The randomized phase II NEOSTAR trial, which examined single-agent and combined neoadjuvant immune checkpoint inhibitor therapy in patients with stage I to III non–small cell lung cancer (NSCLC), found combination therapy produced a significant clinical benefit (as assessed by major pathologic response [MPR] rate) as well as enhanced tumor immune cell infiltration and immunologic memory. These findings were published by Tina Cascone, MD, PhD, and colleagues in Nature Medicine.

The NEOSTAR trial examined combined neoadjuvant nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy, in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with 8 of 21 treated patients (38%) achieving MPR, defined as ≤ 10% viable tumor at surgery. MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in 5 of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

Tina Cascone, MD, PhD

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable early-stage disease.

“More than 50% of patients with localized NSCLC will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity,” said Dr. Cascone, Assistant Professor of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “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 immunologic memory. This may translate into a reduced risk for tumor relapse in more patients with early-stage NSCLC.”

NEOSTAR Details

The phase II, single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years; 64% were male. Participants were 84% White, 9% Black, and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomly assigned to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone, and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial, and 2 patients underwent surgery off-trial after additional therapies.

MPR Across Regimens

Among the 37 patients who underwent surgical resection while on the study, the combination arm showed higher MPR rates (50% vs 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% vs 50%). Combination therapy also showed better pathologic complete response rates than monotherapy (38% vs 10%). After a median follow-up of 22 months, median overall survival and lung cancer–related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory Analyses

In an exploratory analysis of resected tissues, investigators found higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3⁺ and CD3⁺ CD8⁺ T lymphocytes, tissue-resident memory T cells, and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells. 

The researchers analyzed the gut microbiome as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that have also been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

“Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer,” said Dr. Cascone. “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.”

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year; a fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.  

“The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting,” concluded Dr. Cascone. “This is a population with potentially curable disease…. [W]e should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients.”

Disclosure: For full disclosures of the study authors, visit nature.com.