Trouble for R Squared?

The big Follicular Lymphoma news from the past week or so has been the report from the phase III RELEVANCE trial, which looked at R-squared (Rituxan + Revlimid/Lenalidomide), plus R-squared maintenance) and compared it to Rituxan + chemo (CHOP, CVP, or Bendamustine) plus Rituxan Maintenance. The patients in this trial did not have any previous treatments for FL.

This is the first trial to do a direct comparison between FL patients who are getting traditional chemotherapy and patients who are getting a treatment that does not include chemo.

The first reports find that the R-squared was not superior to the chemo. There was no difference in Progression Free Survival -- the R-Squared did not extend the time that it took for patients' FL to get worse. There was also no difference in the percentage of patients who had a response.

The reactions to this have been kind of mixed -- and kind of fascinating.

A lot of the reports that I had seen about this are from business websites (like this one). The company that  makes Revlimid/Lenalidomide is one of the sponsors of the RELEVANCE trial, and made the announcement. Their stock price fell and their outlook was downgraded. Basically, investors think they aren't going to make as much money off of Lenalidomide as they had hoped.

But the medical and oncology websites are more hopeful (like this one -- OncLive is always great about exploring things from lots of different sides). So while there is some disappointment about the results, there is a lot of positive that is coming from it, too.

The lead researcher for the trial, Dr. Gilles Salles, said "This is the first phase III trial to evaluate a chemotherapy-free regimen to the established standard of care in patients with previously untreated follicular lymphoma and represents a landmark study in this disease setting. We look forward to further analyzing and presenting these important data at a future medical congress."


So that's the first positive here. For all of the talk of the future of treatment being chemo-free, this is the first trial that has actually done a direct comparison. Half of the patients got R-squared and half got R + chemo.  Other trials look at non-chemo treatments, but they compare them to previous trials that are already finished. This one took the same group of patients, making sure they are easier to compare, and divided them up. That's important. Direct comparisons are the best way of testing treatments.

But the other important thing that Dr. Salles said was that they will continue to analyze the data and will present it at future conferences. This was just the initial look at the numbers.

What else will they look for? Dr. John Leonard is quoted in the OncLive article: “Follicular lymphoma patients frequently choose less effective treatments—like rituximab alone versus rituximab/chemo—based on perceived quality of life advantage. R2 might be a choice made by some patients, even if less effective. The details of efficacy, toxicity, and qualify of life are key here.”

In other words, maybe the R-squared won't be as effective as the chemo, but it has fewer or less harsh side effects, making it possible to live a more normal life. Quality of Life is a big issue for Dr. Leonard, who recognizes that many of us could be living with FL for a very long time. What makes a treatment "effective" isn't just that it has met an endpoint like OS or PFS or CR, but that it helps us live our lives -- on our own terms, whatever they may be.

And so, I added the question mark to the title of this post. Is there trouble for R-Squared? Yes, in some ways, since it didn't do what it was hoping to do. But that doesn't necessarily mean it's a failure, and it doesn't necessarily mean it won't be approved.

It's also important to keep in mind that the RELEVANCE trial is for R-squared in untreated patients. Another trial, the MAGNIFY trial, is looking at R-squared in FL patients who have already had at least one treatment. They received R-Squared, and then maintenance with either R-Squared or just Rituxan. Unlike the RELEVANCE trial, the MAGNIFY trial did not do a direct comparison with another treatment.

And then there's the AUGMENT trial, which does do a direct comparison -- R-Squared versus Rituxan alone -- for patients who have had at least one treatment.

Both of those other trials seem to be doing well. So R-Squared isn't going away completely.

But it will be interesting to see how the RELEVANCE trial is analyzed, and what the reaction to it will be when the results are presented (maybe at ASCO or Lugano next spring/summer?). Just how important will Quality of Life end up being in the analysis?

Stay tuned.