Durable Responses With Tisagenlecleucel

An update from the phase 2 ELARA trial showed durable responses with tisagenlecleucel in patients with relapsed/refractory FL.2 The trial (ClinicalTrials.gov Identifier: NCT03568461) enrolled patients with grade 1-3A FL that was refractory to the second or later line of therapy, that relapsed within 6 months after the second or later line of therapy, or that relapsed after an autologous transplant. 

“Two-thirds of patients had high-risk disease, and two-thirds were double-refractory — not the usual kind of patients with FL,” said Martin Dreyling, MD, of the Medizinische Klinik III, LMU Klinikum in Munich, Germany, who presented the study at ASH 2022. 

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The patients were allowed to receive bridging chemotherapy. This was followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel (0.6-6 x 108 CAR+ viable T cells).

Dr Dreyling reported safety results in 97 patients. There were no new safety signals reported during the long-term follow-up. Three new deaths were reported, but none were deemed related to treatment. 

In the 94 patients who were evaluable for efficacy, the overall response rate (ORR) was 86%, and the complete response (CR) rate was 69%, both of which were previously reported.6 

At a median follow-up of 29 months, the median duration of response, median progression-free survival (PFS), and median OS were not reached.2 At 12 months, the PFS rate was 67%, and the OS rate was 95%. At 24 months, the PFS rate was 57%, and the OS rate was 88%.

“Overall, after 24 months, two-thirds of patients were still in remission,” Dr Dreyling said. “People with a CR benefited the most.”

Among patients with a CR, the PFS rate was 87% at 12 months and 75% at 24 months. The OS rates in this group were 98% at 12 months and 95% at 24 months.

Although CAR T-cell therapy appears effective in FL, it cannot yet be given in the community setting, noted Pallawi Torka, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, who was not involved in this study. 

“We won’t see CAR T-cell therapy in the community setting for the next 10 years,” she said. “Logistically and financially, it is very challenging. The toxicity is also very high and unpredictable, which makes it difficult to manage in the community setting.”

Dr Dreyling also noted the logistical difficulties with administering CAR T-cell therapy, though he stressed that this is a matter of training. The high cost of CAR T-cell therapy, which can be hundreds of thousands of dollars, remains a significant barrier for many patients as well.

“Potential for Cure” With Odronextamab 

In the phase 2 ELM-2 trial, odronextamab produced durable responses in patients with relapsed/refractory FL.3 Odronextamab is a bispecific antibody that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity in malignant B cells, explained study presenter Tae Min Kim, MD, PhD, of Seoul National University Hospital in South Korea. 

The ELM-2 trial (ClinicalTrials.gov Identifier: NCT03888105) included 131 patients with grade 1-3A, relapsed/refractory FL. The patients had received a median of 3 prior lines of therapy (range, 2-13). Most (71.0%) had disease that was refractory to the last line of therapy, 74.8% had disease that was refractory to an anti-CD20 antibody, and 43.5% had double-refractory disease.

Odronextamab was given with weekly step-up dosing during cycle 1 to mitigate the risk of cytokine release syndrome (CRS). After cycle 1, patients received odronextamab at 80 mg weekly until the end of cycle 4. After cycle 4, patients received odronextamab at 160 mg every 2 weeks until disease progression or unacceptable toxicity. 

The median follow-up was 22.4 months. A majority of patients (57.3%) discontinued treatment, most due to progression (19.8%) or withdrawal of consent/physician decision (17.6%). 

By independent review, the ORR was 81.8%, and the CR rate was 75.2%. Results were consistent across high-risk subgroups. The median duration of response and the median duration of CR were both 20.5 months.

The median PFS was 20.2 months, and the median OS was not reached. At 18 months, the PFS rate was 55.3%, and the OS rate was 76.3%. 

Most patients (90.1%) had treatment-related adverse events (AEs), and 55.7% had grade 3 or higher treatment-related AEs. The most common treatment-related AEs of any grade were CRS (55.7%), neutropenia (32.1%), and infusion-related reactions (28.2%).

Most cases of CRS were grade 1. One patient had grade 3 CRS, but there were no cases of grade 4 CRS. All CRS events resolved. The median time to resolution was 2 days (range, 1-51 days).

There was 1 case of immune effector cell-associated neurotoxicity syndrome and 1 case of tumor lysis syndrome. There were 3 treatment-related deaths — 1 due to pneumonia, 1 due to progressive multifocal leukoencephalopathy, and 1 due to systemic mycosis.

Dr Kim noted that there is concern that odronextamab and other bispecific antibodies can deplete patients’ B cells, hindering the immune system’s ability to fight off infections with viruses such as SARS-CoV-2. In the current study, 7 patients (5.3%) died from COVID-19.

“We should be balanced between risk and benefit,” Dr Kim said. “The benefits are potency and potential for cure. However, this agent can deplete dormant B cells. Some patients, particularly elderly patients, are susceptible to serious opportunistic infection.”