AstraZeneca's Imfinzi Approved in Japan for First-Line Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

August 22, 2020 News /Bio ValleyBIOON/ --AstraZeneca(AstraZeneca) recently announced that Japanese regulatory authorities have approved the anti-PD-L1 therapy Imfinzi (brand name: Imfinzi; generic name: durvalumab), in combination with standard-of-care (SoC) platinum-based chemotherapy (etoposide plus carboplatin, or etoposide plus cisplatin), for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). This approval provides an important first-line treatment option for patients with ES-SCLC in Japan. SCLC is an aggressive, rapidly growing cancer that, despite initial response to platinum-based chemotherapy, typically relapses and progresses quickly.

In the United States, Imfinzi was approved in late March 2020FDAApproved for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with platinum-based chemotherapy (etoposide plus carboplatin or etoposide plus cisplatin). This indication is currently under regulatory review by the European Medicines Agency (EMA).

It is worth noting that,Imfinzi is the only PD-1/PD-L1 immunotherapy proven to provide significant survival benefits and improved response rates when combined with standard-of-care platinum-based chemotherapy (etoposide plus cisplatin or carboplatin).

This approval is based on the results of the Phase III CASPIAN trial. The relevant data have been published in The Lancet, a top-tier international medical journal. The data demonstrated that fixed-dose Imfinzi in combination with standard-of-care (SoC) platinum-based chemotherapy yielded statistically significant and clinically meaningful improvements in overall survival (OS) compared with SoC platinum-based chemotherapy alone.

Dr. Makoto Nishio, Director of Medical Oncology in the Department of Thoracic Medicine at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research and an investigator in the CASPIAN study, stated: “In Japan, patients with extensive-stage small cell lung cancer (ES-SCLC) urgently need therapies that can provide long-termTumorNew treatment options that provide sustained improvement in disease control and overall survival. This approval of Imfinzi offers Japanese patients a new, effective, and well-tolerated first-line treatment regimen, giving physicians the opportunity for the first time to combine immunotherapy with cisplatin in the treatment of these patients.”

AstraZenecaTumorDave Fredrickson, Executive Vice President of the Business Unit, stated: “The approval of Imfinzi provides an important new immunotherapy option for patients in Japan with extensive-stage small cell lung cancer (ES-SCLC). The prognosis for these patients is particularly poor, with only 2% surviving beyond five years. Imfinzi, in combination with chemotherapy, offers sustained survival benefits and prolonged treatment response duration through a convenient dosing regimen administered once every four weeks during the maintenance phase.”

CASPIAN is a randomized, open-label, multicenter, global Phase III study comparing the efficacy and safety of Imfinzi plus standard-of-care (SoC) platinum-based chemotherapy (etoposide plus cisplatin or carboplatin), Imfinzi plus tremelimumab plus SoC platinum-based chemotherapy, and SoC platinum-based chemotherapy alone as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC). The Imfinzi plus tremelimumab plus SoC platinum-based chemotherapy regimen is a dual immune checkpoint blockade combined with chemotherapy, consisting of the CTLA-4 checkpoint inhibitor tremelimumab (an anti-CTLA-4 monoclonal antibody), the PD-L1 checkpoint inhibitor Imfinzi (an anti-PD-L1 monoclonal antibody), and SoC chemotherapy. In the study, Imfinzi was administered at a fixed dose of 1500 mg every three weeks for four cycles. Patients in the experimental arms received up to four cycles of SoC chemotherapy, whereas those in the control arm were allowed up to six cycles of SoC chemotherapy and prophylactic cranial irradiation (PCI). The study was conducted at more than 200 clinical centers across 22 countries, including the United States, Europe, South America, Asia, and the Middle East. The primary endpoint was overall survival (OS).

In June 2019, the CASPIAN trial met one of its primary endpoints: a planned interim analysis conducted by the Independent Data Monitoring Committee (IDMC) demonstrated a 27% reduction in the risk of death with Imfinzi plus standard-of-care (SoC) chemotherapy compared with SoC chemotherapy alone (hazard ratio [HR]=0.73; 95% confidence interval [CI]: 0.591–0.909; p=0.0047), significantly prolonged overall survival (median OS: 13.0 months [11.5, 14.8] vs. 10.3 months [9.3, 11.2]), and a substantially higher 18-month survival rate (33.9% vs. 24.7%). Furthermore, across all efficacy endpoints, the Imfinzi plus SoC chemotherapy regimen showed therapeutic benefits compared with SoC chemotherapy alone, including significantly improved progression-free survival rates at 12 months (PFS rate: 17.5% vs. 4.7%), higher confirmed objective response rates at 12 months (ORR: 67.9% vs. 57.6%), and a greater proportion of patients with sustained duration of response at 12 months (DOR: 22.7% vs. 6.3%).

Latest analysis released in late May 2020 showed: After a median follow-up of more than 2 years, Imfinzi + SoC chemotherapy demonstrated sustained efficacy compared to SoC chemotherapy alone,Reduced the risk of death by 25% (HR=0.75; 95% CI: 0.62-0.91; nominal p=0.0032). The updated median OS was 12.9 months, compared with 10.5 months in the SoC chemotherapy group. In a post hoc analysis, the estimated 24-month survival rate was 22.2% in the Imfinzi + SoC chemotherapy group and 14.4% in the SoC chemotherapy group. The post hoc analysis showed that the 24-month progression-free survival rate was 11% in the Imfinzi + SoC chemotherapy group and 2.9% in the SoC chemotherapy group. Furthermore, the Imfinzi + SoC chemotherapy group maintainedHigher Objective Response Rate (ORR: 68% vs. 58%), in the post-hoc analysis, the proportion of patients with a duration of response of 24 months was 13.5% in the Imfinzi + SoC chemotherapy group and 3.9% in the SoC chemotherapy group. At 24 months, 12% of patients in the Imfinzi + SoC chemotherapy group continued to receive Imfinzi treatment.

Based on the findings of this study,Imfinzi is the first to demonstrate survival benefit and improved durable response in patients with ES-SCLCTumorImmunotherapy.However, it is worth noting that in the final analysis, the Imfinzi + tremelimumab + SoC regimen did not meet the primary endpoint of statistically significant improvement in OS compared with SoC alone. In this study, the safety and tolerability profiles of Imfinzi and tremelimumab were consistent with their known safety profiles.

Lung cancer is the leading cause of cancer-related deaths in both men and women, accounting for approximately one-fifth of all cancer deaths. Lung cancer is broadly classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with SCLC comprising about 15% of cases. Approximately two-thirds of patients with SCLC areDiagnosisExtensive-stage disease, meaning the cancer has spread widely throughout the lungs or metastasized to other parts of the body. SCLC is an aggressive, rapidly growing cancer that, although initially responsive to platinum-based chemotherapy, tends to recur and progress quickly. The prognosis is particularly poor, with only 6% of SCLC patients surviving five years after diagnosis.

Imfinzi (Yingfeifan, durvalumab) is a humanized PD-L1 monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80, thereby blockingTumorImmune escape and release of suppressed immune responses. To date, Imfinzi has been approved in more than 60 countries (including the United States, Japan, China, and the entire European Union) for the curative treatment of patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent chemoradiotherapy with platinum-based chemotherapy. Additionally, Imfinzi has been approved in more than 10 countries, including the United States, for the treatment of patients with advanced bladder cancer who have previously received platinum-containing chemotherapy.

As part of the extensive development program for lung cancer, Imfinzi is also being evaluated in another Phase III clinical trial, ADRIATIC, which assesses the use of Imfinzi following concurrent chemoradiotherapy (CCRT) in patients with limited-stage small cell lung cancer (SCLC). Data from this study are expected in 2021.

Tremelimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), blocks CTLA-4 activity, promotes T-cell activation, and initiatesTumorimmune response, promoting cancer cell death. Tremelimumab and Bristol-Myers Squibb's marketed antibody drug Yervoy (ipilimumab) target the same checkpoint, CTLA-4.

Currently, AstraZeneca is conducting a large-scale clinical program to evaluate Imfinzi as monotherapy and in combination with tremelimumab and other agents for the treatment of NSCLC, SCLC, bladder cancer, head and neck cancer,Liver Cancer, cervical cancer, biliary tract cancer, and other solid tumors. (Bioon.com)

Original source: Imfinziapproved in Japan for the treatment of extensive-stage small cell lung cancer