The medical journal eJHaem just published an article called "A Phase 2 Study of Frontline Pembrolizumab in Follicular Lymphoma." It's very interesting to me for several reasons, most importantly because it reports the results of a clinical trial for Follicular Lymphoma. But there are others, too, which i will get to.
Pembrolizumab is also known as Keytruda, and it is a very important treatment in cancer. It is a PD-1 inhibitor, meaning it stops the effects of PD-1, or Programmed Death 1. It's a very cool immunotherapy treatment. PD-1 is a protein that is an important part of the immune system, because it keeps immune cells from doing their job too well. If an infection occurs, PD-1 keeps the immune system from attacking too many cells, which would result in an autoimmune issue, where the immune system attacks healthy cells. It send s a"programmed death" signal to some immune cells, basically telling them to stop working.
In terms of cancer, PD-1 works on immune cells that could be going after cancer cells. So a PD-1 inhibitor stops the PD-1 from stopping the immune cells. In other words, it allows the immune system to work on the cancer cells.
What makes Pembrolizumab so important is that it works on lots of different cancer cells. We usually think of cancer in terms of body parts -- breast cancer, colon cancer, blood cancer. When we think that way, it makes us think of the cancers as all being very different. A traditional chemotherapy that works on breast cancer probably won't work on lung or brain cancer.
But the discovery of PD-1 changed all of that. PD-1 is present in the cells of lots of different body parts. So Pembrolizumab has been approved for use in patients with lots of different types of cancer -- melanoma, several lung cancers, classical Hodgkin's Lymphoma, urothelial carcinoma, head and neck cancer, and renal cell cancer. Former U.S. President Jimmy Carter received Pembrolizumab; he might be its most famous user.It's been a real game-changer for many patients with many types of cancer.
But not Follicular Lymphoma.
I've written about Pembrolizumab and FL a few times. The first time was in 2016. I looked at a couple of pieces that Dr. John Leonard had written about new treatments for FL, and he mentioned a phase 2 study of Pembrolizumab and Rituxan. In the other times I've mentioned it, it was usually to say that results from a study weren't as strong as researchers had hoped.
And that's the case with this one, too. It look at a phase 2 study of just Pembrolizumab indolent B cell lymphoma, including FL. In this fairly small study, 9 patients with Follicualr Lymphoma were enrolled. The Pembrolizumab wasn't very effective -- 3 of the patients had a partial response, 3 had stable disease, and the other 3 had their FL get worse. Safety wasn't much better than effectiveness. Two of the patients had grade 3 (serious) side effects. Both had transaminitis (high levels of liver enzymes and the blood) and one of them also had hypophysitis (an inflamed pituitary gland).
All of that was enough for the researchers to say "Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME [Tumor Microenvironment] in FL should be explored." in other words, this one isn't working.
It certainly makes sense to give Pembrolizumab a try in FL. Why not? It works in lots of other cancers, even in another blood cancer (Hodgkin's Lymphoma). But for whatever reason, inhibiting PD-1, at least with this treatment, just doesn't do the job.
As I said, the results are most interesting to me, but there are some other things about the article that are also interesting.
First, I love the title -- "A Phase 2 Study of Frontline Pembrolizumab in Follicular Lymphoma." If this had been a successful trial, the results would have been given to us upfront, something like "Pembrolizumab Induces Durable Response in Follicular Lymphoma: Results of a Phase 2 Study."I learned that lesson long ago. When you're writing an email with good news, put the good news in the subject line. If it's bad news, make the subject line neutral and bury the bad news in the middle of a paragraph halfway through the email. It's fascinating that the same strategy turns up here.
But even more fascinating is that the bad news turns up at all. It is very rare to see a negative study get published. I could find dozens of examples in this blog over 16 years of reports of phase 1 and phase 2 studies that were very enthusiastic, but were never heard from again. The later studies weren't successful, the researchers never reported the results. I would love to see more negative studies published. They can be just as helpful as the successful ones.
But those studies were also probably commercial, and if a business has sent millions of dollars trying to develop a treatment, they really have no incentive to advertise to the world that the treatment didn't work out. More likely, the company died and the people working for it moved on to something else.
What makes this study different is that Pembrolizumab was already a successful treatment, already making billions for its makers. The authors aren't business people; they are academics and researchers, doing a study with a treatment that has already been approved. They really do have some incentive to share what they learned, even if the treatment wasn't successful. The study was successful -- we learned something from it.
So I'm enjoying this "failure," because it is so rare to read one. I don't think we've seen the last of Pembrolizumab for Follicular Lymphoma. There are still some studies out there. Maybe one of them has just the right combination or the right dosage to make it work. It would be great to add FL to that long list of cancers that Pembrolizumab can treat successfully.
But in the meantime, as the authors of the article say, it's time to try something new and stay hopeful.
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