Neoadjuvant Nivolumab Appears Safe and Feasible in Lung Cancer

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We found that neoadjuvant administration of nivolumab is safe and feasible in stages I–IIIA NSCLC, and we also saw a preliminary signal that anti–PD-1 immunotherapy may have activity in early-stage disease.
— Patrick Forde, MD

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Neoadjuvant immunotherapy with the programmed cell death protein 1 (PD-1) inhibitor nivolumab (Opdivo) is safe and feasible in early-stage non–small cell lung cancer (NSCLC). The results come from the first report of PD-1 blockade prior to surgery in this tumor, according to Patrick Forde, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who reported these findings at the 2016 European Society for Medical Oncology (ESMO) Congress.1

“Thirty-nine percent of patients with early-stage NSCLC treated with two doses of nivolumab had major pathologic responses associated with immune cell infiltration of tumor,” Dr. Forde reported. “One hypothesis is that having tumor in situ when you give anti–PD-1—having more antigen present—may be better than giving it in the adjuvant setting, where only micrometastases may be present.”

The study aimed to determine the safety and feasibility of neoadjuvant nivolumab in 18 patients with stages I–IIIA NSCLC. Patients received two doses of nivolumab at 4 weeks and then 2 weeks prior to surgical resection. Treatment was considered feasible if it did not delay surgery. Pathologic tumor response was an exploratory endpoint.

The researchers are also performing correlative analyses of the pretreatment biopsy and posttreatment tumor samples, including programmed cell death ligand 1 (PD-L1) staining, multiplex immunohistochemical studies, and T-cell–receptor sequencing.

Key Study Findings

Dr. Forde reported there were no significant safety concerns and no delays to surgery after neoadjuvant nivolumab. In an exploratory analysis, 4 of 18 patients (22%) achieved radiologic responses, and 13 patients (72%) had stable disease; only 1 patient had progressive disease. Of 17 patients who underwent resection, 9 had at least 50% regression of the tumor. Seven patients (39%) had major pathologic responses after neoadjuvant treatment, meaning they had < 10% residual viable tumor at resection. One patient had a pathologic complete response.

Responders’ tumors showed dense infiltration of immune cells. Although three robust responders were positive for PD-L1 expression (≥ 1%) by immunohistochemical assay, the relationship was not clear-cut. One responder was PD-L1–negative, and one strongly PD-L1–positive patient did not respond, added Dr. Forde.

Neoadjuvant Nivolumab in Early-Stage NSCLC

  • A study of 18 patients proved that 2 doses of nivolumab prior to resection for early-stage NSCLC was safe and did not delay surgery.
  • Of 18 patients, 4 (22%) achieved radiologic responses, and 13 (72%) had stable disease; only 1 patient had progressive disease.
  • Seven patients (39%) were pathologically downstaged; one patient had a complete response.

Multiplex immunohistochemistry demonstrated infiltration of cytotoxic T cells into the tumors. New T-cell clones were detected in the posttreatment tumors that were not identified in the pretreatment biopsy. Genetic profiling in a small number of tumors analyzed so far showed that patients with major pathologic responses had higher absolute numbers of mutations, “similar to what we see in metastatic NSCLC,” he pointed out. Absolute levels of predicted neoantigens were also higher in major responders.

“Comprehensive genomic, immunohistochemical, T-cell–receptor clonality, and tumor-infiltrating lymphocytes functionality studies are ongoing, and larger follow-up clinical studies are planned,” added Dr. Forde.


Treatment-related toxicities were consistent with those seen in other studies of nivolumab, and there were no treatment-related deaths. Of 19 patients evaluated for safety, adverse events of any grade were reported by 32%; only 1 patient (5%) had grade 3/4 toxicity, and this led to treatment discontinuation; however, the subsequent surgery was uncomplicated.

“We found that neoadjuvant administration of nivolumab is safe and feasible in stages I–IIIA NSCLC, and we also saw a preliminary signal that anti–PD-1 immunotherapy may have activity in early-stage disease,” Dr. Forde commented.

Based on these results, the study is being expanded. One cohort will receive a third dose of nivolumab, and the other cohort will receive the combination of nivolumab and ipilimumab (Yervoy) preoperatively. This expanded study will be conducted in collaboration between Johns Hopkins University and Memorial Sloan Kettering Cancer Center. The Lung Cancer Mutation Consortium is also conducting larger studies of neoadjuvant immune checkpoint inhibition in NSCLC. ■

Disclosure: Dr. Forde received institutional research grants from Bristol-Myers Squibb, Novartis, AstraZeneca, and Kyowa outside of this submitted work and also consulted for AstraZeneca and Celgene.


1. Forde PM, Smith KN, Chaft JE, et al: Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small cell lung cancer. 2016 ESMO Congress. Abstract LBA41_PR. Presented October 7, 2016.

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