2021 New antibody drugs: Dostarlimab-gxly

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2021 New antibody drugs: Dostarlimab-gxly

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2021 New antibody drugs: Dostarlimab-gxly.

Dostarlimab is a humanized anti-PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2.

On April 22, 2021, the U.S. Food and Drug Administration (FDA) approved dostarlimab-gxly (trade name JEMPERLI) for the first time as a monotherapy for the treatment of disease progression and mismatches during or after platinum-containing chemotherapy Defect repair (dMMR) patients with recurrent or advanced endometrial cancer.

It is worth mentioning that dostarlimab is the first A PD-1 therapy approved for the treatment of endometrial cancer, and also the seventh PD-(L)1 drug approved by the FDA. Previously, the FDA granted dostarlimab breakthrough drug status (BTD) and priority review status. This approval is based on the positive results of the single-group, multi-cohort GARNET study data (NCT02715284).

The recommended dose of Dostarlimab is 500 mg for doses 1-4, once every 3 weeks. Follow-up administration starting 3 weeks after the 4th dose (starting from the 5th dose): 1600 mg, once every 6 weeks. Dostarlimab is administered by intravenous infusion and the infusion time is greater than 30 minutes. Dostarlimab was developed by Tesaro, and in 2018, GSK acquired Tesaro for US$5.1 billion.

Pharmacodynamics and pharmacokinetics

Dostarlimab is a humanized IgG4 subtype anti-PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2. The drug works by targeting PD-1/PD-L1 cellular pathways. Dostarlimab helps the body’s immune system fight cancer cells by blocking this pathway.

The pharmacokinetics of dostarlimab has been evaluated in patients with various solid tumors. In the dose range of 1.0 to 10 mg/kg, the average Cmax, AUC0-inf and AUC0-tau increased proportionally. The average values ​​of Cmax and AUC0-tau (coefficient of variation) of dostarlimab in the first cycle were 171 ug/mL (20%) and 35730 ug*h/mL (20%) at a 500 mg dose every 3 weeks, respectively.

The weekly doses of 1000 mg were 309ug/mL (31%) and 95820 ug*h/mL (29%). In the steady state, the average volume of distribution of dostarlimab is 5.3L (12%), the average terminal elimination half-life of dostarlimab is 25.4 days, and the average clearance rate at steady state is 0.007 L/h (31%).

Clinical Trials

The efficacy of Dostarlimab was evaluated in the GARNET study (NCT02715284), a multi-center, multi-center, open study for patients with advanced solid tumors. The enrolled population included 71 patients with dMMR recurrence or advanced EC, who progressed during or after treatment with platinum-containing regimens.

Patients who have previously received PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitors and patients with autoimmune diseases who require systemic immunosuppressive therapy within 2 years are excluded from the study.

The patient was given dostarlimab 500 mg intravenously every 3 weeks for 4 times, and then 1000 mg intravenously every 6 weeks. Treatment continues until the disease progresses or unacceptable toxicity occurs. The main efficacy indicators are total effective rate (ORR) and duration of response (DOR). Blind independent center evaluation (BICR) was performed according to the solid tumor response evaluation criteria (RECIST) v1.1.

Baseline characteristics were: median age 64 years (49% were over 65 years old); 82% white, 3% Asian, 1% black; the performance status of the Eastern Cooperative Oncology Group was 0 (32%) or 1 (68%) ).

At the start of the study, 66% of dMMR EC patients had stage IV disease of the International Federation of Obstetrics and Gynecology (FIGO). The most common histological presentation is endometrioid carcinoma type 1 (70%), followed by serous (6%) and mixed undifferentiated (2.8% each).

All dMMR-EC patients have received anti-cancer treatment, 90% of patients have received anti-cancer surgery, and 79% of patients have received anti-cancer radiotherapy.

About 40% of patients have received two or more anti-tumor treatments. Approximately 11% of patients have received 3 regimens of treatment, and 4% of patients have received 4 or more regimens of treatment.

The results showed that among 71 patients with recurrent or advanced dMMR endometrial cancer who received dostarlimab treatment, 42.3% of the patients achieved complete remission (CR, tumor disappearance) or partial remission (PR, tumor shrinkage). Among patients in remission, 93% of patients had remission duration ≥ 6 months.

Adverse reactions

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia and constipation. In addition, dostarlimab can cause serious diseases called immune-mediated side effects, including inflammation of healthy organs such as lungs (pneumonia), colon (colitis), liver (hepatitis), endocrine glands (endocrine diseases), and kidneys ( Nephritis).

Immunogenicity

Like all therapeutic proteins, dostarlimab is immunogenic. The immunogenicity of dostarlimab was evaluated in the GARNET study. Among 315 patients who took dostarlimab at the recommended therapeutic dose, 2.5% of the patients had detected anti-antibodies (ADAs) against dostarlimab, and the detection rate of neutralizing antibodies was 1.3% .

2021 New antibody drugs: Dostarlimab-gxlyrce:internet, reference only)

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