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ASCO Annual Meeting Spotlight
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Sunday, June 22, 2014
ONLINE FIRST: Advanced NSCLC: Modest Survival Gain with Use of Ramucirumab

By Robert H. Carlson

 

Chicago -- For the first time in a decade, overall survival has improved with a new treatment in second-line therapy for patients with stage IV advanced non-small cell lung cancer.

 

But not by very much.


In the Phase III REVEL trial of the antiangiogenic ramucirumab presented here at the American Society of Clinical Oncology Annual Meeting, median overall survival was 10.5 months for patients receiving ramucirumab plus docetaxel versus 9.1 months for those treated with placebo plus docetaxel (Abstract LBA8006).

 

“This is a positive result, the study made its endpoint, but it’s a modest absolute difference,” said ASCO 2013-1014 President Clifford A. Hudis, MD. “This might not be practice changing, but it is another bit of evidence that there is something in the antiangiogenic world that needs to be better understood. We need to pull out those patients who have tumors that are responsive.”

 

The researcher who presented the study, Maurice Pérol, MD, Head of Thoracic Oncology at Cancer Research Center of Lyon in France, explained that patients entered the trial if they had disease relapse after one treatment with platinum-based chemotherapy. The survival improvement, although small, is significant because patients with advanced NSCLC typically have a very short survival time following second-line therapy, he said.

 

“This is the first treatment in approximately a decade to improve the outcome of patients in the second-line setting,” he said, citing the introduction of pemetrexed in 2004 and erlotinib in 2005.

 

Ramucirumab is currently approved in the U.S. only for advanced gastric cancer treatment.

 

In the study, which was supported by ImClone and which was included in an ASCO news briefing that highlighted new targeted therapies showing key advances for common, hard-to-treat cancers, 1,253 patients with stage IV NSCLC -- 26 percent with the squamous subtype -- who had disease progression after standard platinum-based therapy were randomly assigned to treatment with ramucirumab plus docetaxel or placebo plus docetaxel.

 

The overall response rate was 22.9 percent in the ramucirumab arm versus 13.6 percent for placebo. Median overall and progression-free survival times were 10.5 and 4.5 months in the ramucirumab/docetaxel arm versus 9.1 and 3.0 months, respectively, for placebo/docetaxel.

 

The survival benefits were consistent in the major subgroups of patients, including squamous and non-squamous subtypes, suggesting that this therapy could be suitable for all major subtypes of NSCLC, Pérol said.

 

The safety profile was as expected for an anti-VEGFR agent in combination with docetaxel, with no increase in the rate of pulmonary hemorrhage.

 

Protocol

Ramucirumab is a human immunoglobulin 1 monoclonal antibody that targets the extracellular domain of VEGFR-2. Treatment in REVEL was docetaxel at 75 mg/m2 in combination with either ramucirumab at 10 mg/kg or placebo on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death.

 

The primary endpoint was overall survival, and secondary efficacy endpoints included progression-free survival and objective response rate.

 

Between December 2010 and February 2013, a total of 1,253 patients (26.2 percent squamous cell) were randomly assigned to treatment with ramucirumab/docetaxel (628 patients) or placebo/docetaxel (625 patients).

Grade 3 and above adverse events occurring in more than five percent of patients in the ramucirumab arm versus placebo arm were neutropenia (34.9% versus 28.0%), febrile neutropenia (15.9% versus 10.0%), fatigue (11.3% versus 8.1%), leukopenia (8.5% versus 7.6%), hypertension (5.4% versus 1.9%), and pneumonia (5.1% versus 5.8%).

 

Grade 5 adverse events were comparable between the study arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (2.1% vs.1.6%).

 

Discussant: Benefit Not Clinically Meaningful

The Discussant for the study, Julie R. Brahmer, MD, MSc, Associate Professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, used the glass-half-empty glass-half-full analogy to describe REVEL's results: On the one hand, she said, REVEL did meet its primary endpoints, with improved overall survival, median progression-free survival, and response. And ramucirumab is the first VEGFR inhibitor to benefit patients with squamous cell NSCLC.

 

On the other hand, she said, a 1.6-month improvement in overall survival does not appear to meet ASCO's definition of a clinically meaningful outcome, and more information is needed on patients with prior VEGF therapy.

 

“We have to look at this as a society and decide, when we're sitting in front of a patient, if a not-quite two month increase in survival is worth the cost and increased side effects.” Nevertheless, she said she thought a trial of ramucirumab in the first-line setting might be worthwhile.

 

But to get ramucirumab into the clinic it will need a biomarker of response, she said, and a significant clinically meaningful improvement in overall survival.