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Adding a VEGF inhibitor to osimertinib (Tagrisso) failed to improve survival outcomes in previously treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC), a small randomized study from Japan showed.

For the primary endpoint, the combination strategy of osimertinib plus bevacizumab (Avastin) led to a median progression-free survival (PFS) of 9.4 months, as compared to 13.5 months with osimertinib alone (adjusted HR 1.44, 80% CI 1.00-2.08, P=0.20), reported Hiroaki Akamatsu, MD, PhD, of Wakayama Medical University in Japan, and colleagues in .

The overall response rate (ORR) was superior with the combination (68% vs 54% with osimertinib monotherapy), but patients in this group had a numerically shorter median time to treatment failure (8.4 vs 11.2 months, respectively).

Overall survival (OS) was not significantly different between the two arms, with a median not reached in the combination arm versus 22.1 months with osimertinib alone (P=0.96).

"To our knowledge, this is the first randomized clinical trial to explore the efficacy of adding anti-VEGF inhibitor to osimertinib," the authors wrote. "Although ORR was slightly better in the combination arm, we could not show advantages in PFS and OS. Previous reports have suggested that EGFR-[tyrosine kinase inhibitor] plus anti-VEGF inhibitor might be more beneficial in patients with brain metastasis or pleural effusion; however, none of our subgroup analyses could identify its advantage."

In an , Howard (Jack) West, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, said signals from phase II research on EGFR inhibitors plus anti-VEGF should be heeded before moving on to larger trials.

"Taken together, the available data on the combination of a vascular endothelial growth factor inhibitor with an EGFR inhibitor have not demonstrated a survival benefit over an EGFR inhibitor alone, and the emerging data with osimertinib/bevacizumab are best characterized as disappointing," said West.

West called attention to the fact that a of this combination in untreated patients failed to show superior PFS over historical data on osimertinib alone. Yet despite this, an ongoing will test osimertinib plus or minus bevacizumab anyhow.

Another anti-VEGF/EGFR combination -- ramucirumab (Cyramza) plus the earlier-generation EGFR inhibitor erlotinib (Tarceva) -- was tested in the phase III RELAY trial as first-line therapy. While ramucirumab-erlotinib showed an improvement in PFS, the combination resulted in similar OS at 2 years compared with erlotinib alone, at 79% versus 83%, respectively.

"Unfortunately, we all too frequently see our optimistic hopes based on impressive data from phase 2 trials dispelled when these approaches are battle tested in a larger, multicenter trial; it is almost unprecedented to see results of a phase 3 trial emerge as far superior to those of a preceding phase 2 trial," wrote West. "It is regrettable if we bypass the critical step of awaiting the signal from smaller clinical trials, particularly if that signal is a warning sign of likely futility."

The current phase II study enrolled 87 patients from 2017 to 2018 with EGFR T790M-mutant NSCLC whose disease had progressed on a prior EGFR-directed agent. Six patients were part of a lead-in phase, and all received osimertinib plus bevacizumab, while 81 were randomized to either the combination or osimertinib alone.

Patients in the randomized cohort had a median age of 68, 41% were men, and a fourth had brain metastasis. Most adverse events with osimertinib-bevacizumab were low grade. Rates of grade ≥3 proteinuria (78%) and hypertension (60%) were both significantly higher with the combination.

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