Osimertinib/Bevacizumab Improves ORR, But Fails to Prolong PFS in EGFR T790M+ NSCLC

Hiroaki Akamatsu, MD, PhD

The combination of osimertinib (Tagrisso) plus bevacizumab (Avastin) failed to result in a statistically significant improvement in progression-free survival (PFS) versus osimertinib alone in patients with advanced lung adenocarcinoma that harbored an EGFR T790M mutation, according to findings from a phase 2 trial published in JAMA Oncology.

Results showed that the doublet elicited a higher overall response rate (ORR) than the monotherapy, at 71.8% versus 55.0%, respectively; however, this benefit with osimertinib/bevacizumab failed to translate to a significant PFS benefit over osimertinib alone, at 13.5 months versus 9.4 months, respectively (adjusted HR, 1.44; 80% CI, 1.00-2.08 and 95% CI, 0.83-2.52, respectively; P = .20).

“To our knowledge, this is the first randomized clinical trial to explore the efficacy of adding [an] anti-VEGF inhibitor to osimertinib,” Hiroaki Akamatsu, MD, PhD, Internal Medicine III, of the Wakayama Medical University, and colleagues, wrote in the paper. “Although ORR was slightly better in the combination arm, we could not show advantages in PFS and overall survival [OS].”

In the open-label, multi-institutional study, investigators set out to evaluate whether osimertinib/bevacizumab would be synergistic and tolerable in patients with advanced NSCLC that harbored an EGFR T790M mutation. The trial included a lead-in portion to evaluate the feasibility of the doublet and a randomized phase 2 portion. 

To be eligible for enrollment, patients had to have pathologically confirmed lung adenocarcinoma with an EGFR sensitizing mutation; a diagnosis of stage IIIB or IV per the seventh version of the American Joint Committee on Cancer staging criteria for lung cancer or have relapsed as metastatic disease following curative treatment; have received prior treatment with a first- or second-generation EGFR TKI and have confirmed radiological progression; or have cancer with a confirmed EGFR exon 20 T790M mutation following treatment with an EGFR TKI. Patients also needed to have an ECOG performance status of 0-1, measurable disease per RECIST v1.1 criteria, and acceptable organ function

If they had interstitial lung disease at the time of trial registration, an increased risk of bleeding or embolism, uncontrolled hypertension, leptomeningeal disease, or be positive for hepatitis B virus antigen, they could not participate. Notably, patients with brain metastases were permitted if they were not symptomatic at the time of registration.

In the lead-in portion of the trial, 6 participants were administered osimertinib at a fixed dose of 80 mg per day and intravenous (IV) bevacizumab at a dose of 15 mg/kg every 3 weeks. If more than 2 participants in this group reported dose-limiting toxicities within the first cycle of treatment, the study would have been terminated. 

After feasibility of the combination regimen was confirmed, the phase 2 portion of the trial was launched. The median age of participants in part 2 was 69 years; 40.5% of patients were male, while 59.5% were female. Moreover, 51% of patients were never-smokers and 54% of patients had an ECOG performance status of 1. Across the investigative and control arms, most patients had stage IV disease (83% vs 63%, respectively), followed by recurrent disease (12% vs 32%), and IIIB disease (5% in both).

Thirty-six percent of patients in the doublet arm received a previous first-generation TKI versus 35% in the monotherapy arm; 10% versus 11% of patients, respectively, received a second-generation TKI. Additionally, 75% versus 83% of patients in the osimertinib/bevacizumab arm and osimertinib-alone arms, respectively, did not receive any prior cytotoxic chemotherapy; 25% versus 17%, respectively, received 1 or more of these treatments. Twenty percent of patients on the investigative arm received previous treatment with a VEGF inhibitor versus 10% of those on the control arm, and 30% versus 22%, respectively, had brain metastases.

Participants were stratified based on sex (male vs female), number of previous cytotoxic chemotherapy treatments (0 vs 1 or more), and institution. All participants received oral osimertinib at a daily dose of 80 mg. Those who had been included in the lead-in portion of the trial or were allocated to the doublet group in the phase 2 portion of the research, received IV bevacizumab at a dose of 15 mg/kg on day 1, every 3 weeks. 

Treatment was continued until progressive disease; however, if it was determined to be clinically beneficial, patients had the option to continue treatment following radiological progression. Moreover, if toxic effects were experienced with osimertinib, patients were able to suspend treatment and then continue at a daily dose of 40 mg; with bevacizumab, they resumed at the same dose.

The primary end point of the trial was PFS per investigator assessment, and key secondary end points comprised ORR, time to treatment failure (TTF), OS, and safety.

Additional insight indicated that prior VEGF inhibition had an unfavorable effect on the efficacy of the doublet. Specifically, patients who had previously received a VEGF inhibitor experienced significantly shorter PFS versus those who did not, at 4.6 months versus 11.1 months, respectively (HR, 0.41; 95% CI, 0.13-1.27; P = .03). Notably, previous VEGF inhibition did not impact PFS in those who received osimertinib alone, at 15.1 months versus 13.7 months, respectively (HR, 1.19; 95% CI, 0.31-4.61; P = .85).

Moreover, the TTF proved to be longer in the monotherapy arm versus the doublet arm, at 11.2 months versus 8.4 months (adjusted HR, 1.54; 95% CI, 0.90-2.69; P = .12). No significant difference with regard to median OS was observed, at 22.1 months with single-agent osimertinib versus not reached with osimertinib/bevacizumab (adjusted HR, 1.02; 95% CI, 0.43-2.44; P = .96).

Regarding safety, most toxicities were grade 1 or 2 in severity. The most commonly reported toxicities in the doublet arm included proteinuria (grade 1/2, 55%; grade 3, 23%) and hypertension (grade 1/2, 40%; grade 3 or higher, 20%). Rates of proteinuria and hypertension were noted to be significantly more frequent with the combination, while the incidence of anemia (66%) was found to be significantly higher with osimertinib alone.

Thirty-three percent of patients who received osimertinib needed dose interruptions; however, the proportion of those who required this proved to be comparable between the treatment arms, with 13 in the monotherapy arm and 14 in the doublet arm. A total of 55 patients discontinued treatment; 37 stopped because of progressive disease and 15 stopped because of adverse effects. In the doublet arm, 28% stopped bevacizumab because of toxicities.

Reference

1. Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of osimertinib plus bevacizumab 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