D. Ross Camidge, MD, PhD
Patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) had double the expected response when the PD-L1 inhibitor atezolizumab was added to chemotherapy, according to preliminary data from an ongoing clinical trial reported at the 2015 World Conference on Lung Cancer.
Overall, almost two thirds of 41 evaluable patients had objective responses with atezolizumab plus different platinum-based chemotherapy doublets. The highest response rate occurred with the combination of atezolizumab, carboplatin, and pemetrexed, as 13 of 17 patients (76.5%) had partial responses. Four patients treated with the anti–PD-L1 inhibitor, carboplatin, and nab-paclitaxel had complete responses.
“This preliminary analysis showed a high response rate for the combined non–small cell lung cancer cohort, supporting potential synergy between atezolizumab and chemotherapy,” said D. Ross Camidge, MD, PhD, a professor of medical oncology at the University of Colorado in Denver. “Atezolizumab demonstrated no unexpected toxicities in combination with standard first-line chemotherapy regimens for advanced non-small cell lung cancer.”
Despite advances in treatment of NSCLC, the overall response rate with first-line standard chemotherapy for metastatic disease remains about 30%. Preclinical studies have suggested that chemotherapy leads to antigen release in the tumor microenvironment, potentially affording an opportunity for enhanced effects of immunotherapy.
“Combining PD-L1 inhibition with chemotherapy could create an immunogenic ‘feedback loop,’ increasing the number of antigens presented to the T-cells, thus increasing immune responses and changing the tumor microenvironment to be more favorable to immune response,” said Camidge.
Atezolizumab (formerly MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint but not PD-L2/B7.1 interaction, thus avoiding the risk of autoimmune lung toxicity. Atezolizumab demonstrated single-agent activity in preliminary clinical studies involving patients with advanced lung cancer, providing a rationale to evaluate the immunotherapeutic agent in combination with standard chemotherapy regimens for advanced NSCLC.
Camidge reported findings from a phase Ib trial involving patients with previously untreated metastatic NSCLC. The patients received atezolizumab at a dose of 15 mg/kg IV every 3 weeks in addition to one of three chemotherapy doublets: carboplatin paired with paclitaxel, pemetrexed (nonsquamous histology only), or nab-paclitaxel. Treatment continued for four to six cycles, followed by atezolizumab maintenance therapy until disease progression (and optionally, pemetrexed maintenance in that arm of the trial).
The primary outcome was overall response rate, as determined by RECIST criteria. The trial has an accrual goal of 25 patients per treatment group, and Camidge reported data for 58 patients, 41 of whom were evaluable for response. The patients had a median age of 65, and 79% of the cohort had nonsquamous histology. PD-L1 expression was assessed by immunohistochemistry.
Response data showed that four of eight (50%) patients in the carboplatin-paclitaxel cohort achieved objective responses (all partial responses), as did nine of 16 (56%) patients who received carboplatin and nab-paclitaxel in addition to atezolizumab (including all complete responses that have occurred thus far). Overall, 26 of the 41 (63.4%) evaluable patients met criteria for objective response, led by a 77% response rate in the pemetrexed arm.
“The vast majority of patients in all three groups had regression of tumor burden, even though the change did not meet criteria for objective response in all cases,” said Camidge.
All 58 patients were included in the safety analysis. The most common grade 3/4 adverse events across the three treatment groups were neutropenia (36% to 45%, 40% overall); anemia (8.3% to 20.0%, 13.8% overall); and thrombocytopenia (0% to 21%, 12.1% overall).
A preliminary analysis of individual types of adverse events suggested that atezolizumab did not add substantially to the adverse events usually observed with cytotoxic chemotherapy.
“Analysis of the data by specific chemotherapy regimen, corticosteroid use, and PD-L1 expression levels are in progress,” said Camidge. “Other endpoints, including duration of response and progression-free survival, are still immature and will be presented at a later data.
“Several phase III studies looking at atezolizumab monotherapy and in combination with other agents in non-small cell lung care are underway.”