Though previous reports have suggested that an EGFR tyrosine kinase inhibitor plus an anti-VEGF agent might offer benefit to patients with brain metastasis or pleural effusion, the study authors could not identify its advantage.
Osimertinib (Tagrisso) plus bevacizumab (Avastin) failed to demonstrate prolongation of progression-free survival (PFS) compared with osimertinib alone in patients with non–-small cell lung cancer (NSCLC) with harboring anEGFR T790M mutation, according to randomized clinical trial (UMIN000023761) results published in JAMA Oncology.1
“Previous reports have suggested that EGFR [tyrosine kinase inhibitor (TKI)]-TKI 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,” wrote the study authors, who were led by Hiroaki Akamatsu, MD, PhD.
This open-label, multi-institutional study consisted of a lead-in portion to determine the feasibility of combination treatment, followed by a randomized phase 2 portion. In the lead-in part, patients with NSCLC who had progressed on prior prior EGFR-TKI therapy treatment and developed an acquired EGFR T790M mutation were treated with a fixed dose of osimertinib and bevacizumab; if more than 2 patients in this cohort experienced a dose-limiting toxicity (DLT) in the first cycle, the study was to be terminated. However, after confirming the feasibility of the lead-in portion, the phase 2 part was initiated, and eligible patients were randomized 1:1 to the osimertinib arm (n = 41) or the combination arm (n = 40).
The primary end point for thestudy was PFS as assessed by investigators. Key secondary end points included overall response rate (ORR), time to treatment failure, overall survival (OS), and safety.
From August 2017 through September 2018, a total of 87 patients were registered for the study, including 6 in the lead-in part portion and 81 in the phase 2part who comprised the intention-to-treat population. Of those who were randomized, the median (range) age was 68 years (range, 41-82) years, 33 (41%) were male, 37 (46%) had an Eastern Cooperative Oncology GroupECOG performance status of 0, and 21 (26%) had brain metastasis.
Ultimately, despite a better ORR was better with osimertinib plus bevacizumab than versus osimertinib alone (68% vs 54%), median PFS was not longer with the combination (9.4 months vs 13.5 months; adjusted HR, 1.44; 80% CI, 1.00-2.08; P = .20). In addition, the median time to treatment failure was also revealed to be shorter in the combination arm versus the osimertinib arm (8.4 months vs 11.2 months; HR, 1.54; 95% CI, 0.90-2.69; P = .12). Median OS did not differ between the combination arm and the osimertinib arm (not reached vs 22.1 months; P = .96).
Overall, the majority of adverse events (AEs) observed in the study were generally grade 1 or 2. The most common AEs of grade 3 or higher in the combination arm were proteinuria (grade 1/2, 55%; grade 3, 23%) and hypertension (grade 1/-2, 40%; grade ≥3, 20%). The rates of proteinuria (78%) and hypertension (60%) were also significantly higher in the combination arm, while the incidence of anemia (66%) was found to be significantly higheroccurred more often in the osimertinib arm.
“Reflecting the results of the current trial, the efficacy of osimertinib plus anti-VEGF therapy should be explored as first-line treatment,” noted the authors. “Several randomized studies (ie, WJOG 9717L trial [UMIN000030206] and NCT04181060) are ongoing, and these results are anticipated with interest.”
In an editorial written by Howard (Jack) West, MD, of the City of Hope Comprehensive Cancer Center, it was suggested that when smaller clinical trials such as the current studythis produce warning signs of likely futility, those results should be strongly considered when determining whether to proceed to a phase 3 trial.2
“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,” West wrote in the editorial. “Phase 2 trials are conducted to identify which strategies demonstrate such clear promise that they merit being explored in phase 3 trials, which require vast investment, including the opportunity for patients to participate in research that has a meaningful probability of becoming a significant clinical advance.”
West concluded by stating: “Regardless, a phase 3 randomized clinical trial of osimertinib with or without bevacizumab (ClinicalTrials.gov Identifier: NCT04181060) is being conducted through ECOG-ACRIN, propelled by a presumption of benefit rather than an assessment of the clinical data available.”
1. Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of osimertinib plus vevacizumab vs osimertinib in patients with EGFR T790M–mutated non–small cell lung cancer previously treated with epidermal growth factor receptor–tyrosine kinase inhibitor. JAMA Oncol. Published online January 7, 2021. doi:10.1001/jamaoncol.2020.6758
2. West H. When the signal from phase 2 research should be a warning sign. JAMA Oncol. Published online January 7, 2021. doi:10.1001/jamaoncol.2020.6598