Bevacizumab-erlotinib combo falls short in EGFR-mutant advanced NSCLC

Addition of bevacizumab to erlotinib, the standard first-line therapy, failed to improve outcomes in patients with advanced epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC), according to a multicenter, phase 2, randomized, controlled trial.

“The development of erlotinib as a first-line therapy was an important advance, but there was interest in improving the efficacy of erlotinib,” noted the investigators, led by Thomas E. Stinchcombe, MD, of the Duke Cancer Institute in Durham, N.C. Preclinical data suggested that adding an antiangiogenic agent could overcome resistance, and subgroup analyses of a phase 3 trial hinted at greater efficacy of this combination in patients with EGFR-mutant disease (Lancet. 2011;377:1846-54).

The new trial was conducted among 88 patients with previously untreated stage 4 EGFR-mutant NSCLC eligible to receive bevacizumab. Two-thirds had an EGFR exon 19 deletion.

The patients were assigned evenly to receive erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor, either alone or in combination with bevacizumab (Avastin), an antibody directed against vascular endothelial growth factor.

Results reported in JAMA Oncology showed that, during a median follow-up of 33 months, median progression-free survival (PFS) – the trial’s primary endpoint – was 17.9 months with the combination and 13.5 months with erlotinib alone, a nonsignificant difference (hazard ratio, 0.81; P = .39).

There was also no significant difference between groups in objective response rate (81% vs. 83%; P = .81) and overall survival (median, 32.4 vs. 50.6 months; HR, 1.41; P = .33).

Relative to the erlotinib monotherapy group, the combination therapy group had higher rates of grade 3 or worse acneiform rash (26% vs. 16%), hypertension (40% vs. 20%), and proteinuria (12% vs. 0%), but a lower rate of grade 3 or worse diarrhea (9% vs. 13%).

“Our study, unlike previous randomized clinical trials, did not reveal a significant improvement in PFS with the combination of erlotinib and bevacizumab. ... One consideration is that our trial used investigator assessment of response and disease progression, whereas previous randomized trials used blinded independent radiologic review,” Dr. Stinchcombe and coinvestigators summarized.

“Future studies will investigate novel osimertinib [Tagrisso] combinations and molecular markers to identify patients most likely to experience disease progression with single-agent EGFR TKIs,” they concluded.

Dr. Stinchcombe reported no relevant conflicts of interest. The trial was supported by Genentech/Roche.

SOURCE: Stinchcombe TE et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1847.

Addition of bevacizumab to erlotinib, the standard first-line therapy, failed to improve outcomes in patients with advanced epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC), according to a multicenter, phase 2, randomized, controlled trial.

“The development of erlotinib as a first-line therapy was an important advance, but there was interest in improving the efficacy of erlotinib,” noted the investigators, led by Thomas E. Stinchcombe, MD, of the Duke Cancer Institute in Durham, N.C. Preclinical data suggested that adding an antiangiogenic agent could overcome resistance, and subgroup analyses of a phase 3 trial hinted at greater efficacy of this combination in patients with EGFR-mutant disease (Lancet. 2011;377:1846-54).

The new trial was conducted among 88 patients with previously untreated stage 4 EGFR-mutant NSCLC eligible to receive bevacizumab. Two-thirds had an EGFR exon 19 deletion.

The patients were assigned evenly to receive erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor, either alone or in combination with bevacizumab (Avastin), an antibody directed against vascular endothelial growth factor.

Results reported in JAMA Oncology showed that, during a median follow-up of 33 months, median progression-free survival (PFS) – the trial’s primary endpoint – was 17.9 months with the combination and 13.5 months with erlotinib alone, a nonsignificant difference (hazard ratio, 0.81; P = .39).

There was also no significant difference between groups in objective response rate (81% vs. 83%; P = .81) and overall survival (median, 32.4 vs. 50.6 months; HR, 1.41; P = .33).

Relative to the erlotinib monotherapy group, the combination therapy group had higher rates of grade 3 or worse acneiform rash (26% vs. 16%), hypertension (40% vs. 20%), and proteinuria (12% vs. 0%), but a lower rate of grade 3 or worse diarrhea (9% vs. 13%).

“Our study, unlike previous randomized clinical trials, did not reveal a significant improvement in PFS with the combination of erlotinib and bevacizumab. ... One consideration is that our trial used investigator assessment of response and disease progression, whereas previous randomized trials used blinded independent radiologic review,” Dr. Stinchcombe and coinvestigators summarized.

“Future studies will investigate novel osimertinib [Tagrisso] combinations and molecular markers to identify patients most likely to experience disease progression with single-agent EGFR TKIs,” they concluded.

Dr. Stinchcombe reported no relevant conflicts of interest. The trial was supported by Genentech/Roche.

SOURCE: Stinchcombe TE et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1847.

Addition of bevacizumab to erlotinib, the standard first-line therapy, failed to improve outcomes in patients with advanced epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC), according to a multicenter, phase 2, randomized, controlled trial.

“The development of erlotinib as a first-line therapy was an important advance, but there was interest in improving the efficacy of erlotinib,” noted the investigators, led by Thomas E. Stinchcombe, MD, of the Duke Cancer Institute in Durham, N.C. Preclinical data suggested that adding an antiangiogenic agent could overcome resistance, and subgroup analyses of a phase 3 trial hinted at greater efficacy of this combination in patients with EGFR-mutant disease (Lancet. 2011;377:1846-54).

The new trial was conducted among 88 patients with previously untreated stage 4 EGFR-mutant NSCLC eligible to receive bevacizumab. Two-thirds had an EGFR exon 19 deletion.

The patients were assigned evenly to receive erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor, either alone or in combination with bevacizumab (Avastin), an antibody directed against vascular endothelial growth factor.

Results reported in JAMA Oncology showed that, during a median follow-up of 33 months, median progression-free survival (PFS) – the trial’s primary endpoint – was 17.9 months with the combination and 13.5 months with erlotinib alone, a nonsignificant difference (hazard ratio, 0.81; P = .39).

There was also no significant difference between groups in objective response rate (81% vs. 83%; P = .81) and overall survival (median, 32.4 vs. 50.6 months; HR, 1.41; P = .33).

Relative to the erlotinib monotherapy group, the combination therapy group had higher rates of grade 3 or worse acneiform rash (26% vs. 16%), hypertension (40% vs. 20%), and proteinuria (12% vs. 0%), but a lower rate of grade 3 or worse diarrhea (9% vs. 13%).

“Our study, unlike previous randomized clinical trials, did not reveal a significant improvement in PFS with the combination of erlotinib and bevacizumab. ... One consideration is that our trial used investigator assessment of response and disease progression, whereas previous randomized trials used blinded independent radiologic review,” Dr. Stinchcombe and coinvestigators summarized.

“Future studies will investigate novel osimertinib [Tagrisso] combinations and molecular markers to identify patients most likely to experience disease progression with single-agent EGFR TKIs,” they concluded.

Dr. Stinchcombe reported no relevant conflicts of interest. The trial was supported by Genentech/Roche.

SOURCE: Stinchcombe TE et al. JAMA Oncol. 2019 Aug 8. doi: 10.1001/jamaoncol.2019.1847.