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Neoadjuvant combination immunotherapy with nivolumab (Opdivo) plus ipilimumab (Yervoy) produced a significant clinical benefit for patients with operable stage I-III non-small cell lung cancer (NSCLC), researchers reported.

The phase II NEOSTAR study randomly assigned 44 patients with operable NSCLC to neoadjuvant nivolumab with or without ipilimumab followed by surgery. Among those, 38% of patients that received the combination achieved major pathological response (MPR) -- defined as 10% or less viable tumor at surgery -- and met the study's primary efficacy endpoint threshold of six MPRs in 21 patients, according to Tina Cascone, MD, PhD, of the MD Anderson Cancer Center in Houston, and colleagues.

This rate was higher than historical neoadjuvant chemotherapy controls and higher than nivolumab alone, they reported in .

"The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory," Cascone said in a press release. "This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

The study showed enhanced tumor immune cell infiltration with nivolumab plus ipilimumab, including higher densities of CD3+, CD3+CD8+ tumor infiltrating lymphocytes, and tissue-resident memory and effector memory T cells. Immune infiltration of tumors was independent of MPR.

Matthew D. Hellman, MD, of Memorial Sloan Kettering Cancer Center in New York City, told 名媛直播, that the study "affirms the promising role of anti-PD-1-based therapies in the treatment of patients with operable NSCLC, which I anticipate will become a routine treatment strategy in the near future."

"This study also highlights the remarkable biologic insight that can be gleaned from the neoadjuvant approach. It is a blueprint for discovery," said Hellman, who was not involved in the study.

Unlike combination treatment of nivolumab plus ipilimumab, nivolumab monotherapy did not meet the criteria for the primary endpoint. MPRs occurred in 22% of patients assigned to monotherapy. Historically, neoadjuvant chemotherapy has resulted in MPR rates of 7% to 27% in localized disease, the researchers noted.

Pathologic complete response (pCR) occurred in 29% of patients treated with the combination compared with 9% of patients treated with nivolumab alone.

The overall resectability rate among patients who had at least one dose of neoadjuvant immune checkpoint inhibition (ICI) was 89%. All of these patients had complete resection.

The researchers also performed a sensitivity analysis of samples taken from the 37 patients who successfully went on to surgery. Among these patients, the MPR rate was twice as high for the combination than for nivolumab alone (50% vs 24%). The 50% MPR rate "is promising and provides a platform for further evaluation in larger studies," they said, reporting that pCR rates were 10% and 38%, respectively. Additionally, toxicities were manageable with no new safety concerns.

Mediation duration of follow-up was 22.2 months and median overall survival and lung cancer-related survival were not yet reached, Cascone's group noted.

Finally, they conducted an exploratory analysis of the gut microbiome and found that ICI had no significant impact "on the diversity, structure, and composition of microbiomes." There was an increased amount of gut Ruminococcus and Akkermansia spp. that was associated with MPR to dual therapy, the authors stated.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said in the press release. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

Cascone and colleagues noted that the results of the study were exploratory and hypothesis-generating only. However, despite any limitations, "this is the first completed randomized study comparing the impact of neoadjuvant nivolumab monotherapy and combined nivolumab + ipilimumab in resectable NSCLC." Results from a third arm of the trial testing neoadjuvant nivolumab plus chemotherapy are expected later in 2021.

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