COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).Paul Baas, MD, PhD, from the department of thoracic oncology at the Netherlands Cancer Institute in Amsterdam.
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”