Treatment with neoadjuvant nivolumab, a PD-1 inhibitor, in resectable non-small cell lung cancer (NSCLC) did not delay surgery, and almost half of patients treated had a major pathologic response. The study, led by Patrick M. Forde, MB BCh, from Johns Hopkins University School of Medicine in Baltimore, MD, was published in The New England Journal of Medicine.
Prior studies have shown that drugs that block the PD-1 protein result in tumor regression and improved survival in some patients with advanced NSCLC, but PD-1 inhibitors have not been tested in resectable NSCLC.
The investigators conducted the pilot study to assess the safety and feasibility of nivolumab, based on treatment-related surgery delays. In addition, the relationship between the tumor genomic profile and the pathologic response, the effects of nivolumab on the primary-tumor microenvironment, and the dynamics of intratumoral and peripheral neoantigen-specific T-cell clonotypes were examined.
Approximately four weeks before surgery was planned, eligible patients who had surgical resectable stage I, II, or IIIA NSCLC received nivolumab 3 mg/kg intravenously. A second dose was administered two weeks later.
The primary endpoints were safety and feasibility, prospectively defined as any delay in the planned surgery of no more than 37 days.
The key secondary and exploratory endpoints were radiologic and pathologic responses to treatment and immunologic, genomic, and pathologic correlates of response in blood and tumor.
Patients underwent baseline tumor staging, including pretreatment biopsy, pathologic evaluation of mediastinal lymph nodes, and contrast-enhanced CT or MRI of brain and chest; chest CT was repeated within 7 days before surgery.
Participants were offered conventional adjuvant chemotherapy or radiotherapy, if clinically indicated.
Primary lung tumor and lymph-node surgical specimens were staged to evaluate tumor size, affected lymph nodes, and metastases. Primary tumors were assessed for the percentage of residual viable tumor, and tumors with no more than 10% viable tumor cells were considered to have had a major pathologic response.
Whole-exome sequencing was performed on pretreatment tumor samples and matched normal tissue samples to identify somatic and germline alterations. Assays were performed to evaluate immunologic correlates and T-cell receptor sequencing.
A total of 22 patients were enrolled in the study; 62% had adenocarcinoma, 81% had stage II or IIIA disease, and 86% were current or former smokers.
Treatment with neoadjuvant nivolumab was not associated with any previously unreported toxic effects. Five patients (23%) reported treatment-related adverse events of any grade, and only one event was of grade 3 or higher.
Of the 22 patients enrolled, 20 received two planned doses of nivolumab, and there were no treatment-related surgical delays. The median interval between the second dose of nivolumab and surgery was 18 days, and 95% of eligible patients underwent complete tumor resection.
Of the 21 patients who had evaluable radiographic results, two patients (10%) had a partial response, 18 (86%) had stable disease, and one (5%) had disease progression.
At a median of 12 months of postoperative follow-up, 16 of 20 patients (80%) who had undergone surgical resection were alive and recurrence-free. One patient without recurrence died due to an event unrelated to the study treatment, and three patients had disease progression. The rate of recurrence-free survival at 18 months was 73%.
A major pathologic response occurred in nine of 20 patients (45%). Three patients had no viable tumor cells in the primary tumor, which was deemed a complete pathologic response. The median degree of pathologic regression in the primary tumor was −65% (range −100 to 0).
Large numbers of infiltrating lymphocytes and macrophages were observed in primary tumors with a major pathologic response. This finding was compatible with an immunologic mechanism of response, along with necrotic tumor associated with fibrotic tissue repair.
A major pathologic response occurred in both PD-L1 positive and PD-L1 negative tumors. A median of 92 somatic mutations per tumor were noted; specific driver mutations identified were consistent with previous observations in patients with NSCLC.
There was a significant correlation between pathologic response and the pretreatment tumor mutational burden, and the number of T-cell clones increased after PD-1 blockade in both tumor and peripheral blood.
The authors acknowledge that the study was limited by the small number of patients and the short postoperative follow-up period.
“Neoadjuvant administration of two doses of nivolumab in patients with early-stage lung cancer was associated with few immediate adverse events, did not delay planned surgery, and led to a major pathologic response in 45% of tumors that could be evaluated,” concluded the authors.
They suggested that larger studies are needed to determine the most effective regimen for neoadjuvant therapy and the best predictive biomarkers of response.
To read more about this study, click here.