乌鸦传媒

Almost 100% of patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) responded to treatment with the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel, Yescarta), data from an ongoing study showed.

Overall, 89 of 96 (93%) evaluable patients achieved objective responses, including complete responses in 80% of cases. Responses were durable in most cases, reflected in a median duration of response of 20.8 months and a median progression-free survival (PFS) of almost 2 years.

The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia and decreased neutrophil count. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 8% and 17% of patients, respectively, as reported during the American Society of Clinical Oncology (ASCO) virtual meeting.

"Axi-cel demonstrated high rates of durable responses," said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute in Boston, in a prerecorded presentation. "With a median follow-up of 15.3 months, 68% of patients with follicular lymphoma remained in response. The safety profile was manageable and largely consistent with prior studies of axi-cel in aggressive non-Hodgkin lymphoma. Most symptoms occurred early in treatment and were generally reversible."

"Axi-cel may be a promising therapeutic approach for patients with relapsed and refractory NHL," she added.

Not So Indolent?

The trial addressed a patient population that has long perplexed hematologists -- the significant proportion of patients with indolent lymphomas that are not so "indolent," said ASCO invited discussant Krish Patel, MD, of Swedish Medical Center in Seattle. To illustrate the point, he referenced an analysis of a with follicular lymphoma (FL), showing that 37% of patients required second- or later-line therapy. The same analysis showed a diminishing duration of PFS with third-line or later therapy.

Two separate analyses showed that relapse within 24 months was associated with a 50%-60% decrease in and 3-year OS for (MZL).

The PI3K inhibitor drug class comprises the only approved therapies for third-line treatment of FL. Patel recently published a study showing that the drugs in the class have objective response rates (ORR) of 42% to 59%, few complete responses, a median PFS of 10-11 months, and 20%-30% discontinuation rate for AEs.

Acknowledging the limitations of cross-study comparisons, Patel said, "Informally, the results of the phase II ZUMA-5 study of axi-cell appear to contrast favorably with data existing for the PI3 kinase-delta inhibitors."

In the field of lymphoma, most of the clinical experience to date with CAR T-cell therapy has involved aggressive disease subtypes, such as diffuse large B-cell lymphoma. Little information had accumulated regarding the safety and efficacy of the agents in relapsed/refractory iNHL.

Investigators in the multicenter ZUMA-5 trial enrolled patients with relapsed/refractory FL (grades 1-3a) or MZL (nodal or extranodal). Eligible patients had received at least two prior lines of therapy, one of which must have included an anti-CD monoclonal antibody plus an alkylating agent. All patients received 3 days of conditioning with fludarabine and cyclophosphamide, beginning 5 days before infusion of axi-cel. The trial had a primary endpoint of ORR.

Of 148 patients enrolled, 140 received conditioning therapy and axi-cel (124 with FL and 16 with MZL). The cohort had a median follow-up of 15.3 months for efficacy and a median follow-up of 12.8 months for safety. The efficacy cohort comprised 80 patients with FL and all 16 patients with MZL.

The patients had a median age of 63, half of the cohort had bulky disease, and 70% of them had received three or more prior lines of therapy. About three-fourths of the patients had refractory disease, more than half had progressive disease within 24 months from initial anti-CD20 therapy, and a fourth of the patients had undergone stem-cell transplantation.

ZUMA-5: Key Results

The ORR of 93% included 77 complete responses and 12 partial responses. An additional two patients had stable disease, and five patients had no disease at baseline or at follow-up assessments. The median time to first response was 1 month.

In the subgroup of 80 patients with FL, 65 patients had complete responses and 11 had partial responses, resulting in an ORR of 95%. Ten of the patients had a partial response at week 4 and later converted to complete response. The MZL subgroup had 12 complete responses and one partial responses for an ORR of 81%. Median duration of response was 20.8 months in the FL subgroup and 10.6 months in the MZL subgroup.

Media PFS was 23.5 months for the entire cohort, including 23.5 months for the FL subgroup and 11.8 months for the MZL subgroup. The median OS had yet to be reached in either subgroup. The 12-month OS was 94.3% overall, 93.4% in the FL subgroup, and 100% in the MZL subgroup.

The most common TEAEs were pyrexia (84%), hypotension (49%), fatigue (44%), headache (44%), nausea (39%), neutropenia (36%), anemia (35%), and sinus tachycardia (34%). CRS occurred in 79% of the patients but reached grade ≥3 severity in 8%. Neurologic events occurred in 58% of patients, including grade ≥3 in 17%. The most common neurologic effects were tremor (51%) and confusional state (41%).

Patel noted that CAR T-cell therapy could face competition from a bispecific antibody in the setting of relapsed/refractory iNHL. for mosunetuzumab as third-line therapy and beyond for FL showed a 64% OR and complete responses in 44%. CRS occurred in 29% of patients and reached grade ≥3 severity in only 1.1% of patients.

"There may be tradeoffs between efficacy and easy of delivery and toxicity," said Patel. "Further studies are needed to evaluate these issues."

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