Drug Combo Disappoints as Second-line Therapy for Advanced NSCLC With EGFR and T790M Mutations

Sharon Worcester

May 24, 2021

Adding bevacizumab (Avastin) to second-line osimertinib (Tagrisso) provided no overall benefit vs osimertinib alone for advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) and T790M mutations in the randomized, open-label, phase 2 European Thoracic Oncology Platform (ETOP) BOOSTER trial.

The combination treatment did, however, show superiority over osimertinib alone in current and former smokers in the study, say the investigators.

"The use of osimertinib and bevacizumab was associated with longer progression-free survival in the subgroup of patients who were former or current smokers (hazard ratio, 0.57)," Ross Soo, MD, reported during a European Society of Medical Oncology virtual plenary session.

The findings were also published May 12 in Annals of Oncology.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) with selective activity toward EGFR-sensitizing and T790M resistance mutations, is the standard treatment in this patient population, but progression inevitably occurs.

Based on preclinical studies suggesting that the angiogenic pathway is implicated in EGFR TKI resistance, the current study was designed to assess the efficacy and safety of combined osimertinib and the anti-angiogenic agent bevacizumab vs osimertinib alone in patients who progressed on prior EGFR TKI therapy, explained Soo, a senior consultant in the Department of Hematology-Oncology at the National University Cancer Institute, Singapore.

Median overall progression-free survival (PFS) at a median follow-up of 34 months was 15.4 months vs 12.3 months in 78 patients in the bevacizumab/osimertinib combination therapy group and 77 patients in the osimertinib monotherapy group, respectively — which translated into a nonstatistically significant difference (HR, 0.96).

In the current and former smoker subgroup, median PFS was 16.5 months and 8.4 months with combination vs monotherapy, respectively (HR, .57), Soo said.

An exploratory analysis showed that the effect of the combination therapy was statistically different in current/former smokers vs never-smokers (HR, 0.52 and 1.47, respectively), he noted.

For the secondary study endpoint of overall survival (OS), no significant difference was seen overall with the combination vs monotherapy (24.0 vs 24.3 months; HR, 1.03) or the current or former smoker subgroup (HR, 0.54).

However, in the current and former smoker subgroup, the effect of the treatment combination "was in the same direction and similar in magnitude to progression-free survival, but did not reach statistical significance," Soo noted.

The exploratory analysis showed OS hazard ratios of 0.59 and 1.54 in the current/former smokers vs never-smokers, respectively.

Smoking Data May Be Important

Study participants were adults with a median age of 67 years who had exon 19 del or L858R and T790M mutation at progression on prior EGFR TKI therapy. Most (62%) were women and 40% were current or former smokers. They were enrolled between 2017 and 2019 from 22 centers in 6 countries and randomly assigned to receive bevacizumab at a dose of 15 mg/kg intravenously on day 1 every 3 weeks plus osimertinib at 80 mg daily or osimertinib alone.

The median time to treatment failure (TTF) was 8.2 months in the combination therapy, (with TTF of 8.2 months for bevacizumab and 12.4 for osimertinib), compared with 10.8 months for osimertinib monotherapy.

Overall response was 55% in both groups, and disease control rates were 90% and 82% in the groups, respectively. Median duration of response was 14.5 months vs 16.6 months, Soo said.

Grade 3 or greater treatment-related adverse events occurred in 47% and 18% of patients in the combination and monotherapy groups. The most frequent adverse event in both groups was diarrhea. Proteinuria and hypertension occurred more often in the combination therapy group.

Based on these findings, osimertinib remains the standard of care in patients with advanced NSCLC with acquired EGFR TKI resistance harboring EGFR T790M mutations, he concluded.

The findings are in line with those from prior smaller studies, and are "hypothesis generating," said invited discussant Edward B. Garon, MD, professor and director of the thoracic oncology program at the David Geffen School Of Medicine, UCLA Santa Monica Medical Center, California.

The new data are hypothesis generating and will help in analyzing other studies to determine whether there is a difference based on smoking history, he said. 

Garon also noted that there has been increasing interest in similar combination approaches in the frontline setting, but to date there is little to support frontline use, he said.

"It is certainly a situation where there is room for studies exploring other approaches in the frontline setting," he concluded.

This study was supported by Astra Zeneca and Roche. Soo reported financial relationships (advisory board membership, research grants) with Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Otsuka, Pfizer, Roche, Synthorx, Taiho, Takeda, and Yuhan. Garon reported relationships (consulting/advising and/or grant/research support) with ABL-Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, Dynavax Technologies, Eli Lilly, EMD Serono, Eisai, Genentech, GlaxoSmithKline, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Natera, Neon, Novartis, Regeneron, Sanofi, Shionogi, and Xilio.

Ann Int Med. Published online May 12, 2021. Abstract  

European Society for Medical Oncology Virtual Plenary: Abstract VP3-2021. Presented May 12, 2021.

Sharon Worcester is a reporter for MDedge News, part of the Medscape Professional Network.

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