* is for medical professional reading reference only
effective, safe and convenient, and a trinity!
immunotherapy is a major breakthrough in the field of anti-tumor treatment today. Many studies have confirmed its clinical therapeutic value and have been widely used in the treatment of various digestive tumors such as esophageal cancer, gastric cancer , colorectal cancer, etc. Enwolizumab is the world's first subcutaneously injectable PD-L1 inhibitor. It has achieved excellent anti-tumor efficacy and safety in previous studies, and has brought new treatment options to patients with advanced solid tumors in microsatellite highly unstable (MSI-H)/mismatch repair defect (dMMR) in my country.
2022 Chinese Society of Clinical Oncology (CSCO) Annual Meeting will be held from November 5th to 12th in a combination of online and offline mode. The conference held a summary analysis of three studies, KN035-CN-001, KN035-JP-001 and KN035-US-001, which evaluated the efficacy of envolizumab in patients with advanced solid tumors. In this regard, the editor has sorted out the relevant questions for readers.
Figure 1 2022 CSCO Summary number 12915
ORR reaches 50%! Can RCC patients become the next benefit group?
At present, immunotherapy has gradually become an important new anti-tumor treatment method. At the same time, relevant studies have shown that MSI-H/dMMR can effectively predict whether patients with advanced solid tumors can benefit from the treatment of immune checkpoint inhibitors (ICIs). [2]. In addition, the study released the occurrence of MSI-H on 18 cancers, of which 14 cancer patients had MSI-H, while the highest incidence of endometrial cancer was 30% [2].
Now, immunotherapy represented by ICI has gradually become a "broad-spectrum" anti-tumor treatment method and has been widely used in a variety of tumor patients, which has also brought the concept of "two diseases and the same treatment" from ideals to reality. A summary analysis of three studies including KN035-CN-001, KN035-JP-001 and KN035-US-001 was reported at the CSCO annual meeting. A total of 350 patients were included, covering 36 different tumor types such as renal cell carcinoma (RCC), gastric cancer, and esophageal cancer.
Not only that, the analysis results show that among the patients included in the study, 92.6% were patients with stage IV tumors, and 47.7% of the patients had received at least 3-line or above systemic treatment before enrollment (Figure 2) [3]. Among the 270 patients with evaluable efficacy, the objective response rate (ORR) reached 12.2% (33/270, 95% CI 8.6%-16.7%), which is comparable to previous clinical studies on PD-1/PD-L1 inhibitor phase I. In addition, the benefits of anti-tumor treatment brought by enwolizumab were relatively long-lasting, with the median duration of remission (DoR) of patients reaching 11.3 (95%CI 5.7-unevaluable) months, and the median overall survival (OS) was 13.8 (95%CI 11.6-15.9) months.
Figure 2 Patient baseline characteristics [3]
It is worth mentioning that among the 36 patients with different tumors, the ORR of RCC patients was as high as 50% (5/10). Among the 5 RCC patients who experienced remission, 3 DoR reached more than 6 months, and another patient had DoR reached 11 months and was still receiving treatment. The median progression-free survival (PFS) of patients was 11.1 (95%CI 5.6-14.1) months, and the median OS has not been achieved.
In November 2021, Nwolizumab was approved by the National Drug Administration (NMPA) for the treatment of adult patients with advanced solid tumors with unresectable or metastatic MSI-H or dMMR, and was recommended by 5 CSCO guidelines, including "Guidelines for Diagnosis and Treatment of Gastric Cancer 2022", "Guidelines for Diagnosis and Treatment of Colorectal Cancer 2022", "Guidelines for Diagnosis and Treatment of Endometrial Cancer 2022", "Guidelines for Diagnosis and Treatment of Cervical Cancer 2022", and "Guidelines for Clinical Application of CSCO Immune Checkpoint Inhibitors 2022". Judging from the data released this time, RCC patients have the potential to become another patient group that can benefit from the treatment of enwolizumab in the future.
Enwolizumab has good safety for patients of all ages
With the widespread use of immunotherapy drugs in clinical practice, while providing patients with excellent anti-tumor treatment effects, some immune-related adverse reactions (irAEs) will also occur.Although most irAEs are mild and self-limiting in clinical practice, there are still some serious irAEs that are unpredictable, which can affect the efficacy of immunotherapy and may even lead to treatment suspension or patient death [4]. Therefore, in addition to the clinical efficacy of the drug, the safety of the drug will also attract the attention of tumor clinical workers and patients.
According to the summary analysis data released this time, the incidence of irAE in patients treated with enwolizumab was 25.4%, mainly based on grade 1 and 2 irAE, and the incidence of irAE above grade 3 is only 7.4%, and it is mainly endocrine and skin-related toxic adverse reactions (Figure 3) [3]. According to the age of the patient, after stratified analysis of the patients with critical values of at 50 and 65 years old, it was found that the incidence of irAE in patients of different ages was similar to that of [3], which is consistent with the relevant results of the latest subgroup data of the KN035-CN-006 study published at this CSCO annual meeting [5].
Figure 3 Patient irAE related data [3]
It is worth noting that the study data showed that until the patient received subcutaneous administration of enwolizumab 10mg/kg once a week (QW), no dose-limiting toxicity (DLT) was observed. In addition, since envolizumab can be administered by subcutaneous injection, adverse infusion reactions can be avoided during clinical application, and the adverse injection reactions are also relatively mild, which well proves that envolizumab has good safety.
Is enwolizumab expected to further extend the dosing interval in the future?
Enwolizumab is designed with a molecular weight of only about half of conventional antibodies. It can spread quickly and evenly throughout the body, and has good tissue penetration ability and can penetrate evenly in tumor tissue. Subcutaneous injection also gives it a unique convenience advantage, which not only meets the treatment needs of patients who cannot intravenous infusion, but also helps to improve the patient's treatment experience and quality of life.
In the summary analysis of this report, the drug metabolic kinetics (PK) simulation data on enwolizumab showed that the dosing regimen of 300 mg Q3W and 400 mg Q4W can maintain the patient's drug steady-state trough concentration above 5 μg/ml. Previously, KN035-US-001 study [6] showed that the patients were treated with a 300 mg Q4W dosing regimen. After the first dose, the average maximum serum concentration (Cmax) was 14 μg/ml, the median peak time (Tmax) was 71.9 h, and the average half-life (T1/2) of the first dose was about 14 days. After 5 cycles of treatment, the drug's steady state T1/2 was about 23 days. KN035-JP-001 study [7] showed that under the 300 mg Q4W dosing regimen, Tmax was 166 hours, the average Cmax was 14 μg/ml, and the median T1/2 for the first dose was about 14 days. After 5 cycles of treatment, the drug's steady-state T1/2 was about 18 days. These all indirectly suggest the feasibility of 300 mg Q3W and 400 mg Q4W dosing regimens in clinical practice.
In August 2022, the usage and dosage scheme of enwolizumab "300 mg Q2W" was approved by NMPA. This newly added dose usage regimen has similar PK, safety and effectiveness characteristics compared with the previously recommended "150 mg QW". At present, clinical research related to the fixed dose dosage regimen of Enwolizumab 400 mg Q4W is underway. In the future, Enwolizumab is expected to further extend the dosage interval, allowing many tumor patients to enjoy a convenient treatment plan of "injection once a month". This not only helps clinicians to administer medications based on the actual situation of the patient, making the treatment plan more flexible, but also directly reduces the frequency of patients seeking medical treatment and improves their medication compliance.
References
[1] Jianming Xu, Kyriakos P. Papadopoulos, Toshio Shimizu, et al. Efficacy of Envafolimab, a Novel Subcutaneous Anti-PD-L1 Inhibitor, in patients with advanced solid tumors: Pooled results from three Phase 1 studies. 2022 CSCO.
[2] Ronald J Hause, Colin C Pritchard, Jay Shendure, et al. Classification and characterization of microsatellite instability across18 cancer types[J]. Nat Med, 2016, 22: 1342-1350.
[3] Chuanhua Zhao, Kyriakos P. Papadopoulos, Toshio Shimizu, et al. Efficacy of Envafolimab, a Novel Subcutaneous Anti-PD-L1 Inhibitor, in patients with advanced solid tumors: Pooled results from three Phase 1 studies[EB/OL]. https://class.medlive.cn/csco/2022?id=0, 2022-11-06/2022.11.15.
[4] Bai Rilan, Cui Jiuwei. Adverse reactions related to the treatment of immune checkpoint inhibitors—new explorations and new challenges[J]. Chinese Journal of Tumor Biological Therapy, 2021, 28(05):419-430.
[5] Shen Lin, Li Jian, Deng Yanhong, et al. Updated and subgroup analysis of key phase II study of MSI-H/dMMR in the treatment of MSI-H/dMMR in Enwolizumab for advanced solid tumors. 2022 CSCO.
[6] Papadopoulos KP, Harb W, Peer CJ, et al. First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors[J]. Oncologist. 2021, 26(9):e1514-e1525.
[7] Shimizu T, Nakajima TE, Yamamoto N, et al. Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors[J]. Invest New Drugs. 2022, 40(5):1021-1031.
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
