JCO:CAR-T is used for real-world data release of recurrent or refractable large B-cell lymphoma, with consistent results with the results of the trial.

. Car-T products from Gilead/Kite, Yescarta (Axicabagene Cilleucel, Axi-Cel), were approved by the FDA in the fall of 2017 based on the results of its single-arm Phase II clinical trial ZUMA-1 for treatment in adult patients with recurrent or refractive large B cell lymphoma (LBCL). Since then, it has also been approved in the European Union and Canada (report:
Lancet oncol: Axicabagene ciloleucel (self-resistant cd-cd-encrusted antigen receptor T-cell therapy) for the treatment of recurrent/refractive large B-cell lymphoma and the long-term safety and efficacy
). The ZUMA-1 study showed that 101 patients treated with Axi-cel had a median follow-up time of 15.1 months. Of the 34 patients who reached partial response (PR) at 1 month, 11 (32%) achieved full remission CR during long-term follow-up. The objective mitigation rate (ORR (CR plus PR) observed between the researcher's assessment and the IRC assessment was highly consistent (77 percent - 79 percent) and the CR was 58 percent during all assessment periods. The landmark analysis of the non-progression survival rate (PFS) based on the response state stratification assessed by the researchers showed that the majority of the 60 cases that reached disease control (disease stability SD or better) over a three-month period achieved longer disease control and the 12-month PFS rate was 73%. Cr was 42 cases at 3 months, PR in 9 cases, and 79% and 78% in 12 months, respectively.Given that clinical trial experience often does not represent real-world clinical practice, the efficacy and safety of the drug in the vast majority of patients remains a concern after its launch. Members of the U.S. Lymphoma CAR-T Alliance evaluated the safety and efficacy of Yescarta as standard therapy (SOC) in its approved indications at 17 participating centers.

, Dr. Loretta J. Nastoupil
, a

at the MD Anderson Cancer Center in Houston,
, and colleagues published this real-world data online in the
journal
Journal of Clinical Oncology, showing that their
is as safe and effective in a larger patient population as in a key clinical trial, ZUMA-1, withnos of excessive or unexpected toxicity.


. Dr Nastoupil said: "Our results are striking, as compared to the results of the ZUMA-1 trial, which has stricter eligibility criteria. We found that while most patients did not really reflect the study population in ZUMA-1, the safety and efficacy looked very similar. You might imagine that when beyond the eligibility criteria, there will be more patients with more diseases, and that's what we've found. "




the latest real-world data



reviewed data from patients with recurrent/refractive LBCL who underwent white blood cell removal in the
of 17 U.S. institutions in
on September 30, 2018.


. Patient distribution and flowchart

in 17 U.S. facilities
. (Photo source: DOI: 10.1200 / JCO.19.02104)

275 (92%) of 298 patients who underwent white blood cell removal received
Yescarta
therapy. Compared to the registered ZUMA-1 trial, 129 patients (43%) in the SOC study did not meet the ZUMA-1 eligibility criteria due to comorbidities during leukocytosis.

the best overall remission rate
(ORR) was 82%
and total remission
rate (CR) was 64%
of the 275 patients treated with Yescarta. Compared to the 83% ORR and 58% CR in the ZUMA-1 trial, the results were generally consistent, although more than 40% of patients did not meet the eligibility criteria for the trial.

Since the CAR-T cell infusion, the median progression-free survival (PFS) was 8.3 months (95% CI, 6.0-15.1 months) for 12.9 months of the median follow-up period, and the median overall lifetime (OS) has not yet been reached.


. Compared with the data from the ZUMA-1 trial

(Picture source: DOI: 10.1200 / JCO.19.02104)

safety, 91 percent of the 275 patients in
had cytokine release syndrome (CRS), 7 percent had cytokine release syndrome (CRS), 7 percent had a patient level of 3; neurotoxicity occurred in 69% of patients, with 31% of patients. In addition, a total of 97 patients died, of which 84 (31%) were lymphoma-related deaths, and 12 (4.4%) died from non-relapsing causes, one died of phagocytophatic lymphatic hyperplasia (HLH) and one died of cerebral edema, but all other neurological adverse events were resolved.


. Safety Results

(Picture: DOI: 10.1200 / JCO.19.02104)


the average response time of patients who responded was 30 days, and no patient spent more than 90 days without the first response. 121 patients were completely remissioned on the 30th day, of which (78%) maintained remission at 90 days. Ninety-three patients experienced partial reactions on the 30th day, with one third of them experiencing a full response on the 90th day. Of the 14 patients who were stable on the 30th day, only 1 was completely remissioned on the 90th day.


.


.
Kymriah
vs.

Yescarta




only two are currently available in CAR-T therapy, and the other is Novartis's Kymriah. Kymriah is priced at $475,000 and Yescarta is priced at $373,000. Kymriah is currently approved for use in adult patients
recurrent/refractive diffuse large B cell lymphoma (DLBCL) as well as children and young people with acute lymphocytic leukemia (ALL), and is currently the only CAR-T cell therapy approved for both indications.


.
at ash's annual meeting in December, Novartis and Gilead released their real-world data.


.
Kymriah for r/r DLBCL:

. efficacy of

:


clinical efficacy data were comparable to those in the JULIET study in patients treated with Kymriah.
after three months or more of administration to 80 r/rDLBCL patients, the data show edimen (ORR) of 58%, of which 40% is full remission (CR). In the 4.5-month FOLLOW-up OF THE JULIET trial, the ORR was 52% and CR was 38% in 115 patients in the 4.5-month-long JULIET trial (N - 115).


.

Safety:




the prediction and management of adverse events in CAR-T cell therapy is critical to the successful implementation of this innovative treatment. In the data analysis of this clinical trial (safety group, N-83), the incidence of cytokine release syndrome (CRS) and neurotoxicity at level 3 or higher was 4% and 5%, respectively, while in JULIET's clinical trials (safety group, N-115), the incidence was 23% and 11%, respectively,
which fully demonstrated the reliability of drug safety.


. In addition, in CRS patients, 20 percent of patients in this trial used toosizumab, 4 percent used corticosteroids, while in the JULIET trial, 27 percent of patients used tothilezumab and 19 percent used corticosteroids. In the trial, some patients received toxizumab earlier than in clinical trials,
suggests that early use of supportive prevention may reduce the incidence of high-level CRS.
, some of the 14 patients who died after treatment were due to progression of the disease and were not related to the toxicity of Kymriah.


.
Kymriah for r/r
. ALL
:




efficacy:


this clinical trial is similar in effectiveness and safety performance compared to ELIANA's critical trial 4-6.
of the 146 r/rALL children and young people treated, their CR reached 85 per cent after three months or more of administration, compared with 82 per cent for ELIANA (N-79).

safety:

14% and 8% of eLIANA clinical trials during 6 months of follow-up (safety group, N-154), level 3 or higher cytokine release syndrome (CRS) and neurotoxicity events, respectively, compared with 48% and 13% in ELIANA clinical trials.
can see that the safety of its drug use is trustworthy.

. Yescarta
for r/r LBCL:

the results of the trial are comparable to those obtained in the ZUMA-1 clinical trial.
specifically, the analysis included 533 patients, with a higher proportion of elderly patients (not less than 65 years of age) and a higher proportion of patients with two or three recurrences of lymphoma (36%). By comparison, the figures in the ZUMA-1 trial were 25% and 11%, respectively.


. Follow-up results of 6 months and above showed that, after receiving a single yescarta treatment, the ORR reached 84% of
the 326 patients who were evaluated for efficacy, and CR reached 66%.
80% orR in patients under 65 years of age.
or 92% of patients over 65 years of age.
the total remission rates of the two groups were 62% and 72%, respectively.
in terms of safety, the risk of
stage 5 side effects (CRS and neurotoxicity) is about 1%, similar to the clinical trial of ZUMA-1.

its full-year revenue for 2019 was $22.4 billion, according to Gilead's 2019 earnings, with CAR-T cell therapy Yescarta's 2019 sales of $456 million, significantly higher than Kymriah.


.
source: Novartis Quarterly, Gilead Quarterly
from the data, Gilead Yescarta's treatment effect, or ORR and CR ratio, seems to be more optimistic, in a sense, Yescarta's treatment effect and security may be stronger than Kymriah.
this may also be the main reason why Yescarta sales have been higher than Kymriah's sales in multiple quarters.

it's worth noting that nearly half of the lymphoma patients who received Gilead's CAR-T Yescarta
, listed by Gilead, survived at least three years after a one-time infusion of CAR-T cell therapy, according to data released at the 2019 ASH annual meeting.
47 of 101 patients with malignant blood cancer (difficult-to-treat large B-cell lymphoma) treated with Yescarta survived at least three years later.


. In 2019, a CCTV9 documentary tells the story of Emily, the world's first child of leukemia who was treated with CAR-T cells (Kymriah) and who was treated in 2012 and is still cancer-free.


.
anyway, these data give us a sense of the miracle of CAR-T therapy.


.


.
Gilead's CAR-T layout

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.

Gilead has been promoting a range of cancer therapies in the blood system for malignancies and solid tumors, including cell therapy, immuno-oncology and targeted therapy, since acquiring Kite Pharma's first listed CAR-T therapy, Yescarta, in 2017.

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