from The New England Journal of Medicine
Dr. Kellie Smith, recipient of an LCFA/IASLC 2016 Lori Monroe Scholarship in Translational Lung Cancer Research, along with her research team, outlines their study supported in part by the grant from Lung Cancer Foundation of America
Antibodies that block the immune inhibitory pathway of programmed death 1 (PD-1) protein have provided a major treatment advance in patients with cancer. In some patients with advanced non–small-cell lung cancer (NSCLC), these drugs unleash antitumor immunity, resulting in tumor regression and improved survival.
Effective therapies are needed for patients with early-stage NSCLC. Five-year survival rates range from 50% for stage IA disease to 20% for stage IIIA disease, with most patients having postsurgical tumor relapse. Perioperative platinum-based chemotherapy is associated with a survival rate that is only 5.4 percentage points higher than that with surgery alone, with rates of toxic effects of grade 3 or higher of more than 60%. PD-1 pathway blockade in patients with early-stage lung cancer may have enhanced antitumor effects owing to greater fitness of host immunity and reduced tumor clonal heterogeneity. Neoadjuvant immunotherapy is attractive, since the primary tumor may be leveraged as an antigen source for expansion and activation of tumor-specific T cells and systemic surveillance of micrometastases. In addition, neoadjuvant approaches provide an opportunity to study the in vivo effect of PD-1 blockade on the primary-tumor microenvironment and peripheral blood.
We performed this pilot study to examine the safety and feasibility of the use of neoadjuvant nivolumab in a small group of patients with early NSCLC. We also examined the relationship between the tumor genomic profile and the pathological response, the effects of nivolumab on the primary-tumor microenvironment, and the dynamics of intratumoral and peripheral neoantigen-specific T-cell clonotypes.
Eligible patients were 18 years of age or older and had stage I, II, or IIIA NSCLC that was deemed to be surgically resectable before enrollment. All the patients had an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (on a 5-point scale in which higher numbers reflect greater disability), normal organ function, and adequate pulmonary function. Key exclusion criteria were immunodeficiency, ongoing systemic immunosuppressive therapy, active autoimmune or infectious disease, and clinically significant concurrent cancer.
This single-group study was developed by the authors and conducted at two medical centers in the United States. The patients received two doses of intravenous nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks. It was planned that surgery would be performed approximately 4 weeks after the first dose. All the patients provided written informed consent.
The primary end points were safety and feasibility. The key secondary and exploratory end points were radiologic and pathological responses to treatment and immunologic, genomic, and pathological correlates of response in blood and tumor.
All the patients were monitored for adverse events, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Feasibility was prospectively defined as any delay in the planned surgery of no more than 37 days (i.e., a surgical delay of >30 days and 7 days for scheduling). In a safety run-in phase, an initial 6 patients were followed for perioperative adverse events of grade 3 or 4 for 90 days after the administration of the last nivolumab dose (or day 30 after surgery). With the goal of exploring the antitumor immune response in depth, the study then expanded to enroll a total of 20 patients who underwent complete tumor resection.