In the phase II NEOSTAR trial, adding ipilimumab to a neoadjuvant combination of nivolumab plus platinum-based chemotherapy resulted in a major pathologic response in half of all treated patients with early-stage, resectable non–small cell lung cancer (NSCLC). New findings from the NEOSTAR study, published by Tina Cascone, MD, PhD, and colleagues in Nature Medicine, provide further support for neoadjuvant immunotherapy-based treatment as an approach to reduce viable tumor at surgery and to improve outcomes in NSCLC. The combination also was associated with an increase in immune cell infiltration and a favorable gut microbiome composition.
The current study reports on the latest two arms of the NEOSTAR trial, evaluating neoadjuvant nivolumab plus chemotherapy (double combination) and neoadjuvant ipilimumab plus nivolumab and chemotherapy (triple combination). Both treatment arms met their prespecified primary endpoint boundaries of six or more patients achieving major pathologic response (defined as 10% or less residual viable tumor in the resected tumor specimen at surgery), a candidate surrogate endpoint of improved survival outcomes from prior studies.
In the intention-to-treat population, the triple combination resulted in a major pathologic response rate of 50%, whereas 32.1% of patients achieved major pathologic response after double combination treatment. Both treatment arms also exceeded the historical major pathologic response rates of 15% achieved by neoadjuvant chemotherapy alone.
Tina Cascone, MD, PhD
“The results we see with neoadjuvant dual immunotherapy and chemotherapy are very encouraging,” said corresponding author Dr. Cascone, Assistant Professor of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “This is a population of patients that can potentially be cured, but they need more effective treatment strategies to reduce their risk of disease relapse and improve their outcomes. The NEOSTAR platform provides us with a quick readout of potentially effective regimens and allows us to perform translational analyses and correlative research work before and after treatment.”
Among patients diagnosed with NSCLC, roughly 30% have potentially resectable disease. While many of these patients can potentially be cured with surgery, it is estimated that more than half will have a cancer recurrence without additional therapy. Unfortunately, chemotherapy given either before or after surgery provides only a minimal survival benefit. Previous reports from the NEOSTAR trial demonstrated that neoadjuvant nivolumab plus ipilimumab induced higher major pathologic response rates relative to historical controls of chemotherapy and nivolumab alone and resulted in greater immunologic memory relative to nivolumab monotherapy.
Triple Combination Reduces Viable Tumor, Enhances Markers of Immune Activation
Each study arm enrolled 22 patients with surgically resectable stage IB to IIIA NSCLC between December 2018 and December 2020. In the double combination arm, participants were 86% White, 14% Asian, and 45% male; in the triple combination arm, participants were 82% White, 5% Asian, 14% Black, and 68% male.
The NEOSTAR trial was not designed for direct comparisons between arms, but an exploratory analysis of clinical and pathologic findings showed that adding a single dose of ipilimumab resulted in an increase in beneficial tumor immune cell infiltration and reduced residual viable tumor at surgery.
Patients treated with the triple combination had a median of 4.5% residual viable tumor at surgery, compared to 50.5% residual viable tumor in patients treated with the double combination. All patients achieving major pathologic response in the triple combination cohort and 86% of those achieving major pathologic response in the double combination cohort had less than 5% residual viable tumor at surgery. All patients treated with the double combination and 91% of those treated with the triple combination underwent surgery. No new safety signals were observed in both treatment arms.
Further analyses showed treatment with the triple combination resulted in an increase in tumor-infiltrating lymphocytes—including subtypes of CD8-positive T cells and B cells—and in markers of specialized immune cell clusters called tertiary lymphoid structures. The triple combination also reduced infiltration of immunosuppressive cells, all of which can be signs of enhanced antitumor response.
Upon analyzing the gut microbiome in patients who achieved major pathologic response, the researchers found an enrichment in beneficial bacteria previously associated with favorable responses to immunotherapy in lung cancer, melanoma, and other cancer types, along with reduced abundance of potentially pathogenic microbes.
NEOSTAR Platform to Rapidly Test Neoadjuvant Therapies
Interestingly, an exploratory comparison indicates some results from the double combination arm of the NEOSTAR trial are similar overall to those seen in the recent CheckMate-816 trial. This global randomized phase III study evaluated neoadjuvant nivolumab plus chemotherapy compared to chemotherapy alone in patients with resectable NSCLC, and results from the study led to the first U.S. Food and Drug–Administration approved neoadjuvant therapy for NSCLC.
Both CheckMate 816 and NEOSTAR showed similar overall major pathologic response rates and event-free survival benefits from adding neoadjuvant nivolumab to chemotherapy. The similarity between the two trials suggests that the NEOSTAR platform may offer a viable strategy to rapidly evaluate neoadjuvant therapies.
“The modular platform of the NEOSTAR trial provides an opportunity to test promising regimens and quickly make a ‘go’ or ‘no-go’ decision,” Dr. Cascone said.
The results of these latest two arms of the study support the addition of neoadjuvant CTLA-4 blockade to nivolumab plus chemotherapy prior to NSCLC resection for improving outcomes and suggest that this combination merits further investigation.
Disclosure: The NEOSTAR trial was supported by the Bristol Myers Squibb Company. Additional research support was provided by Lung Cancer Moon Shot®, part of MD Anderson’s Moon Shots Program®, the National Institute of Health/National Cancer Institute, the American Society of Clinical Oncology’s Conquer Cancer Foundation Career Development Award, the Andrew Sabin Family Foundation, the Connie Rasor Endowment for Cancer Research, David Bruton, Jr. Chair, the Translation Molecular Profiling Immuno-profiling Laboratory, the MD Anderson Physician Scientist Program, the Khalifa Bin Zayed Al Nahyan Foundation, Rexanna’s Foundation for Fighting Lung Cancer, and the Bob Mayberry Foundation. For full disclosures of the study authors, visit nature.com.
