The median age was 67 years (range: 34 to 88); 66 percent of individuals had visceral metastasis (bone, liver, or lung), including 34 percent with liver metastasis. Lymph node only metastasis were present in 13 percent of individuals. Sixty-six percent of individuals had ECOG performance status of 1, and 41 percent of individuals had a baseline creatinine clearance < 60 mL/min. The Bellmunt risk score (which includes ECOG performance status, baseline hemoglobin, and liver metastases) was 0 in 23 percent, 1 in 38 percent, 2 in 29 percent, and 3 in 9 percent of individuals. Twenty percent of individuals had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy. Seventy percent of individuals received prior cisplatin, 30 percent prior carboplatin and 35 percent received ≥ 2 prior lines of systemic therapy.
Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182 individuals, 52 percent were classified as PD-L1 high (if ICs involve > 1 percent of the tumor area, TC ≥ 25 percent or IC ≥ 25 percent; if ICs involve ≤ 1 percent of the tumor area, TC ≥ 25 percent or IC = 100 percent), 40 percent as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples for 8 percent were not evaluable.
In the urothelial carcinoma cohort of Study 1108, the median follow-up time was 5.6 months. In 37 individuals who had received only neoadjuvant or adjuvant therapy prior to study entry, 24 percent responded. Among the total 31 responding individuals, 45 percent had ongoing responses of 6 months or longer and 16 percent had ongoing responses of 12 months or longer.
Durvalumab demonstrated efficacy in a small open-label trial of individuals with locally advanced or metastatic urothelial carcinoma in which they had progressed while on or after a platinum-based therapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The safety profile was manageable.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
NON-SMALL CELL LUNG CARCINOMA
On February 16, 2018, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca Inc.) for patients 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 a ECOG performance status 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 vs. ≥ 65 years), and smoking history (smoker vs. 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 RECIST v1.1-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 BICR RECIST v1.1, and overall survival (OS). Additional efficacy outcome measures included ORR and DoR assessed by BICR.
Of the 713 individuals who underwent randomization, 709 received the assigned intervention (473 individuals received durvalumab 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 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 overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73 percent CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio 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 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 overall survival, progression-free survival, and a greater objective response rate compared with placebo in a study in individuals with stage III non-small cell lung cancer who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy.
SMALL CELL LUNG CARCINOMA
On March 27, 2020, the US 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 vs. chemotherapy alone. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1. Median OS was 13.0 months (95 percent CI: 11.5, 14.8) in the durvalumab (Imfinzi™) plus chemotherapy arm compared with 10.3 months (95 percent CI: 9.3, 11.2) in the chemotherapy alone arm (hazard ratio 0.73; 95 percent CI: 0.59, 0.91; p=0.0047).
The study demonstrated first-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group.