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Yescarta has received FDA approval as first CAR T-cell therapy for initial treatment of relapsed or refractory large B-cell lymphoma


The U.S. Food and Drug Administration ( FDA ) has approved Yescarta ( Axicabtagene ciloleucel ), a CAR T-cell therapy, for adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Yescarta has demonstrated a clinically meaningful and statistically significant improvement in event-free survival ( EFS; hazard ratio, HR=0.398; P less than 0.0001 ) over the current standard of care ( SOC ) that has been in place for decades.
Event-free survival was determined by blinded central review and defined as the time from randomization to the earliest date of disease progression, commencement of new lymphoma therapy, or death from any cause.

Additionally, 2.5 times more patients receiving Yescarta ( 40.5% ) were alive at two years without disease progression or need for additional cancer treatment, after their one-time infusion of Yescarta versus SOC ( 16.3% ), and the median EFS was four-fold greater ( 8.3 months vs 2.0 months ) with Yescarta vs SOC.

Yescarta was initially approved by the FDA in 2017 based on the ZUMA-1 trial for a smaller population of LBCL patients who failed two or more lines of therapy.
The ZUMA-1 trial has recently reported durable 5-year survival results, with Yescarta showing 42.6% of study patients alive at 5 years and that 92% of those patients alive at 5 years have needed no additional cancer treatment at this important milestone.

The FDA approval of Yescarta CAR T-cell therapy for adult patients with large B-cell lymphoma ( LBCL ) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy is based on results from the ZUMA-7 study.
Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous stem cell transplant ( ASCT ).
Results were presented at the American Society of Hematology’s ( ASH ) Annual Meeting in December 2021 and simultaneously published in the NewEngland Journal of Medicine ( NEJM ).

ZUMA-7 is a randomized, open-label, global, multicenter, phase 3 study evaluating the safety and efficacy of Yescarta versus current standard of care for second-line therapy ( Platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [ HDT ] and ASCT in those who respond to salvage chemotherapy ) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy.

In the study, 359 patients in 77 centers around the world were randomized ( 1:1 ) to receive a single infusion of Yescarta or current SOC second-line therapy.
The primary endpoint isevent-free survival (EFS) as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause.
Key secondary endpoints include objective response rate ( ORR ) and overall survival ( OS ). Additional secondary endpoints include patient reported outcomes ( PROs ) and safety.

Yescarta has demonstrated a 2.5-fold increase in patients who were alive at two years and did not experience cancer progression or require the need for additional cancer treatment ( 40.5% vs 16.3% ) and a four-fold greater median EFS ( 8.3 vs 2.0 months ) compared to SOC ( hazard ratio, HR=0.398; 95% CI: 0.308-0.514, P less than 0.0001 ).
ZUMA-7 study participants on the Yescarta arm did not receive additional bridging chemotherapy that could have potentially confounded results.

Nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment ( 94% ) versus those randomized to SOC ( 35% ) who received on-protocol HDT+ASCT.
More patients responded to Yescarta ( ORR: 83% vs 50%, odds ratio, OR=5.31 [ 95% CI: 3.1-8.9; P less than 0.0001 ) and achieved a complete response ( CR ) with Yescarta ( CR rate: 65% vs 32% ) than with SOC.
At a pre-specified interim analysis at the time of the primary EFS analysis, overall survival has not met the criteria for statistical significance, but favored Yescarta.

Fifty-five percent of patients in the SOC arm subsequently received CD19-directed CAR T-cell therapy off study.

In the study, Yescarta had a safety profile that was consistent with previous studies.
Among the 168 Yescarta-treated patients evaluable for safety, grade greater than or equal to 3 cytokine release syndrome ( CRS ) and neurologic events were observed in 7% and 25% of patients, respectively.
In the SOC arm, 83% of patients had high grade events, mostly cytopenias.

Globally, LBCL is the most common type of non-Hodgkin lymphoma ( NHL ).
In the United States, more than 18,000 people are diagnosed with LBCL each year.
About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse or become refractory to initial treatment. ( Xagena )

Source: Kite Pharma / Gilead Sciences, 2022

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