ctDNA Analysis Predicts PFS With Odronextamab in FL and DLBCL

Jon E. Arnason, MD

According to findings from a circulating tumor DNA (ctDNA) analysis of odronextamab (REGN1979) based on the ELM-2 trial (NCT03888105), the ongoing monitoring of ctDNA may be an important early progression marker in relapsed/refractory (R/R) follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL).1

Findings presented by Jon E. Arnason, MD, showed that using this non-invasive method, experts can molecularly characterize patients who do not have available tissue, which leads to the identification of patients in high-risk subgroups.

Patients in ELM-2 received odronextamab via intravenous in 21-day cycles. In cycle 1, odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg. Cycles 2 through 4 gave patients odronextamab at 160 mg on days 1, 8, and 15 of each cycle. Further, the maintenance therapy consisted of 320 mg odronextamab every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity.

Baseline ctDNA and tumor biopsies were used for molecular profiling and minimal residual disease (MRD) determination was based on ctDNA analysis using a modified AVENIO workflow. MRD negativity was defined when the P value for variant allele frequency was >.005.

The biomarker population included 53 patients with FL and 63 patients with DLBCL. MRD negativity at C5D1 correlated with significantly longer progression-free survival (PFS) in both disease types, and TP53 mutations in FL were associated with MRD-positive status. TP53 also predicted shorter PFS in this space. Additionally, using LymphGen classification in DLBCL identified subtypes with different PFS outcomes.

Overall,treatment with odronextamab demonstrated significant associations between MRD status, molecular characteristics, and PFS in patients with FL and DLBCL, and TP53 mutations in FL and LymphGen classification in DLBCL were deemed potential predictors of treatment response.

In an interview with Targeted Oncology^TM, Arnason, physician scientist at Beth Israel Deaconess Medical Center, Boston, Massachusetts, discussed an analysis looking at ctDNA among patients with FL and DLBCL from the ELM-2 trial.

lymphoma cells : © Dr_Microbe - stock.adobe.com

Targeted Oncology: Can you provide a brief overview of this ctDNA and MRD analysis of odronextamab in DLBCL and FL as part of the ELM-2 trial?

Arnason: Odronextamab is a CD3xCD20 antibody that directs T-cell function against B-cell malignancies. It showed significant clinical efficacy in a phase 1 trial. ELM-2 is a phase 2 trial looking at both diffuse large B-cell lymphoma and follicular lymphoma. My role at [the American Society of Hematology] meeting was to discuss the ctDNA analysis. Working with a [CAncer Personalized Profiling by deep Sequencing (CAPP-Seq)] lymphoma-specific panel, we were able to measure ctDNA in a subset of patients with diffuse large B-cell lymphoma and follicular lymphoma.

What were the main primary and secondary end points of the study?

The primary end point was to look at the correlation between minimal residual disease as measured by ctDNA and progression-free survival. We were happy to see that there was a correlation between achievement of minimal residual disease negativity at cycle 4, day 15, and subsequent improvement in progression-free survival.

What data were presented at the meeting?

We looked at the correlation between a number of other risk factors and then progression-free survival. We looked at cell of origin, ABC vs GCB, and found that there was no correlation between cell of origin and progression-free survival in diffuse large B-cell lymphoma. That traditional risk factor does not seem to affect outcomes when using this bispecific antibody.

We also looked at the presence of TP53 mutations, which was the most common mutation found in both follicular lymphoma and diffuse large B-cell lymphoma. While it was not statistically significant, we saw that there was a trend towards worsened survival for those patients who had abnormalities in TP53.

How might these findings influence future research?

It is significant to find that with bispecific antibodies and with T-cell directed therapy, we can generate an MRD-negative state. I don't think that was something that we could assume before. I think achieving MRD negativity is a requirement for long-term remissions, which is what our hope is with the bispecific agents, that we are able to treat patients, get them into a MRD-negative state, and hopefully, they'll stay there. Time remains to tell us what's going to happen. Are these patients going to relapse? But I think this is a good first start. I think these tools can also be used to measure for early relapse. One of the open questions with many of the bispecific antibodies is duration of therapy. In the future, we can look at using MRD status as a marker to potentially end therapy, given that it looks like those patients who achieve MRD-negative status have prolonged progression-free survival.

What is next for this research?

Building on this research, the sponsor is planning a number of randomized phase 3 trials, and the plan is to incorporate the ctDNA analysis into those trials. We'll learn more about the role of minimal residual disease with bispecifics.

For oncologists in the community setting, what are the key takeaways from this research?

The world is changing, and there's still a role for chemoimmunotherapy. I think that that continues to be our first-line treatment. In the second-line setting, [chimeric antigen receptor (CAR) T-cell therapy] has replaced autologous bone marrow transplant, and I think that there is the role for bispecific antibodies to fit in those niches as well. For patients where there were no longer good options after CAR T failure after multiple lines of therapy, we've seen good efficacy with bispecific antibodies. We continue to refine how to use those in combination, so it's an exciting time.

What other data regarding bispecifics should oncologists be aware of?

There's a ton of data, and it's impossible to keep up. What I would say is that the big question is that [with] all these different bispecific antibodies, how do you choose between them? I would say that they have more in common than they have in difference. Again, time will tell which of these ends up being indicated for which diseases.

Are there any factors that influence your decision to treat in your clinical practice?

We always try to enroll patients on clinical trials when we're dealing with an ambiguous space in regard to best options. Then for choosing bispecific antibodies based on label, there are currently very few options and so we just follow the labels. It's almost unbelievable how much science and medicine is happening and every year things advance so quickly. It's a remarkable time to be doing what we do.