SUMMARY: The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and about 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Patients with extensive stage SCLC are often treated with a combination of Carboplatin or Cisplatin with Etoposide as first line treatment and the tumor response rates are as high as 60-80%. However, majority of the patients relapse within months of completing initial therapy, with a median Overall Survival of approximately 10 months. Patients often receive HYCAMTIN® (Topotecan) for recurrent or progressive SCLC (second-line treatment) and after failure on second-line therapy, treatment options are limited. The 5 year survival rate for Extensive Stage SCLC is less than 5%, with a median survival of 9-10 months from the time of diagnosis.
Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic and could respond to immune-checkpoint inhibitors. TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody that directly binds to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells and blocks the interaction of PD-L1 with PD-1 and B7.1 receptors and thereby enables the activation of T cells and restores tumor-specific T-cell immunity. In a phase I trial, TECENTRIQ® monotherapy demonstrated durable responses, with an acceptable safety profile in patients with relapsed or refractory SCLC. A combination of checkpoint inhibition with cytotoxic chemotherapy was therefore studied, for synergy and improved efficacy.
The IMpower133 trial is a multinational, randomized, double-blind, placebo-controlled Phase III trial which evaluated the benefit of TECENTRIQ® plus Carboplatin and Etoposide in chemo naïve patients with extensive-stage Small-Cell Lung Cancer. Enrolled patients were randomized in a 1:1 ratio and the induction phase consisted of four cycles of Carboplatin AUC 5 mg/ml/min IV on day 1 and Etoposide 100 mg/m2 IV on days 1-3 of each 21-day cycle, with either TECENTRIQ® 1200 mg IV day 1 of each cycle (N=201) or placebo (N=202). The induction phase was followed by a maintenance phase during which patients received either TECENTRIQ® or placebo (based on previous random assignment) and treatment was continued until disease progression or unacceptable toxicities. The median age was 64 yrs and PD-L1 testing was not a requirement. Prophylactic cranial irradiation was permitted during the maintenance phase of treatment but thoracic radiation therapy was not permitted. The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS) and Secondary end points included Objective Response Rate (ORR) and Duration of Response. At a median follow up of 13.9 months, the median OS was 12.3 months in the TECENTRIQ® group compared to 10.3 months in the placebo group (HR=0.70; P=0.007). The median PFS which was a Coprimary endpoint was also longer in the TECENTRIQ® group than in the placebo group (5.2 months versus 4.3 months, HR=0.77; P=0.02). This data led to the approval of TECENTRIQ® for the first line treatment of extensive-stage Small-Cell Lung Cancer.
The authors now reported the Overall Survival (OS) outcomes after a follow up of more than 2 years. At a median follow up of 22.9 months, the median OS for the patients randomized to TECENTRIQ® persisted at 12.3 months versus 10.3 months in the placebo group (HR=0.76; P =0.01). The authors noted that there was no correlation between efficacy of the TECENTRIQ® combination and blood Tumor Mutational Burden level. Further, the OS benefit was not influenced by tumor tissue PD-L1 expression. There was no change in the Adverse Events rate noted, in this updated analysis.
It was concluded that with a follow up of close to 2 years, the addition of TECENTRIQ® to standard chemotherapy, for treatment of patients with extensive stage Small Cell Lung Cancer, continues to demonstrate improved Overall Survival, compared to chemotherapy alone. IMpower133: Updated Overall Survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Reck M, Liu SV, Mansfield AS, et al. Presented at ESMO September 27-October 1, 2019; Barcelona, Spain. Abstract 17360.