Phase 2 Trial of Opdivo for FL

An article in the medical journal Blood Advances from this week had some very intriguing results.

The article is called "Nivolumab and rituximab in treatment-naïve follicular lymphoma: the phase 2 1st FLOR study," and it gives the results of a phase 2 clinical trial being run in Australia. If you read the blog, you probably know what rituximab is (also know as Rituxan or MabThera, depending on where you live). But you might not know about Nivolumab, and that's what makes this so interesting to me.

Nivolumab is also known as Opdivo. It's a very widely used cancer treatment, and works as as a PD-1 inhibitor. PD-1 stands for "Programmed Death." Our cells are not meant to live forever. Some only live for a few days, like skin cells, which do a lot of work. Cells have a mechanism built into them so they will die off after a certain time. When they don't die off -- when they keep living, growing, and making more cells -- what you end up with is cancer. PD-1 is a protein on the surface of cells tat helps with this signaling. When there are problems with PD-1, cells don't get the signal that it's time to die off. A PD-1 inhibitor works to stop (or inhibit) that problem from happening, so cells are able to die off as they are supposed to, and thus prevent cancer. 

What makes Opdivo so interesting is that PD-1 affects lots of different types of cancer. We often think of cancer in terms of body parts -- breast cancer, colon cancer, skin cancer -- and most cancer treatments work on only a very specific type of body part cancer. But because PD-1 problems can result in lots of different cancers, a PD-1 inhibitor like Opdivo isn't confined to just one body part. It has been approved to treat different specific subtypes of cancers of the skin, lungs, kidneys, stomach, blood, and others. There are other PD-1 inhibitors as well (Keytruda is probably the best known one), and they have helped thousands of cancer patients. 

And while they are successful in treating lots of different types of cancer, they aren't always successful. Early attempts at treating Follicular Lymphoma with Opdiva and Keytruda were not successful (most recently last fall).

But this study suggests that a different way of using Opdivo might have found a way of using the PD-1 inhibitor successfully.

As the article says, the research describes results from a phase 2 clinical trial, so it's fairly small -- 39 patients with Follicular Lymphoma who had not yet received treatment. The patients were first given 4 cycles of priming Nivolumab. The idea here is that a few doses on Nivolumab on its own will prime or prepare the immune system by removing some cells that have PD-1 problems. That's the part that's a little different from what is usually done. And the priming process actually resulted in a few patients getting a Complete Response. In fact, 5% of them had CR, 26% had a Partial Response, 28% had stable disease, and the rest (41%) saw their FL get worse.

But then came the next step -- the patients who had a CR after those 4 rounds continued to receive only Nivolumab. The rest were given a combination of Nivolumab and Rituxin. The combination continued after they achieved a response -- one more year of Nivolumab and two years of Rituxan.

The results were very good. For the whole group, 92% of patients had a Response, including 59% having a Complete Response.  The median time to a Complete Response was 6.5 months, and 7 patients who had initially had a Partial Response eventually had a Complete Response. After following up for a median of 51 months, the median duration of response was 59 months, and Progression Free Survival was 61 months. However, 19 patients (36%) did eventually have their disease get worse at some point during the study, and 14 of them required additional treatment. 

Interestingly, the Primary Endpoint of the study -- the factor they use to determine if it is a success or not -- was not something like PFS, which is typical. Instead, it was measuring safety instead of efficacy -- how well the patients tolerated any side effects. This was a success -- the study met its primary endpoint. Only 33% of patients had a grade 3 or higher Adverse Effect (in other words, a serious side effect) during the first part of the study, and 59% during both parts of the study. It's unusual to focus on that, since it's usually a concern in phase 1 trials. But there was no phase 1 for this study, since both treatments have already been approved. But it's the first time they have combined in this way, and any combination of two treatments means there is a possibility for doubling the seriousness of side effects. This study showed that it didn't happen.

It will be very interesting to see where this research goes from here. They don't explicitly say that they are planning a phase 3 trial, though they do think this has some lessons for "future research." One of those lessons is that they saw a connection between patients who did well with this combination and having high CD8A gene expression. In other words, they think they found a biomarker that would help determine whether this kind of combination might work on an individual patient. They are also pleased that their Primary Endpoint was successful -- they showed that  combining a monoclonal antibody and an PD-1 inhibitor was safe, and that other combinations might be worth trying.

So I'm not sure we'll see this combination in the clinic any time soon, but it's certainly helps move our knowledge along. And that's always a very good thing.