Ruiqi Orenxel is expected to become the first spot for new treatment options for follicular lymphoma

Professor Song Yuqin from Peking University Cancer Hospital, at the 63rd ASH Annual Meeting, orally reported on the relapse and refractory of adult patients after the second-line or above systemic treatment of WuXi Junuo's CAR-T product that targets CD19.
Preliminary analysis results of phase II RELIANCE trial for follicular lymphoma (r/r FL)
.

The research results are published on the ASH website in abstract form (Abstract No.
2434)
.

The results showed that the treatment of r/r FL by Regiorenx showed good efficacy (92.
6% CRR and 100% ORR), and safety (no severe CRS, severe neurotoxicity 3.
6%)
.

As a kind of adoptive cellular immunotherapy, CAR-T cell therapy is receiving widespread attention due to its remarkable curative effect on refractory hematological tumors, and has attracted many companies to invest in research and development
.

In 2017, two autologous CAR-T therapies, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), were successively approved by the US FDA, becoming the world's first CAR-T therapy approved by regulatory agencies and put into clinical use
.

In China, the research and development of CAR-T therapy has also risen rapidly in recent years, and breakthroughs have been made this year.
Two CAR-T cell therapy products have been approved by the National Food and Drug Administration for the treatment of second-line or above systemic treatments.
Adult patients with relapsed or refractory large B-cell lymphoma (LBCL)
.

Among them, relmacabtagene autoleucel (relma-cel), which targets CD19, is China’s first class 1 biological product for CAR-T cell therapy.
It was developed by WuXi Juno in Juno Therapeutics, USA Based on lisocabtagene maraleucel (Breyanzi), it was independently developed
.

In addition to the approved indications, Ricky Orenxil currently has 5 ongoing clinical trials registered on clinicaltrials.
gov, including 2 phase II clinical trials and 3 phase I clinical trials for the study of this cell Therapeutic products treat relapsed and refractory large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma
.

At the just-convened 63rd Annual Meeting of the American Society of Hematology (ASH), WuXi Biotech announced the Phase II RELIANCE study (NCT04089215) of Recchio Lunza in China for the treatment of relapsed and refractory B-cell NHL (NCT04089215).
The preliminary safety and efficacy results of lymphoma patients were reported online by Professor Song Yuqin from Peking University Cancer Hospital
.

Professor Song Yuqin made an online oral report at the 63rd ASH Annual Meeting.
Source | ASH Good Efficacy and Safety This study included the recurrence of stage 1 to 3a recurrence after previous second-line and above treatment or autologous hematopoietic stem cell transplantation (HSCT) Or patients with refractory follicular lymphoma (FL)
.

The pretreatment regimen is daily fludarabine 25mg/m2 + cyclophosphamide 250mg/m2 for three consecutive days
.

Then they were randomly assigned 1:1, and received low-dose (100×106) or high-dose (150×106) Regiorenxel treatment
.

The primary endpoint of the study is the 3-month complete response rate (CRR) assessed by the investigator, and the secondary endpoints include 3-month objective response rate (ORR), best complete response rate (BCR), adverse events (AE), remission duration (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and pharmacokinetic pharmacodynamic and so on
.

Source|Professor Song Yuqin's oral report PPT at the 63rd ASH Annual Meeting From June 2018 to September 10, 2021, at the end of the data, a total of 28 patients had received the treatment of Ricky Orenxel
.

The 28 patients had a median age of 54 years (36-71 years), and 50% were men
.

Of these patients, 5 (17.
8%) had received at least five-line treatment
.

The proportions of relapse and refractory were 64.
3% (18 patients) and 78.
6% (22 patients), respectively
.

The preliminary research results released showed that, excluding 1 patient who developed gastric adenocarcinoma before reinfusion, the researchers assessed that 27 patients with evaluable efficacy had a CRR of 85.
2% (23/27) after treatment for 3 months, the best CRR It is 92.
6% (25/27)
.

The 3-month ORR reached 100% (27/27)
.

The results of the Independent Reading Committee (IRC) evaluation are comparable to the results of the above-mentioned investigator evaluation
.

The median follow-up period was 8.
84 months, and the median values ​​of DOR, PFS and OS were not reached
.

Source|Professor Song Yuqin's oral report at the 63rd ASH Annual Meeting.
PPT 28 patients who received Rigi Orenza treatment can be assessed for safety
.

64.
3% of patients had grade 3 and above AEs related to Rigi Orenza.
The most common grade 3 and above AEs were neutropenia (39.
3%), leukopenia (25.
0%), and lymphopenia ( 17.
9%) and thrombocytopenia (10.
7%)
.

 The incidence of CRS was 42.
9% (all grade 1), and only 5 patients received tocilizumab treatment
.

Five (17.
9%) patients developed neurotoxicity (NT), and only one reached Grade 3
.

There were no deaths
.

 Source|Professor Song Yuqin's oral report at the 63rd ASH Annual Meeting.
The efficacy of PPT is comparable to that of similar overseas products.
The Chinese Follicular Lymphoma Diagnosis and Treatment Guidelines (2020 Edition) pointed out that FL is one of the most common types of NHL, accounting for There are 8.
1%~23.
5% of NHL patients in China, and the incidence is increasing year by year
.

Standard treatments for FL include radiotherapy, chemotherapy and immunotherapy
.

According to related literature, although most patients have a good prognosis, about 20% to 30% of patients will develop resistance to treatment
.

HSCT is the standard treatment for patients who relapse or refractory after standard treatment, but about 40% of patients are not suitable for HSCT treatment, and about half of patients will still relapse after HSCT treatment
.

There is no good treatment method for FL patients who relapse after receiving two-line treatment, and the remission time after the second-line treatment is getting shorter and shorter
.

Therefore, there is an urgent need for new therapies that can improve the treatment of relapsed and refractory FL
.

The continued expression of B cell markers such as CD19 in B cell tumors makes it an ideal target for treatment
.

In March 2021, the FDA approved Yescarta for the third-line and above treatment of r/r FL, becoming the first CAR-T cell therapy approved for this indication
.

In addition, Kymriah is also conducting clinical studies for r/r FL
.

The main efficacy results of the key registration studies of the two CAR-T treatment products r/r FL are as follows: Although it is a clinical trial carried out under different conditions, and Ruiji Orenza only released the preliminary efficacy results of 27 patients.
However, compared with the CAR-T products that have been approved abroad and are under research in FL, the preliminary efficacy data of 85.
2% CRR and 100% ORR of Ricky Orense are still very good
.

Moreover, a further subgroup analysis showed that the best CRR in patients who had previously failed at least five-line treatment was also 80.
0%, showing promising therapeutic potential
.

Low toxicity contributes to clinical application Although CAR-T therapy has a very good effect, like other cancer therapies, it can cause some serious and even fatal side effects, the most common of which is cytokine release syndrome (CRS)
.

The body's T cells release cytokines to stimulate and trigger an immune response
.

However, when CRS occurs, cytokines are rapidly released into the blood in large amounts, resulting in high fever and a sharp drop in blood pressure
.

In severe cases, CRS can lead to organ failure and even death
.

Steroid drugs are the standard drugs for the treatment of CRS
.

In addition, because CRS patients have particularly high levels of IL-6, tocilizumab, which blocks IL-6 activity, is the standard treatment for severe CRS
.

Another serious side effect of CAR-T cell therapy is neurotoxicity.
In many clinical studies of CAR-T cell therapy overseas, there have been reports of serious adverse events such as brain edema and death in patients
.

Therefore, both Breyanzi and Yescarta had a black box warning when they were approved by the FDA and were required to use them under REMS (Risk Assessment and Mitigation Strategies)
.

The good news is that although Kymriah has not yet been approved for FL indications, the Phase II ELARA study data released at the American Society of Clinical Oncology (ASCO) annual meeting in June this year showed that the product is more toxic when used in the treatment of FL patients.
Low, showing good tolerance (see table below)
.

Among the 97 patients whose safety can be assessed, the incidence of CRS was 49%, and there was no CRS of grade 3 and above
.

The incidence of neurotoxicity is only 9%, and there is no neurotoxicity of grade 3 or above
.

Loretta J.
Nastoupil, head of the new drug development department in the Lymphoma/Myeloma Division of MD Anderson Cancer Center and a researcher who participated in the study, said, “Follicular lymphoma is usually not as life-threatening as refractory large B-cell lymphoma.
Therefore, there will be greater demand for well-tolerated CAR-T therapies
.
”
The Ricky Orenza based on Liso-cel also shows potential low toxicity
.

The safety assessment results of 28 patients showed that there was no CRS of grade 3 or higher, only 1 patient (3.
6%) had neurotoxicity of grade 3 or higher, and no patient died during treatment
.

The use rate of steroids and tocilizumab is very low, 3.
6% and 17.
9%, respectively
.

It is reported that WuXi Giant Nuo plans to submit to the China Food and Drug Administration an application for new indications for the third-line treatment of r/r FL patients based on the results of the RELIANCE study next year
.

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