Emerging Data Push Antibody-Drug Conjugates Into Earlier Lines of Therapy in DLBCL

The treatment landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is undergoing rapid change with the emergence of antibody-drug conjugate (ADC) therapy. These agents leverage targeted therapy by using an antibody component to deliver anticancer payloads directly to the tumor cell. When coupled with immunotherapy, this technology delivers impressive responses and outcomes that are highly adaptable.

The strategy of combining ADCs with bispecific T-cell engagers is “very interesting, and the field is starting to get crowded,” Mehdi Hamadani, MD, said during an interview with Targeted Therapies in Oncology. “We see 2 very powerful immunotherapies joining forces,” continued Hamadani, a professor of medicine and chief of hematologic malignancies at the Medical College of Wisconsin in Milwaukee.

LOTIS-7 Trial Design

Emerging trials that community oncologists should be aware of include the LOTIS-7 trial (NCT04970901) and the waveLINE-003 trial (NCT05139017), data from which showcase the potential of these novel agents in DLBCL.

In the multicenter, phase 1b LOTIS-7 trial, investigators evaluated the combination of loncastuximab tesirine (Zynlonta) and glofitamab-gxbm (Columvi) in patients with R/R B-cell non-Hodgkin lymphoma. Both agents are independently approved by the FDA and European Medicines Agency for R/R DLBCL in the third- or later-line setting.

Loncastuximab is a CD19-targeted ADC utilizing the pyrrolobenzodiazepine (PBD) payload. Glofitamab is a CD20-CD3 bispecific engager.

Hamadani explained that the rationale for this dual-antigen targeting (CD19 and CD20) was that it “may mitigate some of the toxicities of glofitamab, particularly the risk of CRS, and it may have synergistic activities.”

In the dose-escalation phase, loncastuximab was evaluated at doses of 90, 120, and 150 μg/kg. In the dose-expansion phase, it was evaluated at 120 or 150 μg/kg.¹

The primary end point of the trial is the safety and tolerability of the combination and to identify the maximum tolerated dose. Secondary end points include pharmacokinetics and antitumor effects.¹

As of the data cutoff on January 25, 2025, 31 patients had received 1 or more doses of loncastuximab. The median age of participants was 73 years. Of the patients, 45.2% were diagnosed with DLBCL, and 16.1% had high-grade B-cell lymphoma. The majority (61.3%) had received 2 or more prior therapies.¹

The most common grade 3 or higher treatment-emergent adverse event (TEAE) was neutropenia (32.3%). Investigators reported that 29.0% of patients had grade 1 cytokine release syndrome (CRS) and 9.7% had grade 2 CRS. Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 0.0% of patients, and 6.5% had grade 2 ICANS.¹

In the efficacy evaluable population (n = 22), the response rates were encouraging, with patients demonstrating an overall response rate (ORR) of 95.5% and a complete response (CR) rate of 90.9%. The median duration of response (DOR) was not reached.¹

“The combination is showing a lot of promise,” Hamadani said, adding that the response rates “look phenomenal.” He continued, emphasizing that the “very high overall response rates as well as the complete response rate seem to be higher than what we would expect with either agent alone.” Hamadani said that these ORR and CR rates “are arguably among the highest that we have seen with either bispecifics alone or any other bispecific ADC combination.”

ROR1-Targeting ADC

Findings from the waveLINE-003 trial show that the addition of the ROR1-targeting ADC zilovertamab vedotin to the standard therapy of rituximab, gemcitabine, and oxaliplatin (R-GemOx) demonstrated promising efficacy with a manageable safety profile in difficult-to-treat patients who have relapsed/recurrent DLBCL.²

Investigators established the recommended phase 2 and 3 dose as 1.75 mg/kg. At that dose, the ORR was 56%, the CR rate was 50%, and the median DOR was 9 months.²

Regarding toxicity, hematologic AEs were severe and ranged from grade 3 to grade 4. Peripheral neuropathy, a concern with oxaliplatin and zilovertamab, was relatively low, with no grade 3 or higher events reported.²

A safety analysis showed that treatment-related AEs occurred in 98% of patients. The most common AEs included diarrhea (45%), nausea (38%), and anemia and platelet count decrease (both 28%). Grade 3 or greater treatment-related AEs were reported in 65% of patients, primarily neutropenia and neutrophil count decrease (both 23%), platelet count decrease (23%), and anemia (20%). Seven dose-limiting toxicities (DLTs) were reported across the cohorts, with 4 occurring in the 2.0-mg/kg dose cohort. That highest-dose cohort also saw 2 patient discontinuations due to AEs (sepsis and respiratory failure) and 1 treatment-related death (sepsis).²

During the 2025 American Society of Clinical Oncology Annual Meeting,² presenting author Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts, said, “The findings of the dose-confirmation study waveLINE-003 determined that the recommended phase 2 dose for the agent was 1.75 mg/kg, with a manageable safety profile. Compared with historical estimates of the use of GemOX alone, the 56% ORR and 50% CR rate appeared to show improved activity in R/R DLBCL.”²

Hamadani noted that pulmonary toxicity should be a focus with ROR1-targeting agents. “Whenever I see data with ROR1 antibodies, I pay attention to any signal for pulmonary toxicity,” he said.

He pointed out a DLT case involving pneumonia. This raises the question of whether such events are infectious pneumonia, common with chemoimmunotherapy, or a “noninfectious pneumonitis that is a theoretical concern with ROR1,” he continued.

Sequencing and Prior Therapy Questions

As the number of ADCs for B-cell lymphoma grows—specifically with the availability of polatuzumab vedotin (Polivy), brentuximab vedotin (Adcetris), and loncastuximab tesirine—the sequencing decision becomes crucial for community oncologists. Hamadani emphasized that clinical decision-making is currently driven by specific patient characteristics and treatment history.

Polatuzumab is increasingly integrated into the frontline setting for patients with advanced-stage DLBCL who have an International Prognostic Index score greater than 1.³ The phase 3 POLARIX trial (NCT03274492) evaluated a modified regimen of rituximab (Rituxan), cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine (Oncovin), and prednisone (R-CHOP) in which vincristine was replaced with polatuzumab vedotin (pola-R-CHP), as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL.³

Findings demonstrated a 2-year progression-free survival rate of 76.7% for pola-R-CHP compared with 70.2% for R-CHOP with comparable safety profiles between the 2 arms.³

“If a patient receives polatuzumab [in the] front line and then presents with primary refractory disease, using the same agent again becomes challenging, which may lead to a decline in polatuzumab’s use in the second-line setting,” Hamadani said.

“For patients who relapse after CD19-directed chimeric antigen receptor [CAR] T-cell therapy and demonstrate true CD19 antigen loss, loncastuximab (CD19 targeted) may become a less attractive option, potentially favoring combinations involving brentuximab vedotin,” Hamadani continued.

Factors to Consider When Selecting ADCs

Two factors that could determine ADC selection include patient fitness and preexisting conditions. These factors should be considered, given the distinct toxicity profile of individual ADCs.

For example, polatuzumab targets CD79b and uses the payload monomethyl auristatin E (MMAE). Its signature toxicity is peripheral neuropathy, which is often cumulative in effect.⁴ The use of brentuximab, which shares polatuzumab’s vedotin payload, may lead to “overlapping” toxicities, including peripheral neuropathy, and myelosuppression, such as neutropenia or thrombocytopenia.⁴

“For a patient with the comorbidity of diabetes, both polatuzumab and brentuximab become less attractive,” Hamadani said.

Loncastuximab, on the other hand, has its own unique toxicity profile, including the potential for reversible hepatic toxicity and effusions.⁵ Data from a safety analysis showed that all patients experienced TEAEs, which mainly included hematologic toxicity, fatigue, nausea, and rash.⁵

Febrile neutropenia was uncommon, with only 3% of patients reporting grade 3 or greater. The most common grade 3 or greater AEs included neutropenia (26%), thrombocytopenia (18%), and elevation of γ-glutamyl transpeptidase (16%) in the absence of other signs of liver toxicity.

Hamadani noted that grade 3 or greater hematological and liver toxicity can be managed by holding the drug until resolution and subsequent dose reductions by 50% if a prolonged toxicity occurs (> 3 weeks). In contrast with other ADCs, peripheral neuropathy was not a common adverse event.⁵

The agent also works rapidly, in contrast with other immunotherapies and cellular treatments, and does not appear to cause tumor flare or tumor lysis syndrome.⁵ This suggests it might be used sequentially or in combination with either lower doses or reduced cycles of chemotherapy in elderly or unfit patients.⁵

“As with all therapies, there are some patient characteristics where you might select one agent over another,” Hamadani said.

The Future of ADC Use

When comparing ADCs combined with bispecific antibodies to cellular therapies such as CAR T-cell therapy, the logistical advantages of ADCs cannot be overlooked. Their logistical advantages are substantial, making them highly relevant for widespread use, especially in the community setting.

Hamadani said that these agents have experienced a “nice uptake in community settings.” And although bispecifics introduce a learning curve due to CAR T-like toxicities such as CRS and ICANS, they are “off-the-shelf therapies that are logistically easier to procure, without the need for apheresis or bespoke manufacturing,” Hamadani continued. Further, the severity and frequency of CRS and ICANS are lower with bispecifics than with CAR T. Bispecific-related CRS is often manageable with steroids and antipyretics, requiring tocilizumab (Actemra) less frequently than for CAR T, and ICANS is “way less common,” according to Hamadani.

Most critically, these readily available combinations, such as loncastuximab plus glofitamab, have the potential to reach patients currently underserved by cellular therapy. Hamadani highlighted that up to “75% of theoretical CAR candidates never receive CAR T-cell therapy due to barriers such as inability or unwillingness to travel to large academic centers.”⁶

“I think for these patients, bispecific [therapy], with or without an ADC combination,...these combinations can theoretically address the need for cell therapy in those patients who cannot get access to CAR T-cell therapy," Hamadani said. He believes the combination may become a “second-line choice for some of those patients.”

While admitting he lacks a crystal ball regarding the pace of community adoption, he stated, “I'm willing to bet that it will happen.” He noted that even large private practices already administering bispecifics demonstrate the feasibility of widespread adoption.

The current landscape of ADCs in DLBCL is defined by innovation—both in targeting novel pathways, such as ROR1 in the case of zilovertamab vedotin, and in leveraging synergistic combinations, such as loncastuximab and glofitamab, to achieve exceptional response rates in heavily pretreated patients. This dual focus offers not only increased efficacy but also provides logistically simpler therapeutic options, which are desperately needed to expand access beyond major academic centers.

REFERENCES

1. Alderuccio JP, Okada C, Crochet G, et al. Initial Results From LOTIS-7: A phase 1b study of loncastuximab tesirine plus glofitamab in patients with relapsed/refractory (r/r) diffuse large b-cell lymphoma (DLBCL). Clinical Lymphoma Myeloma and Leukemia. 2025;25(suppl 1):S758.

2. Armand A, Lee ST, Jurczak W, et al. WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma. Presented at: 2025 ASCO Annual Meeting. May 30-June 3, 2025. Chicago, IL. Abstract 7003.

3. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large b-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304

4. Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability. Cancers (Basel). 2023;15(3):713. Published 2023 Jan 24. doi:10.3390/cancers15030713

5. Calabretta E, Hamadani M, Zinzani PL, Caimi P, and Carlo-Stella C. The antibody-drug conjugate loncastuximab tesirine for the treatment of diffuse large B-cell lymphoma. Blood. 2022;140(4):303–308. doi:10.1182/blood.2021014663

6. Chung AP, Shafrin JT, Vadgama S, et al. Inequalities in CAR T-cell therapy access for US patients with relapsed/refractory DLBCL: a SEER-Medicare data analysis. Blood Adv. 2025;9(18): 4727–4735. doi:10.1182/bloodadvances.2024015634