In a normal immune response, the body can recognize the presence of tumors and mount a response to eradicate them. The process of eradicating a tumor begins with antigen-presenting cells that gather and process the antigens released by tumors. This activates the T cells, which proliferate and attack the tumor.
Tumors have learned to evade the normal immune response by exploiting the immune checkpoint pathway. The Programmed Death Receptor-1 (PD-1) is a checkpoint protein expressed on the membrane of activated T cells. The Programmed Death-Ligand 1 (PD-L1) and The Programmed Death-Ligand 2 (PD-L2) are checkpoint proteins expressed on tumor cells and tumor-infiltrating immune cells. When PD-L1 and PD-L2 attach to PD-1 receptors on the T cells, the T cells become inhibited and will not attack the tumor; thus, the tumor can continue to proliferate.
Durvalumab (Imfinzi) is a human monoclonal antibodies and immune checkpoint inhibitor that binds to PD-L1 on tumor cells and tumor-infiltrating immune cells and block the interaction with PD-1 and B7.1 receptors on T cells and antigen-presenting cells. Consequently, the tumor is no longer able to inactivate the T cells and the antitumor response continues.
DURVALUMAB (IMFINZI) INDICATIONS
NON-SMALL CELL LUNG CARCINOMA (NSCLC)
On February 16, 2018, the US Food and Drug Administration (FDA) approved durvalumab (Imfinzi) for individuals with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
The efficacy of durvalumab (Imfinzi) was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled phase 3 study in individuals with unresectable Stage III NSCLC who completed at least two cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had an Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0 or 1. The study excluded individuals who had progressed following concurrent chemoradiation, individuals with active or prior documented autoimmune disease within two years of initiation of the study or individuals with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years versus 65 years or older), and smoking history (smoker versus non-smoker). Individuals were randomized 2:1 to receive durvalumab (Imfinzi) 10 mg/kg or placebo intravenously every two weeks for up to 12 months or until unacceptable toxicity or confirmed Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-defined progression. Assessment of tumor status was performed every eight weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a Blinded Independent Central Review (BICR) RECIST 1.1, and overall survival (OS). Additional efficacy outcome measures included objective response rate (ORR) and duration of response (DOR) assessed by BICR.
Of the 713 individuals who underwent randomization, 709 received the assigned intervention (473 individuals received durvalumab (Imfinzi) and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3 percent (95 percent confidence interval [CI], 61.7 to 70.4) in the durvalumab (Imfinzi) group, as compared with 55.6 percent (95 percent CI, 48.9 to 61.8) in the placebo group (two-sided p=0.005). Durvalumab (Imfinzi) significantly prolonged OS, as compared with placebo (stratified hazard ratio [HR] for death, 0.68; 99.73 percent CI, 0.47 to 0.997; p=0.0025). Updated analyses regarding PFS were similar to those previously reported, with a median duration of 17.2 months in the durvalumab (Imfinzi) group and 5.6 months in the placebo group (stratified HR for disease progression or death, 0.51; 95 percent CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab (Imfinzi) group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95 percent CI, 0.41 to 0.68). Consolidation therapy with durvalumab (Imfinzi) resulted in significantly prolonged median OS, PFS, and a greater ORR compared with placebo in a study in individuals with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.
SMALL CELL LUNG CARCINOMA (SCLC)
On March 27, 2020, the FDA granted approval for durvalumab (Imfinzi) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of individuals with extensive-stage small cell lung cancer (ES-SCLC).The efficacy of durvalumab (Imfinzi) in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, phase 3, open-label trial (NCT03043872). The study population characteristics were: median age of 63 years (range: 28 to 82); 65 percent ECOG PS of 1; and 93 percent were former/current smokers. Ninety percent of individuals had Stage IV disease and 10 percent had brain metastasis at baseline. A total of 25 percent of the individuals received cisplatin and 74 percent of the individuals received carboplatin. In the chemotherapy alone arm, 57 percent of the individuals received six cycles of chemotherapy, and 8 percent of the individuals received prophylactic cranial irradiation.
The evaluation was based on the comparison of individuals randomized to durvalumab (Imfinzi) plus chemotherapy versus chemotherapy alone. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed PFS and ORR per RECIST 1.1. Median OS was 13.0 months (95 percent CI: 11.5 to 14.8) in the durvalumab (Imfinzi) plus chemotherapy arm compared with 10.3 months (95 percent CI: 9.3 to 11.2) in the chemotherapy alone arm (HR 0.73; 95 percent CI: 0.59 to 0.91; p=0.0047). The study demonstrated first-line durvalumab (Imfinzi) plus platinum-etoposide significantly improved OS in patients with ES-SCLC versus a clinically relevant control group.