Adjuvant Bevacizumab Does Not Improve Survival in NSCLC

Roxanne Nelson

September 11, 2015

DENVER – The addition of bevacizumab (Avastin, Genentech/Roche) to adjuvant chemotherapy does not improve outcomes for patients with resected early-stage non–small cell lung cancer (NSCLC), according to findings presented here at the 16th World Conference on Lung Cancer (WCLC).

The researchers of the 1501-patient randomized phase 3 trial found that the addition of bevacizumab failed to improve either overall or disease-free survival.

"Unfortunately, the overall survival was not different in the two arms," said lead investigator Heather Wakelee, MD, associate professor of medicine (oncology) at the Stanford University Medical Center in California, who presented the study findings. "The hazard ratio was 0.99, and the curves did not separate."

"The same was true for disease free survival," she added. "There was absolutely no difference."

The results come from an interim analysis, which had a median follow-up time of 41 months.

This is not the end of the story. Dr Heather Wakelee

But even though this is a seemingly negative study, "this is not the end of the story," Dr Wakelee pointed out.

"There are many subset analyses that need to be done, as well as a significant amount of correlative work," she explained. To that end, "all patients enrolled in the trial had tissue submitted, and underwent timepoint blood draws."

Toxicities Higher With Bevacizumab

The study involved patients with NSCLC treated from 2007 to 2013. Six to 12 weeks after surgery, they were stratified by chemotherapy regimen, stage, histology, and sex.

The median age of the cohort was 61 years. Disease was stage IB in 26.2% of the patients, stage II in 43.8%, and stage IIIA in 30.0%, and 28.2% had squamous cell histology.

All patients received adjuvant chemotherapy that consisted of a four planned 3-week cycles of cisplatin at 75 mg/m2 plus either vinorelbine, docetaxel, gemcitabine, or pemetrexed. None of the patients received postoperative radiation therapy.

Half the patients also received bevacizumab 15 mg/kg every 3 weeks starting with the first cycle of chemotherapy and continuing for 1 year. The other half served as the control group.

The completion of per protocol treatment was lower in the bevacizumab group than in the control group (80% vs 36%).

"The rationale for this is that adjuvant cisplatin chemotherapy for resected early-stage NSCLC has been shown to have a modest survival benefit," Dr Wakelee explained. "We used the most common chemotherapy regimens in this study."

In addition, she noted, bevacizumab has been shown to improve outcomes when added to platinum-based chemotherapy in advanced-stage nonsquamous NSCLC.

Bevacizumab added no unexpected toxicities, but there was a significant increase in neutropenia and hypertension. Grade 3 to 5 toxicities that were significantly higher in the bevacizumab than in the control group included overall worst grade (84% vs 67%), hypertension (30% vs 8%), and neutropenia (38% vs 33%). There was no significant difference in the rate of grade 5 adverse events between the bevacizumab and control groups (3% vs 2%).

The End of Adjuvant Studies?

Even though the results were essentially negative, "overall survival and disease-free survival are not the only things we can learn from this trial," said Paul Bunn, Jr, MD, distinguished professor from the division of medical oncology at the University of Colorado, Denver.

There are many questions that need to be investigated, he pointed out. For example, was there a difference in any of the chemotherapy doublets in efficacy or toxicity outcome when bevacizumab was present or absent? Also, what biomarker is being used and what correlative studies are being done to assess the benefit of bevacizumab?

How much will be relevant in 10 years that is relevant now?

Dr Bunn questioned whether trial design "is where we should be putting our money and effort."

And because "adjuvant trials take so long and use so many resources," he asked whether "we should abandon trials without good biomarkers and more robust evidence for complete responses and survival prolongation?

In addition, he said, "rather than looking at this type of trial, should we be taking a look at what our breast cancer colleagues are doing and focus on neoadjuvant trials to hasten drug development and achieve pathologic complete response?"

The ECOG-ACRIN cancer research group is supported primarily through research grant funding from the National Cancer Institute. Dr Wakelee and Dr Bunn report financial relationships with several pharmaceutical companies.

16th World Conference on Lung Cancer (WCLC): Abstract plen04.03. Presented September 9, 2015.


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