CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 16, 2024
Expiration: February 15, 2025
ECHELON-3: Phase III Trial of Brentuximab Vedotin With Lenalidomide and Rituximab in R/R DLBCL
Jeffrey P. Sharman, MD:
The ECHELON-3 trial was a phase III study in patients with R/R ) diffuse large B-cell lymphoma (DLBCL). Patients were randomized to brentuximab vedotin or placebo in combination with rituximab and lenalidomide. Eligible patients must have had at least 2 prior lines of systemic therapy and be either ineligible for or have progressive disease after ASCT or CAR T-cell therapy. They had to have measurable disease and could not have significant peripheral neuropathy (grade 2 or higher).
It is important to note that they were stratified by CD30 status at greater than or less than 1%, as well as cell of origin. The key primary endpoint was OS in the ITT population.39
ECHELON-3: Baseline Characteristics
The baseline characteristics were in line with what is typically seen in a study like this. It was a somewhat older population, in part because they were either transplant-ineligible or had failed transplant or CAR T-cell therapy. The median age was slightly older in the experimental arm with brentuximab vedotin compared with the placebo arm, 74 vs 70 years, respectively. Otherwise, their baseline characteristics were relatively similar.39
ECHELON-3: OS and PFS in ITT Population
The addition of brentuximab vedotin to lenalidomide/rituximab significantly improved the median OS from 8.5 to 13.8 months. The PFS was relatively short in this population. Focusing on the trial design, I think it is reasonable to question the nature of the control arm. Consider that this was a study launched at a time where the number of salvage options that had full approval was somewhat less than are available at present. And so, this was an agreed-upon control arm with the FDA with lenalidomide/rituximab. However, you can see a clear benefit for the addition of brentuximab vedotin to this group, with a median PFS of 4.2 months vs 2.6 months.39
ECHELON-3: Median OS by Subgroup
Looking at the subgroup analysis, all evaluated subgroups did benefit from the addition of brentuximab vedotin. Since CD30 is the target of brentuximab vedotin, one would mostly expect that you would need to have CD30 present to benefit from this therapy.
But I think what we have seen in this and other studies is that there remains much to CD30 that we do not necessarily know. And there may very well be shuttling of CD30 to the surface of the membrane. Even in those patients who appear CD30 negative or have a low level of expression, they can still benefit from the addition of brentuximab vedotin.
All patient subgroups benefited, whether patients had prior CAR T-cell therapy, had high IPI scores, were relapsed or refractory, and so forth. Of note, the presence or absence of CD30 did not affect whether there was a benefit with the addition of brentuximab vedotin; patients benefited regardless of their CD30 status.39
ECHELON-3: Response
Shown here are the ORR and CR here. The addition of brentuximab vedotin increased the ORR from approximately 41.5% to 64.3% and the CR rate from 18.6% to 40.2%. And the benefit was consistent, once again, whether patients had CD30-positive disease or not. 39
ECHELON-3: Safety Summary and Subsequent Therapy
In terms of safety, as expected there was some peripheral neuropathy associated with brentuximab vedotin, with grade ≥3 events occurring in 31% receiving brentuximab vedotin and 24% with placebo. There was also febrile neutropenia, but the overall rates were not significantly different (88% with brentuximab vedotin vs 77% with placebo). Finally, the rates of grade 5 toxicity were relatively similar between the 2 treatments (12% and 8%, respectively).39
ECHELON-3: Clinical Implications
For patients with relapsed DLBCL in need of therapy who are neither candidates for cellular therapy nor have experienced treatment failure, this regimen appears to provide meaningful clinical benefit and could be considered in appropriately selected patients.
EPCORE NHL-1: SC Epcoritamab in Patients With R/R Large B-Cell Lymphoma
There were 2 important updates on bispecific antibodies in lymphoma: one with epcoritamab and one with glofitamab. Both epcoritamab and glofitamab are now both approved for the management of patients with R/R DLBCL.40,41
At ASCO 2024, data were presented from the EPCORE NHL-1 trial of epcoritamab with a longer follow-up.42
The EPCORE NHL-1 trial included patients with B-cell non-Hodgkin lymphoma (NHL) who had received at least 2 prior therapies, including a CD20 monoclonal antibody. This report was of the phase II dose expansion.42
EPCORE NHL-1 Update: Baseline Characteristics and Patient Disposition
Looking at the baseline characteristics, this is a slightly younger population, with a median age of 64 years among the entire cohort. Patients were also divided into the entire group with LBCL and those with LBCL and a CR.
There was not anything that stood out in terms of baseline characteristics and response, although not surprisingly, those who had primary refractory disease or those who were refractory to their most recent therapy comprised a greater percentage of patients in the LBCL group compared with those with LBCL and a CR (61% vs 48% and 83% vs 74%, respectively), correlating with reduced responses.42
EPCORE NHL-1 Update: Efficacy
With updated efficacy, the ORR was approximately 60% overall, with CR rates of approximately 40%.42 With these agents, obtaining a CR is of particular importance because those are the patients who derive the most significant and durable benefit.
EPCORE NHL-1: Efficacy in Complete Responders
Recall that approximately 40% of patients had a CR. For those who achieve a CR, the PFS and OS can be quite significant, with 33-month rates of 55% and 71%, respectively.
They also completed an analysis where they adjusted to essentially censor out those who had COVID-19, as this study was completed during peak times of COVID-19. Perhaps not surprisingly, when those events are censored out, the performance of the drug is even a little bit better, with 33-month PFS and OS rates of 69% and 85%, respectively.42
EPCORE NHL-1 Update: Safety
In terms of safety, CRS is notable and occurred in approximately one half (51%) of patients in the overall cohort. Once again, most CRS events were grade 1/2, with a low number being grade 3 (3% in the expansion and 1% in the C1 optimization cohort). More steroids and premedications were added for the optimization cohort and that seemed to mitigate the risk of CRS, with the rates reduced from approximately 51% to 37% overall, with lower rates of grade 3 as well.42
As the study evolved, there was a bit more liberal use of tocilizumab, and I think that is one of the aspects of this molecule that individuals in the community may need to familiarize themselves with: how and when to use tocilizumab.
The study had 9 COVID-related fatalities, and that was in part related to the timing of when the study was conducted.42
EPCORE NHL-1: Clinical Implications
Epcoritamab is now approved for patients with R/R DLBCL and is an effective agent. Understanding the clinical performance of the drug and strategies for mitigating side effects will be important as this agent becomes more broadly used.
Phase I/II Study of Glofitamab Retreatment in Patients With Heavily Pretreated R/R NHL
Next, data were presented on glofitamab retreatment. Although epcoritamab is administered until progression of disease, glofitamab is given as fixed-duration therapy. Therefore, if glofitamab is administered for a fixed duration, a reasonable question to ask is, “How does it work if you retreat?” This study evaluated patients who had achieved either a CR, partial response, or a stable disease following completion of initial treatment with glofitamab and then had subsequent documented progression of disease on a PET/CT scan.
Of note, one way to mitigate CRS with glofitamab is the use of obinutuzumab prior to decrease the quantity of CD20-positive cells. During both the initial treatment and retreatment, obinutuzumab was administered 7 days prior to glofitamab.43
Glofitamab Retreatment: Baseline Characteristics
Looking at the baseline characteristics, what is most notable here is that this was a mix of diseases, including DLBCL, follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL), mantle cell lymphoma (MCL), and transformed FL.43
Glofitamab Retreatment: Efficacy
This is a relatively small study—13 patients overall—but I think we can begin to infer some of the characteristics of those patients who respond and those who do not. We see here that those individuals with DLBCL or HGBCL did not have much of a response. However, those with FL, MCL, or even transformed FL did have responses. The prior response to glofitamab did not seem to correlate with response to retreatment.43 But I think it is important to recognize that, again, those patients LBCL who have relapse do not appear to be responding to retreatment, whereas perhaps the more indolent histologies may be.
Glofitamab Retreatment: Safety
In terms of safety, once again, the most common AE is CRS. In this study, all events were grade 1/2 and all occurred during cycle 1.43 Therefore, healthcare professionals should familiarizing themselves with the management of CRS.
Glofitamab Retreatment: Clinical Implications
Glofitamab is a fixed-duration therapy as opposed to epcoritamab, which is designed to be used as therapy until progression. It is, therefore, important to understand how this therapy performs following relapse. With this early look at the data, it appears that some histologies may do better than others but a larger sample size will be needed before any final determinations can be made.
Cytopenias and Myeloid Neoplasm After CAR T-Cell Therapy: Study Designs
Next, I discuss 2 studies that look at AEs following CAR T-cell therapy. Many of us are referring patients for CAR T-cell therapy and then they may come back with specific therapy-related issues. Therefore, being familiar with some of these potential complications is helpful.
These slides refer to 2 different studies, and I discuss them in parallel. In the study by Habib and colleagues,44 they looked at 190 patients who had received CAR T-cell therapy for R/R NHL. In the study from Silva Corraes and colleagues,45 they included both lymphoma and MM, but they were not only looking at the characteristics of myeloid neoplasms that occur afterwards, but also seeing if they could identify predictors of who might have more complications with CAR T-cell therapy.
Cytopenias and MN After CAR T-Cell Therapy: Study 1 Baseline Characteristics
As might be expected, these studies included younger patients because they were being seen for CAR T-cell therapy at academic institutions, and they had a mix of diseases. I think it is important to note that the median prior lines of therapy were 4 in the patients who developed myeloid neoplasms post-CAR T-cell therapy.44 So these patients had a lot of prior therapies, which is important for some of the conclusions of this study.
Cytopenias and MN After CAR T-Cell Therapy: Study 2 Baseline Characteristics
Recall that the second study, which looked at both the emergence of cytopenias and treatment-associated myeloid neoplasm, included patients who had received CAR T-cell therapy for either NHL or multiple myeloma. And once again, there was a median of four prior lines of therapy45—again, a heavily pretreated population.
Cytopenias and MN After CAR T-Cell Therapies: Incidence
Looking at the data from Habib and colleagues,44 one can see that the frequency of treatment-associated myeloid neoplasms increases with time: At 2 years, it is 1.1%, at 3 years, 3.7%, and at 4 years, 4.6%.45
The rates of treatment-related myeloid neoplasms were higher in the dataset from Silva Corraes and colleagues.45 They separated their results based on those with lymphoma on the left and myeloma on the right. As shown, 17% of patients had prolonged cytopenias and 14% and 7%, respectively, had treatment-associated myeloid neoplasms as well.
Cytopenias and MN After CAR T-Cell Therapies: Predictors of Cytopenias (Study 2)
The investigators at the Mayo Clinic attempted to conduct an analysis to look at predictors of these complications, and they had a number of factors emerge in a univariate analysis. They then conducted a multivariate analysis. Essentially, 3 factors were found to be predictive of cytopenias after CAR T-cell therapy: age older than 65 years, hemoglobin <10 g/dL, and platelets <140,000.45
Cytopenias and MN After CAR T-Cell Therapies: Predictors of Cytopenias (Study 2)
They evaluated those with not only prolonged cytopenias, but also treatment-associated myeloid neoplasms, and again, it was the same variables: patients older than 65 years of age, hemoglobin <10 g/dL, or platelets <140,000—all had significant predictive impact in terms of who developed treatment-associated myeloid neoplasms.45
Cytopenias and MN After CAR T-Cell Therapies: Cytogenetics of MN (Study 1)
In The Ohio State University's dataset, they then looked at the myeloid neoplasms and tried to characterize them to determine whether these were related to the CAR T-cell therapy or more likely to the prior therapy, keeping in mind that these patients had a median of 4 prior lines of therapy.44
What they found were cytogenetic characteristics that are much more typical of treatment-associated disease: abnormalities in chromosome 5 and/or 7 and/or TP53 mutations. These are abnormalities that are typically seen following alkylating agents, anthracyclines, and so forth.
Cytopenias and MN After CAR T-Cell Therapies: Overall Survival
Both studies evaluated OS, including among patients with post–CAR T-cell therapy myeloid neoplasm, cytopenia, or neither.44,45 Keep in mind that some of these myeloid neoplasms were MDS and some were AML, and in many cases, they were probably quite sensitive to these cytopenias and getting bone marrow biopsies done relatively early in the course of the disease. But for those who developed a treatment-associated myeloid neoplasm, median OS was approximately 2 years.45
Cytopenias and MN After CAR T-Cell Therapy: Clinical Implications
Cytopenias following CAR T-cell therapy are a common problem and may affect subsequent treatment options. Furthermore, in some cases, secondary myeloid malignancies may evolve. For healthcare professionals, this risk relative to benefit needs to be considered as patients are referred for immune effector cell therapy.
Pirtobrutinib Plus CAR T-Cell Therapy: Study Design
The final study I discuss is a phase I/II trial evaluating CAR T-cell therapy with prior pirtobrutinib. Pirtobrutinib is currently approved by the FDA for patients with R/R chronic lymphocytic leukemia and MCL. This study evaluated patients who had received lentiviral-transduced bispecific anti-CD20/CD19 (LV20.19) CAR T-cell therapy and pirtobrutinib within 4 weeks prior to apheresis.46
Pirtobrutinib Plus CAR T-Cell Therapy: Baseline Characteristics
In total, 11 patients were included with a mix of NHLs, a median age of 65 years, and a median of 4 prior therapies—a heavily pretreated population.46
Pirtobrutinib Plus CAR T-Cell Therapy: Efficacy and Safety Outcomes
In this small subset, the ORR at Day 28 was 82%, with 7 CRs. The OS rate at 1 year was 83%. In terms of safety, the majority of patients (n = 9) had CRS, although all events were grade 1/2, and immune effector cell–associated neurotoxicity syndrome occurred in 2 patients.46 Overall, these data support the safety of pirtobrutinib prior to CAR T-cell therapy; an ongoing trial will further assess pirtobrutinib as bridging and maintenance therapy prior to LV20.19 CAR T-cell therapy (NCT05990465).
Pirtobrutinib Plus CAR T-Cell Therapy: Clinical Implications
For patients with R/R chronic lymphocytic leukemia, their condition may be stabilized through use of pirtobrutinib, but resistance can evolve fairly quickly. It is important to note that pirtobrutinib does not appear to influence the safety of CAR T-cell therapy and patients may be considered for CAR T-cell therapy while receiving pirtobrutinib.
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