Jason Westin, MD, Director of Lymphoma Clinical Research, Section Chief for Aggressive Lymphomas, MD Anderson Cancer Center, Houston, Texas, discusses a phase 2 study on lenalidomide, tafasitamab, rituximab, and acalabrutinib alone or in combination with chemotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hi, my name's Dr. Jason Weston. I'm the director of lymphoma clinical research and a section chief for aggressive lymphomas at MD Anderson Cancer Center, in Houston, Texas.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Westin: We are launching the Smart Stop clinical trial rituximab, acalabrutinib, tafasitamab, lenalidomide alone and in combination with chemotherapy building upon our prior success in the same general space.

We previously conducted a trial called the smart start trial, which used rituximab, ibrutinib, and lenalidomide as a 2-cycle lead-in prior to adding in chemotherapy to that same combination.

In that trial, the combination of a BTK inhibitor plus an immunomodulatory drug was based on strong preclinical science, showing synergy in the non-germinal center subset of large B-cell lymphoma.

Those drugs appear to have a synthetic lethality basically augmenting the interferon signaling pathway to cause a preferential cell kill.

In that prior trial—the Smart Start trial—we found a very high response rate, 86% prior to any chemotherapy, and most people that had responses had partial responses (PR), but were near CRs.

On our new trial, the one we're talking about today, the Smart Stop trial, we're giving an additional medication—we’re adding in tafasitamab and using a different BTK inhibitor acalabrutinib. Rituxan (rituximab) and lenalidomide also in the mix for 4 cycles. This is basically trying to get more complete responses from the targeted therapy lead in.

OLN: Could you briefly describe the study and its findings?

Dr Westin: The Smart Stop clinical trial is an attempt to try and use targeted chemotherapies in newly diagnosed DLBCL patients, not confounded by the immune suppressive effects chemotherapy.

Here we're using rituximab, acalabrutinib, tafasitamab, and lenalidomide—4 agents that we know have activity in large B-cell lymphoma as a 4 cycle lead-in.

All patients who are eligible for the trial newly diagnosed DLBCL, non-germinal center subtype, all those patients will receive the 4 cycles.

Based upon their response at the end of 4 cycles, they'll receive a response adapted amount of chemotherapy.

Those who have a complete response (CR) to the lead-in would go on to receive 2 cycles of chemotherapy consolidation, as well as additional what we call ltra L-T-R-A, (lenalidomide), tafasitamab, rituximab, acalabrutinib.

For those that achieve less than a CR with the induction 4 cycles, they would go on to receive a standard 6 cycles of chemotherapy with the addition of ltra.

It's a response adapted trial design, where we're going to be reducing the amount of chemotherapy based upon the sensitivity to targeted treatments. That's in the first 30 patients.

The second 30 patients will have the cohort with complete responders get no chemotherapy is consolidation. Assuming that their response are adequate in the first 30 patients and are durable in those first 30 patients.

OLN: What makes this trial different than others?

Dr Westin: The novel features of our Smart Stop trial design are basically not taking the typical dogma of R-CHOP plus X, which has been tried many, many times over and over again, and has failed to succeed many, many times over and over again.

Instead here, we're doing effectively X plus Y. We're taking a targeted therapy inhibitor and adding it to other targeted therapy inhibitors, not confounded by chemotherapy. That's unique. That's something that's not been done very often before.

The main example of this in the past was our Smart Start trial. What we are expecting to see here is the activity of these agents to be quite significant in our prior trial, rituximab-lenalidomide-ibrutinib, was 86% response rate. We're hoping to get somewhere at least in that neighborhood with a complete response rate north of 50% without a drop of chemotherapy.

We think that this study could further augment the approaches in frontline large cell to move away from the 1970s chemotherapy of CHOP and move into the 2020s and beyond of targeted therapies.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Westin: The real-world applications of our Smart Stop trial are not to change standard of care practice overnight. This is something that's going to be a relatively small single center phase 2 trial. This is more of a proof of concept that we don't have to be wed to CHOP chemotherapy forever.

We should envision that CHOP is going to be that the standard of care for 75 years or a 100 years after its initial inauguration. We think that we can begin to move beyond these old chemotherapy approaches.

However, I would not advise treating physicians to try this at home outside of a clinical trial.

The reason we do these studies is to show the concept can work, but additional studies such as randomized trials and select patient populations would be required, in my opinion, to show that this is something that is better than standard chemotherapy.

The applications are interesting and could lead to additional studies, which could be practice changing. In itself, this is more food for thought, not something that someone should try in their clinic next week.

OLN: Do you and your co-investigators indent to expand upon this research? If so, what will be your next steps?

Dr Westin: The next steps beyond the Smart Stop trial, assuming that it succeeds in its goals of shelling that chemotherapy free or targeted therapy combinations are highly effective and safe to deliver in patients with newly diagnosed large cell, would be to further expand our armamentarium in this space.

To have additional combinations, either built on the combinations we already tried—built on that backbone—or to try additional subtype specific combinations of other targeted therapies.

We think that chemotherapy is a powerful weapon for fighting large cell lymphoma. Indeed, it cures probably two-thirds of patients. However, it's quite toxic and it's effectively a shotgun approach, which is not using the beautiful weapons we have in new targeted therapies.

If we could do additional research for subtype specific therapies, either target therapy combinations, targeted therapies plus chemotherapy, or even perhaps cell therapy plus targeted inhibitors in patients to increase our cure fraction and to decrease our toxicities. That would be a downstream implication of the research we're doing now.

OLN: Is there anything else pertaining to your research that you would like to add?

Dr Westin: One other thought that I'd like to add about the research that we're doing is this challenges the dogma of how we do clinical research in the United States and around the world—where that the clinical trials are strictly done as a vehicle for an FDA approval.

Obviously, that's critically important for our patients to have access to clinical trial-vetted medication outside of a clinical trial, but often these trials are done with a limited scope of a tiny iteration based upon what we've done previously.

We take what we did before we change one tiny variable, and then we either declare success or failure based upon a marginal benefit.

I think the potential for this research shows is that we can sometimes effectively start over as opposed to modifying the design of something that's been around for a long time.

As we get more powerful ability to study responders, both through self-free DNA as well as through more powerful analyses of pathology—including machine learning or artificial intelligence techniques, which better allow us to understand who's going to respond to which therapies—this type of trial design of a novel backbone for treatments, not using ancient therapies with a small tweak, but starting over with something smart and targeted. I think this could be the potential paradigm in the future.