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Adding the angiogenesis inhibitor bevacizumab (Avastin) to osimertinib (Tagrisso) failed to slow progression of advanced EGFR-mutant non-small-cell lung cancer (NSCLC) that had progressed on prior anti-EGFR therapy, a randomized trial showed.

Median progression-free survival (PFS) increased from 12.3 months with osimertinib alone to 15.4 months with the combination, but the difference did not achieve statistical significance. Median overall survival (OS) was 24 months in both arms of the trial.

An exploratory analysis revealed a significant interaction between smoking history and treatment, as current and former smokers had a significant reduction in the PFS hazard with the addition of bevacizumab, reported Rolf A. Stahel, MD, of the European Thoracic Oncology Platform (ETOP) in Bern, Switzerland, and coauthors writing in the .

The results are consistent with those of a previously reported Japanese study (WJOG8715L), which showed no difference in PFS between single-agent osimertinib and the combination. Notably, the Japanese study found no benefit from the combination in smokers.

Further dissuading use of the combination, osimertinib has shifted to the first-line setting as a result of the FLAURA trial, which showed an 8-month improvement in OS with osimertinib as initial treatment versus other EGFR inhibitors.

"The results from this current study as well as from the WJOG8715L study do not support further efforts to pursue the combination of osimertinib and bevacizumab in patients with EGFR-mutant NSCLC harboring acquired T790M mutations," Stahel and coauthors concluded. "Further, based on the OS and PFS benefits reported in the FLAURA study, the use of osimertinib has shifted from second-line post-EGFR T790M-acquired resistance to the first line in the treatment-naive setting."

Given the post hoc nature of the data showing a benefit of the combination in smokers, "these results are hypothesis generating and should be interpreted with caution," they noted.

EGFR tyrosine kinase inhibitors have transformed management of advanced NSCLC harboring somatic EGFR mutations, quickly becoming standard first-line treatment. However, resistance inevitably occurs, as a result of EGFR exon 20 T790M mutation. Osimertinib, a third-generation EGFR inhibitor, has demonstrated activity in NSCLC with the acquired T790M mutation.

In the phase III that demonstrated the superiority of osimertinib versus chemotherapy, median PFS with the EGFR inhibitor was only 10 months, emphasizing the need for novel strategies to improve durability of efficacy, the authors noted. The rationale for combining an angiogenesis inhibitor with the third-generation EGFR inhibitor came from evidence in the evolution of resistance to EGFR tyrosine kinase inhibitors (TKIs).

Stahel and coauthors reported findings from the randomized, multicenter, phase II trial, sponsored by ETOP. Eligible patients had stage IIIb-IVb NSCLC associated with an EGFR sensitizing mutation, progression on first-line EGFR TKI therapy, and confirmed T790M acquired resistance mutation.

Investigators in six countries randomized 155 patients to osimertinib alone or in combination with bevacizumab. The primary endpoint was PFS, and the trial had statistical power to detect a 36% improvement with the addition of bevacizumab.

After a median follow-up of 33.8 months, the data showed a nonsignificant absolute difference of 3.1 months in favor of the combination arm (HR 0.94, 95% CI 0.66-1.33). A subgroup analysis showed a significant (P=0.024) interaction between treatment and smoking status. Current and former smokers had improved PFS with the combination (HR 0.57, 95% CI 0.33-0.98), whereas never smokers did not benefit from the combination (HR 1.29, 95% CI 0.82-2.02). The interaction remained significant in a multivariable analysis (P=0.0052).

Grade ≥3 treatment-related adverse events occurred more often with the combination than with single-agent osimertinib (47% vs 13%). Treatment discontinuation related to those events occurred in 25% of patients with the combination and 4% with monotherapy.

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