I am writing in regard to the report and commentary in this issue on the RAISE Trial. To begin, a discussion of this phase III clinical trial presented at the 2015 Gastrointestinal Cancers Symposium (RAISE study) may not be the most appropriate forum to air legitimate views on finances and operating business practices of the drug industry. Although this is a bigger societal, governmental, and professional practice issue, one must be careful not to overlook the fact that in this well‐conducted trial of more than 1,000 patients, ramucirumab (Cyramza) was shown to be an active agent that prolonged patient survival of patients with metastatic colorectal cancer in second-line therapy. However, this also may not have been the best forum to establish appropriate clinical use of an unapproved drug. It is important to remember that, as Dr. Tabernero mentioned (see page 1), studies are needed to establish through available tools (genomic, proteomic, etc) which subpopulations of patients were most likely to benefit on the RAISE trial and other ongoing trials.

That said, I do agree with Dr. Saltz that since ramucirumab has been approved by the U.S. Food and Drug Administration for other indications, there is perhaps some more merit in this situation to ask the question about the appropriateness of its use outside of a clinical trial in colorectal cancer. Although I said at the meeting that ramucirumab should be used only in the context of a clinical trial, I do think it was probably going too far to say it would be irresponsible to use it off-label, ever.

Historically, clinicians have used approved agents off‐label when patients had no better options, and so would it be completely irrational, inappropriate (or irresponsible) to use the drug in any situation off-label outside of a clinical trial in colorectal cancer? We need to be open-minded and not categorically exclude the possibility, as there is probably a chance that the drug may extend survival in a specific patient who may have already been exposed to the approved antiangiogenic agents. In my own practice, I have seen disease control more than I would have expected, for example, from aflibercept in patients who were previously exposed to bevacizumab (Avastin), including beyond disease progression. 

Can we define precisely who is likely to benefit today as someone who does not have similar or better options? I think the answer is no. Should we make it virtually impossible (or frowned upon or possibly looked at as unethical) to use a drug such as ramucirumab in patients who may have no better option given their treatment history and in the judgment of their treating physician? I think the answer there should also be no.

After all, we just learned it is an active drug when added to FOLFIRI (leucovorin, fluorouracil, irinotecan) in a large randomized phase III study vs placebo added to FOLFIRI, and it hasn’t yet been compared with other antiangiogenic options in randomized trials, as was noted. In the era of personalized medicine, where we must acknowledge a lack of sufficient knowledge in many situations regarding responders vs nonresponders or outliers who may  have dramatic responses, it should still be acceptable for treating physicians to consider all available options, discuss these options with their patients, make informed decisions, and hopefully report on their positive experiences. Low-level evidence but evidence nonetheless may be helpful to others. ■

—Wafik S. El-Deiry, MD, PhD, FACP
Fox Chase Cancer Center
Philadelphia, Pennsylvania