard Cite

Background EGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. Methods We retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood–brain barrier (BBB) and explored the potential mechanism. Results Our retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months versus 13.7 months (log-rank test, p = 0.046, HR = 2.867, 95% CI 1.007–8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p = 0.037, HR = 3.401, 95% CI 1.079–10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. Conclusions Our findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

show abstract

Section: Introductionmentioning

confidence: 99%

Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer

Cai

et al. 2022

J Transl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, in the MSKCC phase 2 trial, osimertinib plus bevacizumab resulted in a 100% response rate in 6 patients with brain metastases, including two complete responses ( 35 ). Interestingly, this combination also demonstrated CNS activity in patients with leptomeningeal metastases ( 37 , 38 ). Consistently, the addition of bevacizumab to osimertinib achieved significantly longer PFS than osimertinib alone in our patient, who had multiple brain metastases.…”

Section: Discussionmentioning

confidence: 89%

Case Report: Osimertinib Followed by Osimertinib Plus Bevacizumab, Personalized Treatment Strategy for a Lung Cancer Patient With a Novel EGFR Exon 20 Insertion D770_N771insGT and Multiple Brain Metastases

Zhi

Luo²,

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are the standard of care for non–small cell lung cancer (NSCLC) patients with EGFR exon 19 deletion and L858R mutations. However, no EGFR TKI has been approved for NSCLC patients harboring insertion mutations in EGFR exon 20 (EGFRex20ins), a subgroup of uncommon EGFR mutations resistant to first-generation EGFR TKIs. This unmet clinical challenge is further complicated by disease progression due to brain metastases (BMs), which limits the use of EGFR TKIs with low intracranial activity. Osimertinib, a third-generation EGFR TKI with high CNS activity, has demonstrated superior efficacy as a first-line treatment for EGFR-mutant NSCLC with or without BM. The VEGF pathway is a key mediator of cancer metastasis and resistance to EGFR TKIs. Accumulating evidence has demonstrated that the addition of anti-VEGF agents to EGFR TKIs provides an alternative treatment option for the clinical management of EGFR-mutant NSCLC. We herein report an NSCLC case with a novel EGFRex20ins mutation D770_N771insGT and multiple brain metastases who briefly responded to first-line osimertinib treatment and subsequently achieved prolonged disease control with osimertinib plus bevacizumab as second-line treatment. Our case suggests that osimertinib in combination with bevacizumab may be an effective option for NSCLC patients with specific EGFRex20ins mutations and brain metastases.

show abstract

“…A single-arm study reported that among 49 NSCLC patients with EGFR mutation, osimertinib plus bevacizumab showed an ORR of 80% and a median PFS of 19 months ( Yu et al, 2020 ). Another single-arm prospective trial of osimertinib plus bevacizumab in 14 patients with leptomeningeal metastasis (LM) from EGFR mutation showed an LM ORR of 50%, median PFS of 9.3 months, median OS of 12.6 months, and one-year survival rate of 35.7% ( Lu et al, 2021 ). On the contrary, another phase II study showed that, compared to osimertinib monotherapy, although ORR was slightly better in the osimertinib and bevacizumab combination arm, combination therapy could not show advantages in PFS and OS, even in subgroup analyses ( Akamatsu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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

Cui

Qing-an

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

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.

show abstract

Osimertinib combined with bevacizumab for leptomeningeal metastasis from EGFR‐mutation non‐small cell lung cancer: A phase II single‐arm prospective clinical trial

Cited by 28 publications

References 42 publications

Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer

Potential benefit of osimertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer

Case Report: Osimertinib Followed by Osimertinib Plus Bevacizumab, Personalized Treatment Strategy for a Lung Cancer Patient With a Novel EGFR Exon 20 Insertion D770_N771insGT and Multiple Brain Metastases

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

Contact Info

Product

Resources

About