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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)


Cyramza, New Angiogenesis Inhibitor, Approved with Taxotere for Second Line NSCLC: Let's Review Why
Howard (Jack) West, MD

It may not be the biggest present lung cancer patients could get for the holiday season, but the FDA just yesterday approved Cyramza (ramucirimab), an anti-angiogenic antibody with a mechanism similar to Avastin (bevacizumab) that is already approved for gastric cancer, as a new agent to treat previously treated advanced NSCLC, any histology. This was based on the phase III randomized trial called REVEL that was presented at ASCO 2014, so let's review the evidence that led to this approval. 

The REVEL trial randomized 1253 patients with metastatic NSCLC of any histology (i.e., including squamous) who had received prior platinum-based doublet therapy as first line treatment to receive standard Taxotere (docetaxel), the FDA-approved cornerstone of second-line therapy, with either Cyramza at 10 mg/kg once every 21 days or placebo on that same interval until significant progression or prohibitive side effects. Patients could have received Cyramza's cousin Avastin in the first line setting, but only about 10% of patients did.

The trial was looking for a significant improvement in overall survival (OS) and was technically a positive study.  Both the median progression-free survival (PFS) and median OS improved by about 1.5 months with the addition of Cyramza.

REVEL PFS cyramza ramucirumab(click to enlarge)

REVEL OS cyramza ramucirumab


The objective response rate (ORR) was also modestly higher with the addition of Cyramza. The Taxotere alone arm had a rate of significant tumor shrinkage of 13.6% (which is actually better than the usually 5-10% for Taxotere in many studies), while the combination with Cyramza had an ORR of 22.9%.

The other side of the equation is side effects. Not surprisingly, some side effects were more severe with Cyramza, most notably the drop in blood cell counts, mouth sores, ankle/leg swelling, and eye tearing.  However, these were not substantial or especially serious side effects, and it is important to note that life-threatening or fatal bleeding complications weren't seen, including in the patients with squamous NSCLC who are not recommended to get Avastin due to the high risk of potentially fatal hemoptysis (coughing up blood).

Putting the results into context, it's fair to say that while this was a "positive" trial, it didn't set the world on fire, and there hasn't been a groundswell of pent-up demand for Cyramza to be administered in NSCLC.  In its favor is a six-week survival benefit that is hard to come by in previously treated patients with advanced NSCLC, particularly an option that is available for patients with squamous NSCLC. It also happens to provide this benefit with rather minimal added side effects. But the down side is that this improvement in median OS is a mere 6 weeks, which is really about at the lower limit of what even most proponents would consider to be at all clinically significant. This isn't changing the world, but it's a bit of an improvement.  The cost of about $7000/treatment may well contribute to the ongoing debate about which interventions in cancer are truly worth their cost.  While it may be damning with faint praise, that cost is not at the higher end of what many cancer drugs are costing.

That's a good thing, because the benefit its offering isn't as impressive as anyone would want. The real debate is whether we should be satisfied with bunt singles when we really need big hits, the agents with response rates of >50%, dramatic responses that last for a year or more, etc., so seeing such modest, incremental steps forward don't impress.  The FDA has provided another tool, but it remains to be seen whether Cyramza becomes a widely favored standard of care that is very commonly added to Taxotere. We're hoping for more, but I suppose we need to take our victories as they come.

What do you think? Is this enough to impress you?

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