More Questions about R-Squared

In my last post, I wrote about the most recent research on R-Squared, the combination of Rituxan and Revlimid (also known as Lenalidomide). Results from a phase 3 trial were published in the New England Journal of Medicine last week. The combination has the potential to be the first non-chemotherapy treatment to be as effective on Follicular Lymphoma as standard immunochemotherapy (Rituxan + chemo).

I came across a very interesting podcast discussion of the article.

The podcast is hosted by Dr. Vinay Prasad of the Oregon Heath and Science University. I like Dr. Prasad -- he had a reputation on Twitter for being kind of a pain in the butt.

I mean that in the best way. He liked to point out problems in medical journal articles that made them seem more successful than they really were. I'm not a "numbers" person, and my background in statistics isn't great. But I learned a lot from Dr. Prasad and others who had Twitter conversations with him (like Karl, who runs Lymphomation). They've helped me understand clinical trials a lot more.

I'm talking about Dr. Prasad and Twitter in the past tense, because he seems to have deleted his Twitter account. There is some speculation about why he did. I'm going to be optimistic about this and say that he's now doing a podcast instead of using Twitter because a podcast gives him more room to explain himself. There's only so much you can say in 240 characters, even if you string a bunch of Tweets together.

If there's any question about whether Dr. Prasad will continue his work, then the podcast on the NEJM article on R-Squared should answer it. He spends about 18 minutes tearing it apart.

Among his complaints: the trial is not successful, but it is presented in as successful a light as possible.

The trial was set up as a "superiority" trial. In other words, to be successful, it would have to show that R-Squared was better than R-chemo. A trial can be set up as non-inferior, too -- showing that a new treatment was about as good as the old treatment -- but that's not how this one was set up, and it did not show that R-squared was better (superior) to R-chemo. But the article doesn't say that.

Dr. Prasad also has issues with the surrogate endpoint. A trial can take a very long time to run. Ideally, we want to see how a treatment for FL works over 10 years or so. But, statistically, we can look at other trials and say "Well, the people who did well after 10 years also had a 3 year PFS." So now we can say the 3 year PFS is a surrogate endpoint for 10 year survival. We can guess that something in the short term will tell us something accurate in the long term.

Dr. Prasad doesn't think the surrogate they chose was an accurate choice.

He also points out that the Rituxan doses are not equivalent. For the R-chemo arm of the study, oncologists could choose R-Bendamustine, R-CVP, or R-CHOP. The standard doses for those regiments are different (you get more or fewer doses of Rituxan, depending on which chemo you are getting). Could more Rituxan have shown greater success?

Dr. Prasad points out that the patients in the R-Bendamustine group actually did better than the R-Squared group. So maybe this was the wrong comparison? Maybe R-Squared should go up against just R-B, especially since that seems to be the more popular Immunochemotherapy choice these days?

There are more issues that he pints out (8 in all). But you get the point. The study has some problems.

I have mixed feelings about the podcast.

On the one hand, the Cancer Nerd in me thinks it's very cool, and I really love having things shown to me that I hadn't noticed. I learned a lot. And I do admire a pain in the butt, especially when he's really good at it.

On the other hand, as a cancer patient, I want the R-Squared combo to work. I want that option. I want it to be approved. I don't want flaws pointed out.

So, as I said last time, we'll see where this goes. Will flaws in the study be enough to question its effectiveness? Will it be approved? Will oncologists not worry about surrogate endpoints, and focus more on the "chemo-free" aspect of it? Will patients demand it?

Follicular Lymphoma is already a complicated disease, with no easy answers. It would have been nice to read an article that provided some. But I'm not surprised it doesn't.

(But that does nothing to make me less hopeful about the future.....)