—PFS but not OS improved by angiogenesis inhibitor April 26, 2017
Action Points
.Note that this phase III randomized trial of bevacizumab for extensive-disease small-cell lung cancer (ED-SCLC) showed the anti-angiogenic agent improved progression-free survival (PFS), but not overall survival (OS). .Be aware that the study had relatively low power to detect more subtle beneficial effects in terms of OS.
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Adding the angiogenesis inhibitor bevacizumab (Avastin) to cisplatin and etoposide to treat extensive-disease small-cell lung cancer (ED-SCLC) did not increase overall survival (OS) significantly, according to a 29-center phase III trial reported in the Journal of Clinical Oncology.
At a median follow-up of 34.9 months, survival was similar with or without bevacizumab -- median OS of 9.8 months versus 8.9 months, and 1-year survival rate of 37% versus 27% (HR 0.78; 95% CI 0.58-1.06; P=0.113) -- according to Marcello Tiseo, MD, PhD, of the Medical Oncology Unit at the University Hospital of Parma, Italy, and colleagues. Adding bevacizumab, though, did extend median progression-free survival (PFS) significantly -- from 5.7 months to 6.7 months (HR 0.72; 95% CI 0.54-0.97; P=0.030).
"Recently, there was a glimmer of hope that, perhaps, the antiangiogenic approach, which has allowed a significant step forward in other malignancies, would lead to an improved outcome in patients with SCLC," the Tiseo team wrote. "To our knowledge, this is the first randomized, prospective comparative phase III study assessing the role of adding bevacizumab to standard platinum plus etoposide chemotherapy on survival outcome in the first-line treatment of ED-SCLC."
The researchers studied 204 treatment-naive ED-SCLC patients at 29 centers throughout Italy from November 16, 2009 to October 1, 2015. Approximately half of the participants were randomly assigned to receive cisplatin and etoposide alone; others received cisplatin and etoposide with bevacizumab, for a maximum of six cycles. Bevacizumab patients whose disease did not progress continued with bevacizumab alone as maintenance therapy for a maximum of 12 more courses.
Participants consisted primarily of men (68%) with a median age of 64. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a life expectancy greater than 12 weeks. The research team followed participants for a median duration of 34.9 months.
The primary endpoint of the study was OS, with secondary endpoints of response rate, toxicity, and PFS. The researchers found that neither OS, nor response rate, nor toxicity differed significantly between the groups, although the bevacizumab patients had higher PFS rates. Subgroup analyses suggested that bevacizumab benefitted men and patients over the age of 65 the most, and possibly was detrimental in women. Men had an OS HR of 0.55, compared with 1.55 for women (P=.003). Patients over 65 had an OS HR of 0.55, compared with 0.99 for those 65 and younger (P=.058).
These results are similar to previous studies, including the Study of Bevacizumab in Previously Untreated Extensive-Stage Small Cell Lung Cancer (SALUTE) phase II trial, which also showed improvement in PFS but not OS, and two trials that looked at other antiangiogenic agents: the Canadian BR.20 study and the Cancer and Leukemia Group B (CALGB) 30504 trial.
In an accompanying editorial, Joel Neal, MD, PhD, and Heather Wakelee, MD, both of Stanford University, attempted to unravel why this study failed to meet its primary endpoint. They considered several factors, including the bevacizumab dose tested -- 7.5 mg/kg, which is lower than the FDA-approved dose of 15 mg/kg for non-small cell lung cancer (NSCLC) -- and the study design.
Neal and Wakelee observed that the Tiseo team powered their study for a target improvement in the 1-year survival rate from 40% to 58%, corresponding to a median survival improvement from 9 months to 15 months (HR of 0.6), which might have been too ambitious.
"We feel that an HR of 0.75, corresponding to a more modest target median survival improvement from 9 months to 12 months, would still have been clinically meaningful and more in line with expectation from results in other trials in SCLC and other malignancies," they wrote. They added that this target HR might not have been practical, though, not just because of the huge increase in sample size needed, but because the investigators believed that, given the added toxicity and cost of bevacizumab, only a higher survival rate would have changed treatment practices in Italy.
The Tiseo group also presented a landmark analysis of all patients who completed platinum-based therapy and found that those treated with maintenance bevacizumab had significantly better survival outcomes (HR 0.60; 95% CI, 0.40 to 0.91, P=0.11). This might have been due to selection bias since only patients whose disease did not progress received maintenance therapy, which the authors tried to limit through statistical analysis.
Neal and Wakelee said that findings might indicate that antiangiogenic treatment needs to be extended, perhaps even past the point of radiographic progression. Such a continuation approach was beneficial in observational studies of colorectal cancer, the editorial noted, and currently is being addressed in another trial of bevacizumab in NSCLC.
The study was supported by the Argenzia Italiana del Farmaco.
Tiseo disclosed relationships with AstraZeneca, Eli Lilly, Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Pierre Fabre, and Otsuka. One or more coauthors disclosed relationships with Amgen, Roche, Pfizer, AstraZeneca, Pierre Fabre, Genentech, Eli Lilly, Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, and GlaxoSmithKline, as well as patent interests.
Neal disclosed relationships with Clovis Oncology, CARET, Nektar, Boehringer Ingelheim, ARMO BioSciences, ARIAD, Eli Lilly, Genentech, Merck, ArQule, Novartis, and Exelixis. Wakelee disclosed relationships with Peregrine Pharmaceuticals, ACEA Biosciences, Helsinn Therapeutics, Pfizer, Genentech, Pfizer, Eli Lilly, Celgene, AstraZeneca/MedImmune, Exelixis, Novartis, Regeneron, Clovis Oncology, Xcovery, Bristol-Myers Squibb, Agennix, Gilead Sciences, Pharmacyclics, Clovis Oncology, Novartis, and ACEA Biosciences.
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