Big news in the Lymphoma community -- the FDA has granted Priority Review for Odronextamab. It's being reported on most of the major oncology news sites.
Odronextamab is a CD20 x CD3 bi-specific. As a reminder, a bispecific works like a monoclonal antibody like Rituxan by seeking out a protein on the surface of a B cell called CD20 (just like Rituxan). But it also targets the CD3 protein on T cells, a type of immune cell that will be floating in the blood along with the B cells. A bi-specific will attach to both and bring the T cell in contact with the cancerous B cell and help the immune cell to eliminate it. Right now, the only bi-specific available to Follicular Lymphoma patients is Mosunetuzumab.
The Priority Review is based on phase 1 and phase 2 clinical trial results. I first started writing about Odronextamab about four years ago, when it was still known as REGN1979. The application is for both Relapsed/Refractory FL and DLBCL (that is, the patient's last treatment stopped working or did not work at all). Patients need to have had at least two previous treatments.
Results have been very good. In the phase 2 trial, patients with Follicular Lymphoma had an Overall Response of 82% and a Complete Response of 75%. The median duration of response was 20.5 months and the median Progression Free Survival was 20 months.
As for safety, 100% of the 131 patients with FL experienced side effects (which isn't surprising -- all cancer treatments result in side effects), and 78% of them experienced grade 3 Adverse Events (more serious side effects). The most common side effects were Cytokine Release Syndrome (over half of patients), low blood cell counts, diarrhea, fever, joint pain, and infusion-related reactions. None of the CRS were grade 4 or 5, which are the most serious.
So it seems like the side effects are manageable.
If you've been reading for a while, you know that bi-specifics (along with CAR-T) are the Lymphoma treatments that get oncologists most excited. Given some of the issues that Lymphoma treatments have been having in the last few years, I would expect a very thorough vetting by the FDA. The target date for a decision by the FDA is March 31, 2024. I wouldn't be surprised if we saw some updated trial results at ASH in a few months; the last time any results were presented was at last year's ASH. And I would expect it to be positive (maybe updated numbers on duration of response).
Definitely one to keep an eye on.
3 comments:
Hi there Bob - fellow FL adventurer here. Do you know why so many of these treatments are only approved for third+ line? From what little I’ve been able to glean, approved second line FL treatments are mostly (all?) chemo based, and as someone with POD24 (post R-CHOP) FL, my onc seems pretty certain that any further chemo is unlikely to work, but that if/when I fall out of W&W, and assuming today’s approval landscape, I’d likely have to do some chemo just to fail it and qualify for third line treatments (which seems a bit daft to me).
Any insights? Is it just a matter of time, as I’m naively hoping?
Hey. Sorry to hear about the POD24. The general answer to your question about approvals for third+ line is (from what I can tell) a financial one. The way the FDA works right now, with things like accelerated approvals, a company that develops a first-line treatment is going to have a harder time getting it approved. R-CHOP works, B-R works, even R-squared works, and all of them are widely available and relatively safe. To get approval, a developer needs to show that their treatment is an improvement in what is available -- more effective, more safe, ideally both. That's a high bar. But because there is a greater need for third+ line treatments, with so few available, it's probably easier to get one approved even if it shows a fairly small improvement in PFS (maybe just a few months). It seems like companies take that route, get it approved for one set of patients, begin to make money to pay back research costs, and then move on to trials for a larger group of patients that will need to meet a higher bar. I'm not a doctor, a lawyer, a financier, or a biomedical specialist. Let's be clear about that. But I've read enough about FDA trials and talked to enough people about about "sausage making" behind the scenes to make a decent guess about why they do what they do. Recovering costs with the fastest possible approval (especially accelerated approvals) is the goal.
I hope you don't need to go through another round of chemo to make it happen. There are a few approvals for just relapsed/refractory FL (second line) like Tazemetostat and Revlimid that might be options. Or maybe a clinical trial, where you could access to some of the third+ line treatments that are being tested on R/R patients. I think that's what I would look into before I went to chemo again. Do you have a community oncologist or do you see someone at a research hospital? A second opinion from a lymphoma specialist might be good, and might open you up to some trial possibilities.
I wish you much good luck with the decision. Please do let me know what happens from here.
Thanks Bob - obviously I’m not as concerned about 1st line approvals as I’ve already passed that point. I’m more just intrigued that some CAR-T and bi-specifics are approved for 2nd line DLBCL, but are only approved for 3rd line FL. The sad reality is that the second line FL landscape is pretty sparse, and there doesn’t seem to be much going on to fill that void. And yes I also understand that DLBCL is a more common and far more dangerous form of lymphoma (I was originally diagnosed with both, hence the R-CHOP).
And yes I see a lymphoma specialist at a major US research hospital, and it was his thoughts that I echoed above. He is also pretty negative about bridging treatments, and Revlimid in particular, as the data don’t show any net benefit in terms of overall survival.
He has said that from an approved treatment perspective I’ll be better off if my FL just transforms to DLBCL a second time, rather than the FL slowly becoming a problem without transformation, but obviously neither path (a second DLBCL transformation or failing chemo just to qualify for a 3rd line FL treatment) seem great to me. Immunotherapies seem to have great promise for 2nd line FL, and yet I’m just not seeing or hearing much action on this front.
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