Regulatory Considerations and Challenges Surrounding New and Emerging Therapies for Lymphoma

By Blood Cancers Today Staff Writers - January 13, 2023

A roundtable discussion, moderated by Kami J. Maddocks, MD, of the James Cancer Hospital, Ohio State University Comprehensive Cancer Center, focused on treatment options for diffuse large B-cell lymphoma and follicular lymphoma, including novel emerging therapies and treatment sequencing considerations. Dr. Maddocks was joined by a panel that included Pierluigi Porcu, MD; Pamela Blair Allen, MD, MSc; and Jonathan W. Friedberg, MD.

In the next segment, the panel discusses regulatory hurdles and patient access considerations for non-Hodgkin lymphoma therapies.

Dr. Maddocks: What do you guys see when we’re trying to get these drugs approved and to patients? What do you see as some of the significant regulatory hurdles to the approval of novel therapies?

Dr. Allen: In terms of FDA approval?

Dr. Maddocks: Yeah.

Dr. Allen: Yeah, because when things go on the NCCN guidelines, I have less difficulty getting them even pre-FDA approval, but it’s a very high bar, and I feel like some drugs that get early approval, then we’ve seen this happen in other diseases where then it actually gets revoked if you don’t have that confirmatory phase III study. So I think that’s a barrier and it is challenging sometimes when you see data coming out showing that this is a really promising agent and then you can’t get it for your patients. It’s one thing if it’s a drug that’s been approved in some other mechanism so that you can get it, but if it’s things like a bispecific, you’re not going to be able to get that until we go through the full regulatory process.

Dr. Friedberg: I think the world is changing quickly in this regard. I think we’ve had a period of time where the accelerated approval process frankly did help our patients and help us get access to drugs. You wake up one day and you read that selinexor is approved for diffuse large B-cell and you’re like, okay. And to some degree having those options as a clinician was really quite positive. I think as Dr. Allen said, the ability to then confirm some of those results has been limited, and the FDA has been under some pressure. I fear maybe that the pendulum may go so far the other direction that we’re going to have a hard time getting access to these drugs that we really want. So finding that sweet spot, there’ve been a lot of papers being written about that, but I fear we might be entering another period of time where things take longer.

Dr. Maddocks: And I think we’re kind of seeing that right with the PI3K stuff and now all that concerns about toxicity, exactly what you’re saying, now we have drugs that look very effective in patients who all the standard therapies we have, have stopped working and they’re asking for huge studies to look at the data and toxicity and we may not have access to these for patients.

Dr. Porcu: Just to make things more complicated now companies are designing trials and rolling them out looking at regulatory approval strategy, not just with the FDA but also with EMA, and even though there’s a lot of overlap but not complete, so there are certain nuances about how the EMA, what kind of data they would accept and what the FDA would accept. So I think that companies will start looking at trial design to make sure that they can hit all the proper endpoints. And that’s not always easy to do. The other is just the growing complicated landscape of multiple drugs that makes that chess board game quite complex. So I think that that will definitely kind of complicate things.

Dr. Friedberg: And I do think certainly in follicular lymphoma, but probably large-cell lymphoma too, an overall survival endpoint certainly in the upfront setting is going to be very, very difficult to ever reach. We saw it with rituximab, it’s unlikely we’re going to get another rituximab, especially given enhanced salvage options in both follicular and diffuse large B-cell lymphoma. So that immediately complicates a regulatory strategy because if you had the ability to show improved overall survival, it would be quick.

Dr. Maddocks: So I guess that can take us to our next point, so how would you recommend addressing some of these challenges? I guess with different endpoints, any thoughts?

Dr. Allen: Yeah, I agree. So if you have a strong surrogate endpoint that you know correlates, then I think that that makes sense, and certainly progression-free survival, I think for certain diseases, like diffuse large B-cell lymphoma, makes a lot of sense. And sometimes that endpoint can even be reduction in symptom burden, particularly for patients that are more advanced stage or just showing that the safety is, if the efficacy is equivalent, but the safety is better for some combination. If they were able to incorporate those types of things, it might help.

Dr. Porcu: And then the other big thing is going to be cost. Something that we don’t talk a lot about, but at some point kind of managing the cost of all this incremental availability of drugs and therapies, we’re going to have to figure out how to do that.

Dr. Allen: And it also restricts the ability to develop other innovative trials with these agents because if they need to put all of their resources into making sure they can run this huge phase III trial, well then you’re not going to really be able to use that drug maybe in other diseases or populations or scenarios.

Dr. Friedberg: A potential solution to both of those would be if you had more of a precision medicine approach. And if you treated a smaller group of patients that had a much bigger response rate, you would save money because you would only be giving the patients who really benefited that treatment and it’s more likely that treatment would show impact, potentially even overall survival impact. It’s just been much harder in the lymphoma space as compared to the solid tumor space in part because the frequency of the recurrent mutations is low. It’s a much broader landscape of mutations and because our bar is high that we do well with our current therapies.

Dr. Maddocks: Last question here. Do you see any difference in challenges getting drugs approved in the frontline setting versus the relapsed/refractory setting?

Dr. Allen: It seems that it’s more difficult in the frontline setting.

Dr. Friedberg: I think we’re waiting for the polatuzumab approval. It’s taking longer than maybe we initially thought, and I think the FDA is probably looking at impact of the treatment on subsequent treatments and survival trends and that type of thing, but these diseases now have long natural histories. Our colleagues in multiple myeloma seem to have figured this out pretty well. So hopefully we’ll be able to leverage some of that experience.

Post Tags:Lymphoma Roundtable
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