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Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

In season 3, episode 5 of Targeted Talks, Thomas Habermann, MD, a hematologist at the Mayo Clinic Comprehensive Cancer Center and professor of Medicine at the Mayo Clinic College of Medicine, discusses the latest advances in the treatment of diffuse large B-cell lymphoma (DLBCL).

After administering radiation therapy in the frontline setting to patients with DLBCL for many years, PET-adapted therapeutic approaches were introduced. Then, across roughly 25 clinical trials, explains Habermann, investigators explored the efficacy and safety of the rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), which became the standard of care regimen for DLBCL treatment.

In recent years, clinical trials are assessing targeted therapies and immunotherapies, including chimeric antigen receptor T cells with the goal of improving on the standard of care.

According to Habermann, the most important thing to focus on with the next wave of therapies is curing 100% of patients with DLBCL. Currently, this is only possible in 65% of patients who received R-CHOP, explains Habermann. Improvement in both systemic and radiation therapies signal hope that the field is moving in the right direction, Haberman notes.

In season 3, episode 5 of Targeted Talks, Thomas Habermann, MD, discusses the upcoming advances in the treatment of diffuse large B-cell lymphoma.

The Road to Improving Diffuse Large B-Cell Lymphoma Treatment 

Azercabtagene zapreleucel has been granted fast track designation from the FDA for the treatment of diffuse large B-cell lymphoma.

FDA Grants Azer-Cel Fast Track Status in DLBCL

Matthew Matasar, MD, discussed what the findings from the ELM-1 trial of odronextamab in diffuse large B-cell lymphoma mean for oncologists.

Odronextamab Shows Efficacy in DLBCL Post CAR T-Cell Therapy

During a Case-Based Roundtable® event, Natalie Galanina, MD, reviewed how outcomes have changed in patients with primary refractory or early relapsed DBLCL since the introduction of CAR T-cell therapy.


Early Relapsed DLBCL Outcomes Have Changed Drastically Due to CAR T

During a Case-Based Roundtable® event, Natalie Galanina, MD, discussed data from the ZUMA-7 and TRANSFORM trials in the first article of a 2-part series. 

CAR T-Cells Demonstrate Efficacy, Tolerability in Early-Relapsed DLBCL

Zamtocabtagene autoleucel induced responses, including durable complete responses, in relapsed/refractory diffuse large B-cell lymphoma.

Zamto-Cel Shows Durable Responses in Relapsed/Refractory DLBCL

Shouse Covers the Future of Lymphoma Therapy With Bispecific Antibodies

Geoffrey Shouse, DO, PhD, an assistant professor at City of Hope Comprehensive Cancer Center in Duarte, California, and a member of the lymphoma division, discusses the growing interest in bispecific antibodies within the field of oncology. He specifically highlights their growing role for the treatment of patients with diffuse large B-cell lymphoma.

He highlights the collaborative efforts of several consortia working to gather and analyze data on these therapies. Shouse notes that City of Hope, his institution, is part of a network of over 10 centers contributing to this research, which aims to compile larger datasets on patient outcomes.

The goals of this work include evaluating the efficacy and safety of FDA-approved bispecific antibodies, as well as identifying predictors of treatment outcomes and toxicity. In addition, Shouse emphasizes the importance of examining not only clinical outcomes but also broader issues such as financial toxicity, social challenges, and access barriers that patients may face.

 I know that there are a couple kinds of consortia working together that are trying to pull data about bispecific antibodies. We are contributing to a group of more than 10 centers and we are getting much higher numbers in terms of patients with bispecific antibodies. We are going to be looking individually at outcomes with each of the agents that are FDA-approved, and then kind of taking deeper dives and looking—trying to drill into predictors of outcomes, predictors of toxicity, even financial toxicity and social issues, as well as access issues for bispecifics.

[Bispecifics] really do seem to be a very beneficial therapy for patients with large cell lymphoma. And so, identifying how we can safely get this treatment to patients and get it to patients at all, I think, are important questions that will hopefully be evaluated and answered in the coming months.

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Geoffrey Shouse, DO, PhD, discusses the growing interest in bispecific antibodies within the field of oncology.

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Ayyappan Discusses the Phase 2 ELM-2 Trial of Odronextamab in DLBCL

Sabarish Ram Ayyappan, MD, medical director of hematologic malignancies, City of Hope Cancer Treatment Center, Atlanta, discusses the mechanism of action of odronextamab (REGN1979) and highlights the 

 (NCT03888105) which evaluated the agent in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The open-label, multicohort, multicenter, phase 2 study enrolled patients with relapsed/refractory DLBCL per WHO 2016 classification who had an ECOG performance status score of 0 or 1, and had disease that was refractory to or relapsed after 2 or more prior lines of therapy, including an anti-CD20 antibody and an alkylator.

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

The primary end point of the study was overall response rate (ORR) by independent committee review. Secondary end points included ORR by local investigator, complete response, duration of response, progression-free survival, and overall survival. Investigators also evaluated safety, tolerability, and patient-reported outcomes, and minimal residual disease served as an exploratory end point of the study.

Patients with relapsed and refractory diffuse large B-cell lymphoma tend to have poor outcomes. There have been newer therapies that have been approved include CAR [chimeric antigen] T-cell therapy, but patients do relapse post CAR T, so there is a need for novel agents. 

The new class of drugs called bispecific antibodies have been exciting in this class for treatment of patients with relapsed and refractory diffuse large B-cell lymphoma. Odronextamab is a human IgG4 anti-CD3/CD20 bispecific antibody that has shown activity in diffuse large B-cell lymphoma and other non-Hodgkin lymphoma. As part of evaluating the efficacy and safety of this drug, the phase 2 study was designed and enrolled patients in a global cohort of diffuse large B-cell lymphoma patients who had relapsed and [were] refractory after 3 lines of therapy, including an anti-CD20 alkylator therapy. 

 The study started enrollment in March 2020 and completed enrollment in May 2022, enrolling patients from 14 different countries globally. There are patients that had some high-risk characteristics, including double-hit lymphoma. Twenty percent of patients had transformed lymphoma as a characteristic, [and] patients of older age greater than 75 years of age are constituted about 24% of the patient as well.

Sabarish Ram Ayyappan, MD, discusses the mechanism of action of odronextamab and highlights the phase 2 ELM-2 trial which evaluated the agent in patients with relapsed/refractory diffuse large B-cell lymphoma.

Christopher J. Melani, MD, discusses the ViPOR trial of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide, in patients with DLBCL

Novel Combination Therapy Impresses With Safety/Efficacy in DLBCL

Christopher J. Melani, MD, assistant research physician in the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, discusses updated data from the phase 1b/2 ViPOR trial (NCT03223610) of the combination of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid), in patients with diffuse large B-cell lymphoma (DLBCL).

According to Melani, the combination, which is given in short, non-continuous cycles, showed promising safety and efficacy results and was well-tolerated across all ages. A total of 38% of patients achieved complete remission (CR), and these rates were even higher in certain subtypes.

While further research is needed, the ViPOR study represents a potentially transformative approach for patients with DLBCL.

 I presented data for the relapsed/refractory cohort of the ViPOR study. ViPOR is a novel combination targeted therapy regimen building on some of the synergy that we've seen in preclinical studies of DLBCL, combining several agents that target B-cell receptor signaling, such as ibrutinib, prednisone, as well as lenalidomide, in addition to venetoclax, which targets BCL2 and apoptosis, and obinutuzumab which facilitates innate immunity through CD20. It really is a novel concept because it's modeled after cytotoxic chemotherapy, where all of the targeted agents are given in non continuous cycles, so 2 weeks of study drug, 1 week break for a fixed duration. So only 6 cycles or 18 weeks without any maintenance therapy.

 What was impressive regarding this regimen is 1: it was extremely safe and tolerable for patients of all ages, even upwards into their 80s, compared [with] other types of regimens such as cytotoxic chemotherapy, and it was very effective.


Overall the rate of complete remission was 38% in patients with relapsed/refractory large cell [lymphoma], with a median line of therapy of 3. In some subtypes, such as the ABC or non GCB subtype of diffuse large B-cell lymphoma, as well as high grade B-cell lymphoma double-hit BCL2, the CR rates were in the 62% and 53% range, respectively. Despite the time-limited therapy of only 6 cycles, these remissions were very durable. Overall, our 2-year progression-free survival was 34%. In double-hit, it was 47%, and in high-grade B-cell lymphoma, it was 38% and a median follow-up of 40 months. These were very deep and durable remissions, despite a very fixed limited therapy.

Christopher J. Melani, MD, discusses updated data from the phase 1b/2 ViPOR trial of the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide, in patients with diffuse large B-cell lymphoma.


Sabarish Ram Ayyappan, MD, discusses the final analysis of the phase 2 ELM-2 trial of odronextamab in a cohort of patients with relapsed/refractory DLBCL.

Final Analysis of ELM-2 Shows Promise of Odronextamab in R/R DLBCL

Sabarish Ram Ayyappan, MD, medical director of hematologic malignancies, City of Hope Cancer Treatment Center, Atlanta, discusses findings from the final analysis of the phase 2 ELM-2 trial (NCT03888105) of odronextamab (REGN1979) in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).


 showed that among complete responders in this cohort of patients, treatment with odronextamab achieved an objective response rate (ORR) of 52%. Encouraging progression-free (PFS) and overall survival (OS) rates were also observed.

Further, these results showed that the median duration of response (DOR) was 10.2 months (95% CI, 5.0-17.9), with 12- and 24-month DOR rates of 48.1% (95% CI, 35.1%-59.9%) and 36.9% (95% CI, 24.2%-49.6%), respectively. The median duration of complete response (DOCR) was similar at 17.9 months (95% CI, 10.2-not evaluable [NE]), with 12- and 24-month DOCR rates of 61.5% (95% CI, 44.4%-74.8%) and 47.2% (95% CI, 29.7%-62.9%), respectively.

The overall risk objective response rate was 51% with a complete response rate of 32% in the whole cohort at a median follow-up of 29.9 months. The responses were durable with a median duration of complete response up to 18 months. At 24 months, the complete response was maintained in 47% of the patients. The safety of the drug also was evaluated and consistent with previous reports that odronextamab is safe in patients who received them with relapsed/refractory diffuse large B-cell lymphoma. We reviewed the treatment-emergent adverse events which are about 80%, and adverse events that were noted in the study included cytokine release syndrome, pyrexia, and neutropenia.

 Looking at the cytokine release syndrome, most of the patients had grade 1 cytokine release syndrome, about 12% of patients had grade 2, and only 1 patient had grade 3 and he had ongoing pancreatitis at the time of grade 3 CRS. CRS was resolved in 2 days time with supportive measures. We also described infections that the patients who received odronextamab had during the abstract session. About 60% of patients had any sort of infection in the study, including 18% of the patients who had COVID-19 and 5 COVID deaths. Now in the context of this study being completed in the time of the COVID pandemic, and patients being really immunosuppressed, they had relapsed and refractory disease, this was noted on the study.

Sabarish Ram Ayyappan, MD, discusses findings from the final analysis of the phase 2 ELM-2 trial of odronextamab in a cohort of patients with relapsed/refractory diffuse large B-cell lymphoma.


Olszewski Recaps Results of Mosunetuzumab in Elderly/Unfit DLBCL

Adam J. Olszewski, MD, associate professor of medicine at Brown University, lymphoma clinician at Rhode Island Hospital in Providence, Rhode Island, discusses the promising results of a phase 1b/2 study (NCT03677154) of mosunetuzumab (Lunsumio) for the treatment of elderly/unfit patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

According to findings from the study, treatment with mosunetuzumab was effective and induced durable complete responses (CR) in this patient population. A total of 43% of patients achieved a CR and a median duration of response of 15.8 months.

Additionally, 38% of patients were alive and did not have any evidence of disease after 1 year of follow-up. Overall, these results suggest that mosunetuzumab may be an effective treatment option for elderly/unfit patients with DLBCL who are not candidates for standard chemotherapy.

These responses are built to be durable. Right now, the median duration of complete response is up to 3 years, and we will find out if these patients ever experienced a relapse. So far out of 23 patients who had a complete response only 3 experienced relapse. The other 20 are continuing with complete responses.

Out of 54 patients, 20 elderly patients in my practice and at other practices from investigators who participated in this trial live without any evidence of lymphoma. Some [patients] have passed away from natural causes because it is an elderly population. We have faced challenges related to the COVID pandemic. Mosunetuzumab is a B-cell depleting therapy, which can increase the risk of serious COVID complications, but we have learned how to manage it, especially using the prophylactic measures and available treatments. So altogether, a year after starting this therapy, 3 quarters of these patients were alive, and about 38% of patients were alive without any evidence of disease.

Adam J. Olszewski, MD, discusses the promising results of a phase 1b/2 study of mosunetuzumab for elderly/unfit patients with previously untreated diffuse large B-cell lymphoma.

Hayder Saeed, MD, an associate member in the department of malignant hematology at the Moffit Cancer Center in Tampa, Florida, discusses the mechanism of action of tafasitamab-cxix (Monjuvi) when used to treat patients with diffuse large B-cell lymphoma (DLBCL).

The CD19-directed cytolytic antibody was given an accelerated approval by the FDA in 2020 based off the results of the L-MIND study (NCT02399085), which looked at the use of tafasitamab in combination with lenalidomide (Revlimid). Results from the study initially showed an overall response rate (ORR) of 55% (95% CI, 43%-67%) in 71 evaluable patients with 37% of those response being complete responses (CRs). In 2023, the final 5-year efficacy results showed an increased ORR of 57.0% with CRs accounting for 41.3% of them. 

In the final analysis, at a median follow-up of 44.0 months, median progression-free survival (PFS) was 11.6 months (95% CI, 5.7-45.7) and a median overall survival of 33.5 months (95% CI, 18.3­–not reached). Across all subgroups of patients, benefit was seen for those patients on the combination therapy.

Here, Saeed discusses why the combination therapy has proved potent for patients with DLBCL and how targeting CD19 on the cancer cells makes tafasitamab an important regimen.

It started with something called CD19 on the surface of B-lymphocytes or malignant B-lymphocytes. It can target and kill those cells in multiple ways; it can directly attach itself to that CD19 and enhance the killing of those malignant cells. Also, it can enhance the killing of those malignant cells through facilitating the immune system to recognize those cells.

So, it can bring different types of immune cells that are naturally present in our body and fight cancer and enhance the recognition of the cancer cell and killing it. Different types of cells, such as natural killer cells or macrophages, have enhanced activity while tafasitamab is present. That's why there's some synergistic activity with lenalidomide, which is the compound associated with it, because they both work to enhance the immune system to kill the cancer cells.

Hayder Saeed, MD, discusses how the mechanism of action of tafasitamab makes the therapy a potent cancer cell killer for patients with diffuse large B-cell lymphoma. 

Targeted Therapy With Tafasitamab Proves Effective in DLBCL

Adam J. Olszewski, MD, associate professor of medicine at Brown University, lymphoma clinician at Rhode Island Hospital in Providence, Rhode Island, discusses findings from a phase 1b/2 study (NCT03677154) which evaluated treatment with mosunetuzumab (Lunsumio) for the treatment of elderly/unfit patients who were previously untreated for their diffuse large B-cell lymphoma (DLBCL).

In the study, 43% of patients achieved a complete response (CR), and the median duration of CR was 15.8 months (95% CI, 8.5-not estimable). Eleven of 23 patients who reached a CR maintained it for >12 months. For safety, no new safety signals were observed.

 The treatment is quite safe. It was administered as an outpatient for most patients. It causes CRS, or cytokine release syndrome, in about a quarter of patients, but this is often a low-grade CRS that can be managed with acetaminophen or fewer suppressing agents. Very few patients required hospitalization. Only 1 person required corticosteroids to suppress the CRS, and no patients required intensive care admissions or administration of tocilizumab [Actemra]. It's a safe treatment and many patients did have neutropenia, but it was asymptomatic with only febrile neutropenia. Only 1 of these 54 very elderly patients up to the age of 100 stopped therapy because of treatment-related adverse effects; only 1 in 54.

In terms of the efficacy, it turns out that for many patients who experienced progression early during the first 2, 3 weeks of treatment, these patients moved down to standard treatment, it was available to them without any detriment to their other treatment options. Fifty-six percent of patients achieved the response, and 43% of patients achieved complete response, so 4 out of 10 patients achieved complete response with complete disappearance of lymphoma, typically, after within 3 months of treatment, without any exposure to chemotherapy.

Adam J. Olszewski, MD, discusses findings from a phase 1b/2 study which evaluated treatment with mosunetuzumab for the treatment of elderly/unfit patients who were previously untreated for their diffuse large B-cell lymphoma.

Safety and Efficacy of Mosunetuzumab in Elderly Patients With DLBCL

Elizabeth Lihua Budde, MD, PhD, associate professor in the division of lymphoma in the department of hematology & hematopoietic cell transplantation and executive medical director of the Enterprise Immune Effector Cell Program, at City of Hope in Duarte, California, discusses the design and patient makeup of the phase 3 POLARIX (NCT03274492) study.

This randomized, double-blind, placebo-controlled trial of 879 patients with previously untreated diffuse large B-cell lymphoma, who also had to have an International Prognostic Index (IPI) score of 2-5, compared the use of combination polatuzumab vedotin-piiq (Polivy) in addition to rituximab (Rituxan), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), and prednisone (R-CHP) with standard of care R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], and prednisone). 

The results of this trial demonstrated a statistically significant number of patients had progression-free survival (PFS) at 2 years for patients given the antibody-drug conjugate compared with R-CHOP at 76.7% (95% CI, 72.7%-80.8%) vs 70.2% (95% CI, 65.8%-74.6%), respectively (HR 0.73; 95% CI, 0.57-0.95, 

Overall survival and toxicities remained similar in both arms, but these data were enough to secure an FDA approval in April 2023 for this combination for patients with high-grade DLBCL. Budde discusses the design of this trial that led to the FDA approval and what role polatuzumab plays in this treatment combination.

So, POLARIX is a phase 3 study that [randomly assigned] around 1000 patients to either the standard of care using R-CHOP or [randomly assigned] patients to the group that are using using R-CHP-pola, meaning they were replacing vincristine with polatuzumab. And polatuzumab, as we know, it's a targeted chemotherapy; an antibody-drug conjugate that is targeting CD79b, which is a protein commonly expressed in B-cell lymphoma.

So, these patients were [randomly assigned] to these 2 groups, also based on their IPI score…based on either if they were a 2 or 3-5. So, any patient with IPI 1 will not be in involved in this study. The age is also capped between 18 to 80 [years of age], in a 1:1 randomization. So, these patients received a total of 6 cycles [of treatment] in either arm, followed by 2 cycles of rituximab at the end of the chemotherapy treatment. The primary end point for this randomization study was really to look at the PFS.

Elizabeth Lihua Budde, MD, PhD, breaks down the design and baseline characteristics of the phase 3 POLARIX trial that led to the approval of polatuzumab in combination with R-CHP for certain patients with diffuse large B-cell lymphoma. 

DLBCL

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