Progress in the Treatment of Follicular Lymphoma - Episode 7

Emerging Therapies in Follicular Lymphoma

April 16, 2020

John M. Burke, MD:There are many emerging treatment options that are exciting in follicular lymphoma. As we’ve discussed, the readily available treatments are chemoimmunotherapy, lenalidomide, PI3 [phosphoinositide 3]-kinase inhibitors, and radioimmunotherapy. Right now, that’s what’s available. The ongoing SWOG trial isn’t changing that list. It is designed to help us answer the questions of whether there’s a best choice among that list, so that’s the SWOG trial. Perhaps I won’t discuss that any further because it is really helping us choose for the early relapsers between chemoimmunotherapy, a PI3-kinase inhibitor, and lenalidomide.

Other novel agents on the horizon are important. One is polatuzumab vedotin. Polatuzumab is an anti-CD79b antibody drug conjugate. The drug is conjugated to MMAE [monomethyl auristatin E]. It’s the same drug that is linked in brentuximab vedotin that’s used in the treatment of Hodgkin lymphoma. Polatuzumab is FDA approved now for patients with relapsed diffuse large B-cell lymphoma, but we also know from the early studies that it has activity in follicular lymphoma when given in combination with either rituximab or obinutuzumab. At the ASH [American Society of Hematology] Annual Meeting & Exposition in 2019, Catherine M. Diefenbach, MD, presented results of a phase I/II trial in which patients were treated with POLA [polatuzumab vedotin]-obinutuzumab-lenalidomide, so a triplet combination.

The results were really interesting. The overall response rate was 80%. The complete remission rate was about 60%, which was pretty high. As I mentioned earlier, we think that the complete remission rate with lenalidomide-RITUX [rituximab] or lenalidomide-OBIN [obinutuzumab] is probably in the 40% range. Certainly, this triplet combination would look to be even better than what one gets with a doublet with lenalidomide. So I think there is a lot of promise. The peripheral neuropathy that we know can happen with POLA was not too burdensome in this trial. There was no grade 3 or 4 toxicity reported.

The conclusions from this presentation are that it’s a promising triplet combination that could be considered for patients with relapsed follicular lymphoma. I don’t think it’s ready for prime time, and I think it needs a randomized trial comparing a triplet with a doublet to see if it really can lead to good outcomes for patients. That’s probably going to be the next step, I would think, for polatuzumab in follicular lymphoma.

Another agent that has a lot of potential on the horizon is tazemetostat. As we previously mentioned, the geneEZH2is involved in germinal center development, andEZH2is an important gene in follicular lymphoma. It’s part of the m7-FLIPI [Follicular Lymphoma International Prognostic Index]. Mutations inEZH2occur in about 20% of patients with follicular lymphoma, andEZH2can be overexpressed in follicular lymphoma. Tazemetostat is an orally administered inhibitor ofEZH2. It inhibits both the mutatedEZH2and the wild-type or nonmutated form of EZH2. Epizyme, the sponsor that owns tazemetostat, developed this drug and led a trial. It was a phase II trial where they treated 45 patients who had mutatedEZH2and 45 patients who had wild-type EZH2. The results were impressive.

First of all, in terms of safety, it was a very well-tolerated drug with very few serious adverse effects. Grade 3 and 4 adverse effects were rare. Again, it’s taken orally. In the patients who had a mutation, the overall response rate was about 70%. If you look at the waterfall plots, almost every single patient had at least some reduction in their disease burden. In the patients who did not have a mutation, or were classified as having wild-type, the results were a little bit less impressive. That is, the overall response rate was only about a third, but again on the waterfall plots, roughly two-thirds of patients did seem to have some shrinkage of their disease.

The patients who had a mutation were less heavily pretreated than those classified as having wild-type. That is, patients who had a mutation had received a median of only 2 prior therapies, whereas those classified as having wild-type had received a median of 3 prior therapies. Many of those patients were on fourth-, fifth-line therapies. The patients who had wild-type were destined to do a little worse than the patients with a mutation. That may partially explain some of the difference and results that were seen in those 2 groups. My understanding is that tazemetostat is in front of the FDA right now, which is considering whether to approve it for patients with relapsed disease. We’ll see. So that’s a promising drug on the horizon.

I would say CAR [chimeric antigen receptor] T-cell therapy looks effective in treating follicular lymphoma. This has been reported by Stephen J. Schuster, MD, in theNew England Journal of Medicinewith the Novartis product, KYMRIAH [tisagenlecleucel], and it’s been reported in theBloodjournal with the Juno product, JCAR017. I’m not familiar with every CAR T-cell therapy trial, but it is certainly highly effective treatment in patients with relapsed follicular lymphoma, multiply relapsed, fourth-, fifth-line type therapy patients. Again, it’s expensive and toxic, so it’s certainly not going to be for everyone with relapsed follicular lymphoma but it’s a highly effective treatment modality.

The other modality that I think is really promising in the treatment of relapsed follicular lymphoma is bispecific antibodies that target both CD3 and CD20 antigens. There were several presented at ASH—1 called mosunetuzumab, 1 called a DuoBody, and REGN1979 from Regeneron. All of these have a high rate of efficacy in patients with relapsed follicular lymphoma. Most of them were early results, so I don’t think they’re ready for routine clinical use and none of them are commercially available right now. But I would keep my eyes on those for future research because those look to be effective enough so far, that they may become available in the future for treating relapsed follicular lymphoma.

Transcript edited for clarity.