Treatment of operable non-small cell lung cancer (NSCLC) with neoadjuvant nivolumab plus ipilimumab resulted in higher complete pathologic response (cPR) rates and less viable tumor compared with treatment with nivolumab alone and chemotherapy, according to results from the phase 2 NEOSTAR trial published in Nature Medicine.

The rate of recurrence after resection of NSCLC is more than 50%, and 5-year overall survival rates only improved by 5% with neoadjuvant chemotherapy. The aim of this study was to evaluate nivolumab plus ipilimumab on the tumor microenvironment and clinical activity of resectable NSCLC.

The phase 2 NEOSTAR trial ( Identifier: NCT03158129) randomly assigned 44 patients with operable NSCLC to receive nivolumab or nivolumab plus ipilimumab before surgery. The researchers used historical values with neoadjuvant chemotherapy as the control. The primary endpoint was major pathologic response (MPR).

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Nearly all (41) of the patients completed neoadjuvant treatment, and 39 patients underwent surgery with curative intent. The mean age at baseline was 65.6±8.3 years, 36% of patients were women, and 18% were never smokers. The majority of patients had tumors with adenocarcinoma histology at 59%, followed by 39% with squamous cell carcinoma and 2% with adenosquamous carcinoma.

The MPR was highest with the combination of nivolumab plus ipilimumab at 38% compared with 22% with nivolumab alone. There were 6 cases of cPR in the combination arm and 2 cases in the monotherapy arm. The radiographic objective response rate was similar between the arms at 19% with nivolumab plus ipilimumab and 22% with nivolumab alone.

Pretreatment programmed death-ligand 1 (PD-L1) tumor expression was associated with higher MPR and radiographic response, but some patients without PD-L1 tumor expression experienced a response. Post-therapy PD-L1 tumor expression was not associated with response.

Differences in the abundance of gut bacteria was also associated with pathologic response. In an exploratory analysis, MPR and reduced toxicity were associated with higher abundance of Akkermansia sp. and Bifidobacterium sp. An abundance of Coprococcus_3 sp., Lachnospiraceae_UCG >004, and Lachnospiraceae_unclass were associated with a lack of MPR and increased toxicity.

“These results suggest that abundance of different gut bacteria is associated with pathologic responses, reduced toxicity and, in some cases, higher T-cell clonality and richness after neoadjuvant [immune checkpoint inhibitors],” the authors wrote.

During a median follow-up of 22.2 months, both the median OS and the lung cancer-related recurrence-free survival were not yet reached.

The toxicities were considered manageable, with no new safety concerns; 13% of patients in the nivolumab group and 10% of the combination group experienced grade 3 to 5 treatment-related adverse events (TRAEs) with nivolumab. One patient who received nivolumab monotherapy died of respiratory failure because of pneumonia and pneumonitis. There were 5 serious TRAEs.

Neoadjuvant treatment resulted in changes in the tumor microenvironment. There were higher numbers of tumor-infiltrating lymphocytes, nonregulatory memory T cells, and effector memory T cells after treatment with nivolumab plus ipilimumab compared with nivolumab alone.

The authors concluded that “our findings provide evidence that the addition of neoadjuvant ipilimumab to nivolumab produces higher rates of MPR and pCR and enhances tumor immune infiltrates and immunologic memory.”

They added that these findings warrant further investigation of this regimen among patients with resectable NSCLC.


Cascone T, William WN Jr, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. Published online February 18, 2021. doi:10.1038/s41591-020-01224-2