For the second-line treatment of advanced EGFR T790M–mutated non–small cell lung cancer (NSCLC), the performance of osimertinib alone was not found to be different from that of osimertinib plus bevacizumab in the phase II ETOP 10-16 BOOSTER trial, reported at a European Society for Medical Oncology (ESMO) Virtual Plenary presentation.1 However, patients with a history of smoking appeared to derive some benefit from the addition of bevacizumab, according to the investigators.
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) irreversible tyrosine kinase inhibitor with selective activity toward EGFR-sensitizing and T790M resistance mutations and wild-type EGFR sparing. Although it is currently the preferred standard front-line agent in patients with advanced disease, it was initially developed and approved only for patients who developed an EGFR T790M mutation as a mechanism of resistance at the moment of disease progression. Preclinical studies have suggested that the angiogenic pathway may be implicated in tyrosine kinase inhibitor resistance, and therefore bevacizumab might be a good partner, said Ross A. Soo, MD, Senior Consultant in Oncology at the National University Hospital in Singapore, who presented the findings.
Ross A. Soo, MD
Pilar Garrido, MD, PhD
Although the concept may be sound, the BOOSTER trial found no difference in progression-free survival between osimertinib/bevacizumab or osimertinib alone, reported Dr. Soo. “Osimertinib remains the standard of care in patients with acquired EGFR tyrosine kinase inhibitor resistance harboring EGFR T790M mutations,” he said.
Rationale for This Combination
Moderator of the session, Pilar Garrido, MD, PhD, introduced the presentation by elaborating on the strong biologic rationale for this study. Dr. Garrido is Associate Professor of Medical Oncology at Universidad de Alcalá and Head of the Thoracic Tumours Section in the Medical Oncology Department at the University Hospital Ramón y Cajal, Madrid.
Targeting both the EGFR pathway, such as with osimertinib, and the vascular endothelial growth factor (VEGF) pathway, such as with bevacizumab, makes sense because they are two clinically validated targets in NSCLC, she said. “In EGFR-mutant NSCLC, upregulated EGFR signaling increases VEGF through hypoxia-independent mechanisms. We also know that elevated VEGF contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors,” she explained.
“This strategy is clinically proven, at least when combining bevacizumab or ramucirumab with first-generation EGFR tyrosine kinase inhibitors,” Dr. Garrido continued. “Based on this, it’s relevant to explore the role of adding a VEGF inhibitor to osimertinib, also upon resistance to EGFR tyrosine kinase inhibitors, with the aim of delaying disease progression. That is the aim of the BOOSTER trial.”
About the Phase II BOOSTER Trial
The ETOP 10-16 BOOSTER trial is an open-label randomized phase II study of 155 patients from 6 countries with stage IIIB to IV NSCLC with EGFR-sensitizing and T790M mutations who had experienced disease progression following therapy with one prior EGFR tyrosine kinase inhibitor. Their median age was 67, 62% were female, and 40% were current or former smokers.
Osimertinib remains the standard of care in patients with acquired EGFR tyrosine kinase inhibitor resistance harboring EGFR T790M mutations.— Ross A. Soo, MD
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Patients were randomly assigned to receive osimertinib at 80 mg/d and bevacizumab at 15 mg/kg every 3 weeks or osimertinib alone, until disease progression. The primary endpoint was investigator-assessed progression-free survival.
No Differences in Outcomes
At a median follow-up of 34 months, median progression-free survival was 15.4 months with osimertinib/bevacizumab vs 12.3 months with osimertinib alone (hazard ratio [HR] = 0.96; P = .84). The progression-free survival rates were 60.3% and 50.8%, respectively, at 12 months and 22.1% and 24.2% at 24 months.
Median overall survival was 24.0 months with the combination and 24.3 months with osimertinib alone (HR = 1.03; P = .91). Overall survival rates were similar between the arms: 77.5% vs 72.1% at 12 months and 50.4% and 54.7%, respectively, at 24 months, Dr. Soo reported.
Responses were seen in 55% of each arm. For the combination vs single-agent arms, the disease control rate was 90% and 82%, respectively, and the median duration of response was 14.5 months and 16.6 months.
Some Benefit in Smokers
Smoking history exhibited a significant treatment interaction with outcomes. “The effect of osimertinib and bevacizumab on progression-free survival was significantly different between smokers and nonsmokers, as shown by the interaction test,” stated Dr. Soo.
In the subgroup of patients who were current or former smokers, the combination yielded significantly longer progression-free survival (HR = 0.52), with a median of 16.5 months for osimertinib and bevacizumab vs 8.4 months for osimertinib alone, whereas nonsmokers had no apparent benefit (HR = 1.47; interaction P = .0052).
For overall survival, the effect of the combination vs single agent was also significantly different between smokers and nonsmokers (interaction P = .029), “in the same direction and similar in magnitude with the observed effect on progression-free survival” (HR = 0.59 for smokers and 1.54 for nonsmokers). The statistically significant interaction indicates that the effect of the combination vs osimertinib alone in smokers was significantly different from the effect in nonsmokers. However, explained Dr. Soo, within smokers, this effect on overall survival did not reach statistical significance, as it did for progression-free survival. This could be due to the smaller number of deaths than progression-free survival events observed so far.
No differences in progression-free or overall survival were observed between the arms according to other subgroups. The combination was not favored in either of the key EGFR-mutation subsets, exon 19 deletion or exon 21 L858R (progression-free survival HR = 0.98 and 0.85, respectively). The median time to treatment failure was significantly shorter in the combination arm, 8.2 months vs 12.4 months with osimertinib.
Treatment-related adverse events grade ≥ 3 were observed in 47% of the combination arm and 18% of the single-agent arm; those leading to treatment discontinuation occurred in 25% and 4%, respectively. No treatment-related deaths were reported, but 3 of 77 patients on osimertinib alone died on treatment, related to hepatic failure, lung infection, and pneumonitis.
DISCLOSURE: Dr. Soo has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, Novartis, Pfizer, Roche/Genentech, Takeda, and Yuhan; has served as a consultant or advisor to Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, Novartis, Pfizer, Roche/Genentech, Taiho Pharmaceutical, Takeda, and Yuhan; and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Garrido has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen Oncology, Lilly, MSD Oncology, Novartis/Pfizer, Pfizer, Roche Pharma AG, and Takeda; has an immediate family member who has served as a consultant or advisor to Boehringer Ingelheim, Gebro, Janssen Biotech, and Nordic Group; has participated in a speakers bureau for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen Oncology, MSD Oncology, Novartis, Pfizer, Roche Pharma AG, and Takeda; has an immediate family member who has participated in a speakers bureau for Boehringer Ingelheim, Janssen, and Nordic Group; has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Bristol Myers Squibb, and Roche; and has held other relationships with Janssen Oncology and Novartis.
1. Soo R, Han JY, Dimopoulou G, et al: A randomized phase II study of second-line osimertinib and bevacizumab versus osimertinib in advanced non–small cell lung cancer with epidermal growth factor receptor and T789M mutations: Results from the ETOP BOOSTER trial. ESMO Virtual Plenary. Abstract VP3-2021. Presented May 12, 2021.
Invited discussant of the BOOSTER trial,1 Edward B. Garon, MD, MS, Professor of Medicine and Director of the Thoracic Oncology Program, David Geffen School of Medicine at the University of California Los Angeles, said the study’s research question is appropriate, since osimertinib was established...