Transcript
Alex F. Herrera: My name is Alex Herrera. I am an Assistant Professor of Hematology at City of Hope in the Los Angeles area.
Amitkumar Mehta: I am Amitkumar Mehta. I am an Associate Professor at the University of Alabama at Birmingham, and I am also director of the lymphoma program at UAB.
Ibrutinib, as we all know, has great activity in CLL and some of the B-cell lymphomas, like mantle cell lymphoma.
In DLBLC, especially in activated B-cell subtype, has great activity, about 40 percent response rate in relapsed-refractory setting, especially in activated B-cell, where NF-kB pathway is very activated. There is also preclinical data to suggest that ibrutinib in tumor microenvironment has proinflammatory activity.
We thought that, if we combine ibrutinib, which is not only a BTK inhibitor, but also had some pro-inflammatory activity in tumor milieu, if we combine with either PD-1 or PD-L1 inhibitor, that might be synergistic and might enhance the activity in some of the B-cell lymphomas, like follicular and large-cell lymphoma. That was the basis to conduct this study.
Dr Herrera: I will just add that there were some preclinical studies performed in lymphoma mouse models that actually did appear to show that ibrutinib and PD-1 or PD-L1 blockade really could work together to enhance responses.
There was an excellent preclinical rationale as well to study this combination in non-Hodgkin lymphomas.
This was a phase 1 and 2 study of patients with follicular lymphoma or diffuse large B-cell lymphoma, evaluating the combination of ibrutinib with durvalumab, which is a PD-L1-blocking antibody.
In the phase 1 portion of the study, we assessed the safety and determined the recommended phase 2 dose of the combined drugs. We did find that it was tolerable, so the study moved onto the phase 2 portion.
All in all, we enrolled just over 60 patients. About half had follicular lymphoma. A few more had diffuse large B-cell lymphoma, and there were patients with germinal center B-cell subtype DLBCL, as well as non-germinal center subtype DLBCL included.
As I mentioned, we did find that the combination was tolerable, with the expected toxicities of each of the drugs. No surprises from a toxicity signal perspective.
In terms of the efficacy, patients with follicular lymphoma, the response rate was just over 20 percent, which admittedly is pretty similar to what we see with ibrutinib as a single agent.
In germinal center B-cell subtype DLBCL, the response rate was in the teens. In non-germinal center subtype DLBCL, the response rate was just under 40 percent. Again, as Dr. Mehta mentioned, it is pretty similar to what we see with ibrutinib as a single agent.
I think, in totality, overall, the efficacy seemed similar to single-agent ibrutinib. The safety was similar to what we would see with each individual agent.
In terms of surprises, we had hoped to see a better efficacy with the combination than we observed. Although, when you look at anti-PD-1 or anti-PD-L1 monotherapy, non-Hodgkin lymphomas, it turns out that the larger phase 2 studies have shown that the response rates are relatively low, although there are some durable responses in a small minority of patients.
Maybe in the end, although we had hoped for better results when we planned this study, in retrospect, looking at now the totality of data of PD-1 blockade in non-Hodgkin lymphomas, maybe it is not so surprising after all.
Dr Mehta: I think some of the highlight of the study was the interim analysis did not point toward continuation studies, so we had to discontinue the studies. I always say this, that not always that we publish positive studies.
This is one of the classic examples. I do not want to call this a negative study, but we learned something from this, and it was published. Kudos to the journal who accepted this. That is the important part. That eliminates some of the bias.
The second part, as Alex was mentioning, the highest response rate was, that we see in activated B-cell subtypes, 38 percent response rate, which was similar to single-agent ibrutinib. Technically, we added some immune-related toxicities, but we did not add anything to what single-agent ibrutinib will add to.
From the progression-free survival perspective, it was still higher in follicular lymphoma subtype on this study, about 18 months, compared to just about 5 months in the large-cell lymphoma study. The toxicity, as Alex mentioned, there were no surprises in toxicities.
The toxicities that we see with ibrutinib alone, as well as durvalumab alone, they were the main toxicities. Actually, the highest dose, 560 milligram, could be extended into phase 2. Again, this combination did not add anything, rather than just single-agent ibrutinib, but in a way, we learned a lot from this.
Sometimes, you have a good preclinical rationale, but it may not turn out better in the clinic for our patients.
Dr Herrera: As we have been discussing, the results of this study did not necessarily suggest any additional benefit to adding PD-1 or PD-L1 blockade to ibrutinib.
We will not be using this combination specifically in the clinic, but I think, as we have more new immune therapies or other targeted agents available for the treatment of cancer, and in this case specifically lymphoma, there is always this proliferation of studies to try to combine them and learn more about them.
We often do not hear the results of a lot of those studies for quite a long time. The number of PD-1, anti-PD-1 antibodies plus another drug studies that have been done is very large, but the number of studies that we have actually heard about is very small.
I think it is important to understand, we try out these combinations. Which are the ones that are going to be successful? Which are the combinations that look promising? It is important to know when we did not see the results that we expected or hoped for.
I guess the application of clinical practice is, "Look, we have a lot of exciting drugs. We should continue to evaluate them and study them together, and I think we should continue to publish the results, so that we can learn from our past studies."
Dr Mehta: I totally agree with Alex. It did not move needle in the clinical practice.
The other important aspect of this study was the biomarker analysis. There were extensive gene studies that were done on this study. We did not find any mutation that was leaning toward some prognostic or therapeutic implications on that.
It did not show anything in terms of subgroup analysis or anything. Clinically, I do not think that it will move the needle, but it was an important study to be done, because we wanted to make sure that we are not seeing any signal clinically or benefit to the patient.
At this point, I do not think that we are going to expand on this.
Both large-cell lymphoma and follicular lymphoma, as you know, that there are so many active agents rolling out. In (the) last one year, if you see bispecific, next generation CAR T-cells, they have great single-agent activities.
I do not see that this will be expanded in this particular follicular and large-cell lymphoma space. It was an important study. We learned a lot from this. Hopefully, in future, when we have these newer agents, like CD19 antibody-drug conjugates or CD19 monoclonal antibody, there are potential partners going forward.
They have been explored in a different partnership, but not this combination, per se.
Dr Herrera: I totally agree. I think that, while we do not intend to expand this particular combination in these subtypes of lymphoma, I do think that the lessons that we have learned will be applicable to using each one of these types of drugs—either BTK inhibitors or anti-PD-1 or PD-L1 antibodies—with a lot of the other newer agents that we have that have proven to be exciting and effective in non-Hodgkin lymphoma.
I think, again, an important early immunotherapy combination to have studied that will have lessons and that we can apply as we move forward in the field.
