CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: March 06, 2024
Expiration: March 05, 2025
ELM-2: Final Analysis of Odronextamab in Relapsed/Refractory DLBCL
There are currently 2 CD3xCD20 T-cell engaging bispecific antibodies approved for R/R DLBCL—glofitamab and epcoritamab.15,16 A third agent, odronextamab, is currently under investigation, and the final analysis of the ELM-2 trial that will hopefully lead to its approval by the FDA in the near future was presented at ASH 2023.
The open-label phase II ELM-2 evaluated odronextamab IV, administered in escalating doses, in 127 patients with R/R DLBCL after 2 or more systemic therapies, including an anti-CD20 mAb and an alkylating agent.17 The step-up design was used to mitigate against CRS. Odronextamab was administered weekly for the first 4 cycles, which is a more intensive schedule than similar agents such as glofitamab, which is only administered weekly for the first cycle.15
ELM-2 DLBCL Cohort: Baseline Characteristics
The median age of patients in ELM-2 was 67 years.17 These are patients with phenomenally high international prognostic index (IPI) scores, with 32.3% having a score of 3 and 23.6% having a score of 4 to 5. The median number of prior therapies was 2, with some patients having had as many as 8. Approximately half (55.1%) of patients were primary refractory, which is a subgroup that tends to have inferior outcomes.18 The majority of patients (86.6%) were refractory to their last therapy.17
ELM-2 DLBCL Cohort: Response
The ORR in this study was 52%, with a CR rate of 31.5%. The median DoR was 10.2 months.
ELM-2 DLBCL Cohort: Response by High-Risk Subgroup
Regardless of the presence of high-risk disease, most patients did well with odronextamab. However, unsurprisingly, the patients with a low IPI score (0-1) did better than those with a high IPI score (4-5) (ORR: 84.2% vs 33.3%).
ELM-2 DLBCL Cohort: Survival
In studies with CAR T-cell therapy or a bispecific antibody such as odronextamab, CR rate is key, with PFS varying based on whether a CR is achieved. We saw that play out in ELM-2, where the median PFS was 20.4 months vs 5.8 months in those who achieved a CR (n = 40) or PR (n = 26), respectively. Furthermore, median OS was not reached for those who achieved a CR and was 17.0 months in those who achieved a PR. Thus, odronextamab did elicit durable remissions and prolonged survival in this study.
In the overall population, the median PFS with odronextamab was 4.4 months and the median OS was 9.2 months.
ELM-2 DLBCL Cohort: Safety
The majority of patients (87.4%) experienced a treatment-related adverse event (TRAE), with more than half (53.5%) having a grade 3 or higher TRAE. The most commonly reported TRAEs included CRS (55.1%), pyrexia (22.8%), neutropenia (20.5%), and anemia (16.5%).
ELM-2 DLBCL Cohort: Adverse Events of Interest
Again, CRS is an AE of special interest with this bispecific antibody. The majority of CRS with odronextamab was low grade, with 40.0% grade 1 (a fever) and 11.7% grade 2 (hypotension). Only 1 patient had a grade 3 event.
The median time to CRS onset was 18 hours—so not necessarily occurring during administration. With the exception of mosunetuzumab for FL,6 most bispecific antibodies require hospitalization for observation following infusion. The timing of hospitalization varies for each bispecific antibody and basically aligns with when the peak incidence of CRS is anticipated to occur. Patients also need to understand what to do in the event CRS occurs while receiving a bispecific antibody.
Of importance, no ICANS or neurotoxicity was observed with odronextamab, which is a huge difference from what we see with CAR T-cells.
ELM-1 Subgroup Analysis: Odronextamab in Patients With R/R DLBCL Pretreated With CAR T-Cell Therapy
Of note, patients who had previously received CAR T-cell therapy were excluded from ELM-2 (NCT03888105).17 However, ELM-1, the single-arm dose escalation/expansion phase I study evaluating odronextamab in patients with R/R B-cell malignancies that led to ELM-2, did include this patient population. In the cohort of patients with R/R non-Hodgkin lymphoma (NHL) from ELM-1, 29% of the 145 heavily pretreated patients (median of 3 prior therapies) had received CAR T-cell therapy.19 In a prespecified subgroup analysis, odronextamab achieved an ORR by independent central review of 48% with a CR rate of 32% in patients with R/R DLBCL who had received prior CAR T-cell therapy (n = 31).20
This subgroup analysis was updated at ASH 2023.21 In the post-CAR T setting, an ORR of 48% with a CR rate of 30% was reported for the cohort of 44 evaluable heavily pretreated patients with R/R DLBCL receiving odronextamab. Furthermore, median PFS and OS were longer in patients with a CR vs a PR (median PFS: not reached [NR] vs 5.0 months; median OS: NR vs 7.7 months.) I would consider using a CD3xCD20 T-cell engaging bispecific antibody in the post-CAR T setting.
ELM-2 DLBCL Cohort: Clinical Implications
The data with odronextamab are interesting, and I anticipate it will join our other 2 FDA-approved CD3xCD20 bispecific antibodies for the management of R/R DLBCL in the future.
One question is how do we choose between CAR T-cell therapy and the CD20xCD3 bispecific antibodies for patients with R/R DLBCL? In this setting, we know that CAR T-cell therapy can be curative, so I would use it as the standard for patients who have R/R DLBCL. For patients who are not candidates for CAR T-cell therapy, a bispecific antibody could be considered. But until we have data that show that a bispecific antibody is curative in R/R DLBCL, I will default to CAR T-cell therapy.
ELM-2 Exploratory Analysis: Study Design
The ELM-2 exploratory analysis included patients with R/R FL and DLBCL who had received odronextamab and aimed to evaluate the association between ctDNA-based MRD and clinical outcomes.22
ELM-2 Exploratory Analysis: PFS by MRD Status in the Biomarker Population at C4D15
In patients with both R/R FL and DLBCL, MRD negativity by ctDNA at Cycle 4 Day 15 of odronextamab therapy was found to correlate with PFS benefit.22 In FL, ctDNA-based MRD status was predictive of PFS benefit in those who achieved a CR. For those with DLBCL, ctDNA-based MRD status was predictive of PFS benefit in those who did not achieve a CR.
ELM-2 Exploratory Analysis: Clinical Implications
These data are interesting, but very exploratory at this time. We do not know how to best use ctDNA-based MRD status in lymphoma yet, but there is certainly early and exciting data to suggest that sometimes it can predict how long someone is going to be in remission, and also can be used to monitor for relapse. It is assuring to see data showing that ctDNA-based MRD status may be prognostic in terms of PFS with a bispecific antibody.
EPCORE NHL-5: Epcoritamab SC + Lenalidomide in Relapsed/Refractory DLBCL
Epcoritamab is another bispecific antibody currently approved for R/R DLBCL. It is now being evaluated in various combination regimens as part of the relatively small multicohort phase Ib/II EPCORE NHL-5 study. At ASH 2023, arm 1 of EPCORE NHL-5 evaluating epcoritamab in combination with lenalidomide for R/R DLBCL reported; 35 patients with R/R DLBCL received epcoritamab SC plus lenalidomide PO (12 x 28-day cycles).23
We have data on a similar combination in R/R FL from the multicohort phase Ib/II EPCORE NHL-2 study evaluating epcoritamab combined with standard of care therapies in patients with B-cell NHL (NCT04663347). Arms 2a and 2b evaluated epcoritimab added to lenalidomide/rituximab, a very effective standard-of-care regimen typically used in the second-line setting for FL, and this combination showed a dramatic response rate (ORR: 98%) in patients with R/R FL.24
EPCORE NHL-5 is taking a similar approach in R/R DLBCL.23
EPCORE NHL-5: Baseline Characteristics
The median age of patients was 72 years, and they had received a median of 2 previous lines of therapy. Approximately one fourth (23%) had received CAR T-cell therapy and a small percentage (6%) had a stem cell transplant. Just under half (43%) of patients were primary refractory, which again defines a very poor risk patient population.
EPCORE NHL-5: Responses
The objective response rate with the combination of epcoritamab plus lenalidomide was 71.9%, with 53.1% of patients achieving a CR. The median time to response and median time to CR was 1.8 months and 1.9 months, respectively. There were no major differences in CR rate by subgroup.
Rates of MRD negativity at Cycle 3 Day 1 were also evaluated, and even patients who did not have a CR achieved MRD negativity with the combination at this time point. It will be interesting to see how this compares to other studies for which we do not have data at this time.
EPCORE NHL-5: Safety
The addition of lenalidomide to a bispecific antibody raises the concern of whether toxicity will be increased. We do see an increase in hematopoietic toxicity with the combination,23 which would be expected as we know that lenalidomide, especially with the dose used here (25 mg on Days 1-21 every 28 days) can cause hematopoietic toxicity.
It is not clear to me whether we are seeing a worsening of CRS with the combination compared to epcoritamab monotherapy. A total of 11% of patients had grade 3/4 CRS. One patient developed grade 3 ICANS. This is a small study so it is difficult to know whether these AEs are truly increased with the combination, but we should continue to monitor toxicity with this regimen.
EPCORE NHL-5: CRS
Delving further into the occurrence of CRS with epcoritamab plus lenalidomide, the incidence was relatively high, with an overall rate of 69%. Again, CRS is less of an issue if it is grade 1/2 but more so if it is grade 3 or higher. Four patients (11%) did develop grade 3 CRS, which is a relatively high rate. We will need additional data to determine if this is due to the study size or if it holds up in a larger patient population. In addition, many patients required tocilizumab (54%), corticosteroids (42%), or both (29%) to manage CRS.23
EPCORE NHL-5: Clinical Implications
I am unsure whether we should be combining the bispecific antibodies with lenalidomide in DLBCL, which did not clearly improve response rates but did increase AEs. As I mentioned, the data for epcoritimab combination regimens are more exciting in FL, and DLBCL may be a setting where it will be important to target its use to specific patients.
VALENTINE-PTCL01: Phase II Trial of Valemetostat in R/R Peripheral T-cell Lymphoma
VALENTINE-PTCL01 is a phase II trial that evaluated oral valemetostat, a dual inhibitor of EZH1 and EZH2,25 in patients with R/R peripheral T-cell lymphoma (PTCL) or adult T-cell lymphoma/leukemia who had received at least 1 previous line of therapy (including previous BV for those with anaplastic large cell lymphoma) (NCT04703192). The analysis presented at ASH 2023 was from cohort 1 of patients with R/R PTCL.26
VALENTINE-PTCL01: Baseline Characteristics
PTCL not otherwise specified (NOS) is often the most difficult to treat, and that subgroup of patients comprised 30.8% of patients enrolled on this trial. The median number of prior therapies for the total patient population was 2 (range: 1-12).
VALENTINE-PTCL-01: Key Efficacy Endpoints
The primary endpoint of ORR was 43.7%, with a CR rate of 14.3%, which is relatively low, but not surprising—you would expect a low CR rate in a population that has had a median of 2 prior lines of therapy.
PET/CT-based response was an exploratory endpoint, and the ORR by PET/CT was slightly higher at 52.1%, with a complete metabolic response of 26.9% and partial metabolic response of 25.2%.
VALENTINE-PTCL01: Additional Secondary Endpoints
The median PFS was relatively low at 5.5 months, with a more encouraging median DoR of 11.9 months. Unfortunately, there were not many patients who responded to valemetostat, but those who did appeared to derive a durable benefit.
VALENTINE-PTCL01: Response by PTCL Subtype
As anticipated, patients with PTCL NOS had worse outcomes, with lower ORR and CR rates by CT-based assessment compared to other subtypes. We continue to need additional therapies in PTCL, including for these more difficult to treat subpopulations such as patients with PTCL NOS.
VALENTINE-PTCL01: Safety
Valemetostat was relatively well tolerated compared to many agents that we would use in this setting, which is an advantage. This is a dual EZH1 and EZH2 inhibitor and we have experience in other settings with EZH2 inhibitors showing that the AE profile is relatively benign.
In this challenging patient population with multiple relapses, one concern is the risk of infection. Grade 1/2 neutropenia was reported in 9.0% and grade 3/4 in 17.3%, which is relatively low. Grade 1/2 diarrhea was reported in 25.6% of patients and 3.8% experienced grade 3/4 diarrhea.
VALENTINE-PTCL01: Clinical Implications
In summary, this is a relatively well-tolerated drug in a very difficult to treat patient population. Although the efficacy results were modest, approximately 40% of patients had a response, many of which were durable responses, which is clinically meaningful. Unfortunately, we continue to need better agents with broader applicability in this setting.
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