Immunotherapies targeting PD-1 and PD-L1 have become standards-of-care across all lines of therapy for patients with metastatic non-small cell lung cancer (NSCLC) who do not have targetable driver mutations. Furthermore, the PD-L1 inhibitor durvalumab was recently approved as consolidation therapy after chemoradiation in locally advanced NSCLC. Based on the improved outcomes seen with these agents in advanced NSCLC, they are now being evaluated in early stage NSCLC where effective therapies are needed, as many patients (particularly those beyond stage IB) relapse after surgery, despite neoadjuvant/adjuvant chemotherapy.
A small pilot study evaluated the safety and efficacy of nivolumab (3 mg/kg every 2 weeks) as a neoadjuvant therapy in 21 patients with stage I (>2cm)/II/IIIA NSCLC. The investigators evaluated clinical, pathologic, and immunologic effects after two doses of nivolumab. Only 2 patients had radiologic partial response during this 4-week period of treatment. However, among 20 completely resected tumors, 9 achieved major pathologic response (45%), including 3 complete pathologic responses. While responses occurred regardless of PD-L1 expression status, there was a strong correlation between pretreatment tumor mutational burden and pathologic response. The 12-month rate of recurrence-free survival in patients who had complete surgical resection was 80%.
Levels of neoantigen T-cells, before and after treatment, were evaluated in 9 patients. Nivolumab was associated with an increase in T-cell clones in both the tumor and peripheral blood in 8 of 9 patients. There was a greater increase in clonal T-cell in tumors with a major pathologic response. These circulating T-cells may suggest improved protection against tumor growth.
The toxicity profile associated with neoadjuvant nivolumab was mild and consistent with the known safety profile of nivolumab. Treatment-related adverse events (AEs) occurred in 23% of patients, with only one event of grade 3 or higher (grade 3 pneumonia). Importantly, surgery was not delayed due to treatment-related AEs in any patient.
The investigators concluded that neoadjuvant nivolumab is a safe and promising treatment approach for patients with resectable NSCLC, resulting in high rates of pathologic response and relatively low number of relapses after a median of 12-month follow up. In an accompanying commentary, Thomas Gajewski, MD, PhD (University of Chicago, Illinois, United States), agreed that these data provide important pharmacodynamic information. However, the small sample size and the lack of long-term follow-up preclude complete analysis. Phase III trials are planned that will further investigate the impact of neoadjuvant immunotherapy on long-term recurrence and overall survival.