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Adding Antiangiogenics to Second-Line Treatment in NSCLC Could Improve Survival


Findings of a meta-analysis suggest adding antiangiogenics to second-line treatment in non–small cell lung cancer (NSCLC) may improve survival outcomes, especially in younger patients.

In second-line treatment (2LT) for advanced non–small cell lung cancer (NSCLC), the addition of antiangiogenic (AA) medications significantly prolongs overall survival (OS) and progression-free survival (PFS), according to meta-analysis findings published in European Journal of Cancer.

However, the benefit of this addition is clinically limited and is mainly observed in younger patients and following a shorter time since the start of first-line therapy, authors cautioned, while introduction of AA also significantly increased the risk of grade 3 or higher toxicities.

Previous research has shown overexpression of vascular endothelial growth factor is associated with poor NSCLC prognosis; angiogenic factors work to inhibit immune cells and induce immune suppression at multiple levels, the researchers explained.

Both monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) have AA effects. Although several trials have investigated the addition of AA drugs to chemotherapy or other treatments as 2LT, results have been inconsistent.

To better elucidate this practice as 2LT, the investigators conducted an individual patient data meta-analysis using information from clinical trials that completed accrual before December 31, 2014. All trials compared AA plus standard 2LT with 2LT alone.

OS, defined as the time from randomization to death from any cause or the last follow-up, was the study’s primary end point, and PFS, defined as time from randomization to disease progression, death from any cause, or last follow-up, served as the secondary end point.

Sixteen trials were included; of the 8629 patients, 64% had adenocarcinoma. Over half of the patients included had started 2LT with AA drugs within 9 months of initiating first-line treatment.

Analyses revealed:

  • AA drugs significantly prolonged OS (HR, 0.93; 95% CI, 0.89-0.98; P = .005) and PFS (HR, 0.80; 95% CI, 0.77-0.84; P < .0001) compared with 2LT alone
  • Absolute 1-year OS and PFS benefit for AA were 1.8% and 3.5%, respectively
  • OS benefit of AA drugs was higher in younger patients (HR, 0.87; 95% CI, 0.76-1.00; HR, 0.89; 95% CI, 0.81-0.97; HR, 0.94; 95%CI, 0.87-1.02; HR, 1.04; 95% CI, 0.93-1.17) for patients younger than 50, 50 to 59, 60 to 69, and at least 70 years old, respectively (trend test: P = .02)
  • OS benefit of AA was higher in patients who started AA within 9 months after starting the first-line therapy (HR= 0.88 [95% CI, 0.82-0.99]) than in patients who started AA later (HR =0.99 [95% CI, 0.91-1.08]) (interaction: P= .03)

Findings were similar with regard to PFS. However, “this positive effect was significantly different between the 3 types of combinations (interaction test: P = .0004). The strongest effect was in the combination "mAb (or TKI) added to erlotinib (HR, 0.70; 95% CI, 0.63-0.77), whereas the effect of mAb or TKI added to chemotherapy was HR = 0.79 (95% CI, 0.73-0.86) and HR = 0.85 (95% CI, 0.90-0.91), respectively,” the authors wrote.

Furthermore, 66.2% of those who had AA medications plus 2LT experienced grade 3 or higher toxicity compared with 55% with 2LT alone. AA drugs confer a higher risk of asthenia, neutropenia, hypertension, and proteinuria, while its addition did not increase the risk of deep vein thrombosis, gastrointestinal bleeding, pulmonary emboli or bleeding, or central nervous system ischemic events.

Overall, data showed the addition of AA drugs to standard 2LT in those with advanced NSCLC reduces the risk of progression by 20% and death by 7%, regardless of drug subtype. However, these benefits must be confirmed in clinical trials.

Potential heterogeneity among patients and a lack of analysis on specific subgroups of patients mark limitations to the meta-analysis. In addition, data on subsequent treatment lines following AA introduction were not available in all trials

“This meta-analysis clearly endorses that in the second-line setting of advanced NSCLCs, adding AA [drugs] to standard second treatment modestly but significantly prolongs the outcome,” the authors said.

“This benefit appears independent of the type of AA drugs, but the observed benefit may be higher in younger patients and in those patients with refractory tumors with good and manageable safety profile,” they concluded.


Remon J, Lacas B, Herbst R, et al. ANtiangiogenic second-line lung cancer meta-analysis on individual patient data in non-small cell lung canc: ANSELMA. Eur J Cancer. Published online March 11, 2022. doi:10.1016/j.ejca.2022.02.002

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