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Advanced NSCLC: Phase IV Trial Finds Combined Bevacizumab & Standard Chemo Safe, Relieving Earlier Concerns

Lindsey, Heather

doi: 10.1097/01.COT.0000388582.61725.85
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NSCLC

NSCLC

The combination of first-line bevacizumab and standard chemotherapy is safe in patients with advanced non-squamous non-small-cell lung cancer (NSCLC), according to the Phase IV SAiL (Safety of Avastin in Lung)study, published in the August issue of Lancet Oncology (2010;11:733-740).

There had been concerns from the results of previous trials about bleeding, thrombotic events, and hypertension, explained the SAiL study's lead author, Lucio Crinò, MD, Professor of Oncology at Hospital Santa Maria della Misericordia, in Perugia, Italy. “However, safety results from SAiL were able to overcome these concerns.”

Asked for his opinion, OT Clinical Advisory Editor for Oncology and lung cancer specialist Ramaswamy Govindan, MD, Professor of Medicine in the Division of Oncology at Washington University School of Medicine in St. Louis, commented, “This large Phase IV study with over 2,000 patients was reassuring because no new safety concerns were found when bevacizumab was used in conjunction with chemotherapy in the setting of advanced non-small cell lung cancer.”

While previous randomized Phase II and III trials assessed carefully selected patient populations, SAiL included a broader range of individuals seen in everyday clinical practice, including those over age 65 with a performance status of 2 and who were receiving concomitant treatment, Dr. Crinò noted.

Dr. Govindan explained that when a drug is applied to a broader population, the side effects profile can be a little different than those seen in Phase II and III trials.

The author of an accompanying editorial, Robert Pirker, MD, Professor in the Department of Medicine I at Medical University of Vienna, predicted that the study will likely have an impact on practice for clinicians who have been worried about the safety of bevacizumab—”It might enhance clinical use of the agent,” he said.

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Study Data

The open-label, single-group study was conducted between August 2006 and June 2008, with an intent-to-treat population of 2,212 patients with advanced or recurrent non-squamous NSCLC from 40 countries across six continents.

Patients received 7.5 or 15.0 mg/kg of bevacizumab every three weeks, plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The most common types of chemotherapy used were carboplatin doublets, cisplatin doublets, and taxane-containing regimens. Overall, 38% of patients reported serious adverse events of any grade, with the most common being thromboembolic events in 6% of patients, bleeding in 4%, and gastrointestinal perforation in 1%.

There were few clinically signicant Grade 3 or higher adverse events--specifically, the incidence of thromboembolism was 8%, while hypertension was 6%, bleeding was 4%, proteinuria was 3%, and pulmonary hemorrhage was 1%.

“It was very reassuring that the rate of major bleeding from the lung was low,” said Dr. Govindan. “We've learned over the past several years that when you select the right patients, bevacizumab in combination with chemotherapy is reasonably safe.”

Three percent of patients died because of adverse events, with thromboembolism and bleeding being the most common causes.

LUCIO CRINÒ, MD: Our results confirm the manageable safety profile of first-line bevacizumab I combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC

LUCIO CRINÒ, MD: Our results confirm the manageable safety profile of first-line bevacizumab I combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC

Thirteen percent of patients experienced a serious adverse event that was associated with bevacizumab. The most common Grade 3 or higher serious adverse events that the investigators judged to be associated with the agent were pulmonary embolism in 28 patients and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis, all of which occurred in 13 patients.

RAMASWAMY GOVINDAN, MD: “It was very reassuring that the rate of major bleeding from the lung was low

RAMASWAMY GOVINDAN, MD: “It was very reassuring that the rate of major bleeding from the lung was low

Additionally, of the 281 patients who were assessed as having central nervous system metastases, only 2% experienced CNS bleeding. “There is concern about the possibility of brain bleeding, but this was clearly not the case in the SAiL study,” Dr. Crinò said.

Incidences of adverse events were similar across the various chemotherapies used. However, patients who received carboplatin doublets experienced fewer adverse events of Grade 3 or higher than patients on other chemotherapy regimens did.

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Efficacy a Secondary Endpoint

Efficacy was a secondary endpoint in this study, and 2,211 patients were available for analysis. The median overall survival of patients taking bevacizumab combined with chemotherapy was 14.6 months. SAiL confirmed the median overall survival found in patients with adenocarcinoma in the E4599 trial of 14.2 months, Dr. Crinò noted. Median time to disease progression was 7.8 months.

Dr. Govindan said that the overall survival data from the study was informative because it reflected the approximately year-long survival typically seen these days in practice.

In patients with post-baseline disease assessment (2,036 patients) the disease control rate was 89% and the objective response rate was 52%.

“A minority of patients progressed during study,” said Dr. Crinò. “However, assessment of disease control was weakened because it was a subjective endpoint.” Specifically, according to the paper, there were no uniform assessments of tumor control; they were done according to treating physicians' clinical practices.

“We should be very careful not to over-read the efficacy data, particularly response rates and progression-free survival, as the entry criteria in a Phase IV study like this are looser than those in a typical Phase III clinical trial,” said Dr. Govindan. Typically in these type of studies, response assessments are left to the discretion of treating physicians, including the type of imaging and frequency of assessment, and the radiological studies are not independently verified, he explained.

Dr. Pirker agreed that since this was a single-group study it did not resolve questions about effectiveness—“There's still the issue of how to optimize efficacy. Ideally, clinicians should be able to enhance efficacy of the best available chemotherapy, such as a cisplatin-based protocol, with bevacizumab.”

ROBERT PIRKER, MD, who wrote an accompanying editorial, noted that as a single-group study, SAiL did not resolve questions about effectiveness: “There's still the issue of how to optimize efficacy

ROBERT PIRKER, MD, who wrote an accompanying editorial, noted that as a single-group study, SAiL did not resolve questions about effectiveness: “There's still the issue of how to optimize efficacy

Randomized trials are needed to address such issues, he continued. For example, one randomized, Phase III trial conducted by the Eastern Cooperative Oncology Group (NEJM 2006;355:2542-2550) showed a survival benefit for bevacizumab in addition to paclitaxel plus carboplatin in the treatment of selected patients with NSCLC.

Another randomized Phase III trial, AVAiL, found that patients treated with cisplatin plus gemcitabine had an improvement in progression-free survival without increasing overall survival (Ann Oncol 2010 Feb 11. Epub ahead of print). However, this trial was not adequately powered, Dr. Pirker noted in his editorial.

“The ultimate proof of efficacy will be whether adjuvant chemotherapy and bevacizumab improves the cure rate in patients with resected NSCLC,” he said, referring to the ongoing NCT00324805 trial. “If this regimen works then it will be a major breakthrough.”

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Additional Research

Generally, the oncology community should “encourage development of Phase IV studies such as this or prospective registries to learn more about side effects of newly approved drugs in larger populations,” said Ramaswamy Govindan, MD.

Lucio Crinò, MD, added that also needing to be evaluated is whether prophylactic medications should be given to reduce thrombotic events associated with bevacizumab in combination with chemotherapy. Additionally, Robert Pirker, MD, said, a study indicating that bevacizumab and chemotherapy result in cancer-related symptom improvement would also be beneficial, as well as more research to determine what biomarkers can help clinicians determine who will benefit the most from bevacizumab, he said.

Active research to identify patients who are most likely to benefit from drugs such as bevacizumab using novel imaging and tumor and peripheral blood is ongoing, noted Dr. Govindan.

© 2010 Lippincott Williams & Wilkins, Inc.
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