In a phase II trial led by researchers from the University of Texas MD Anderson Cancer Center, adding ipilimumab to a neoadjuvant or preoperative combination of nivolumab plus platinum-based chemotherapy resulted in a significant disease response (MPR) in half of all patients treated with Early resectable non-small cell lung cancer (NSCLC).
The new results from the NEOSTAR trial, published today in Nature medicineFurther support for novel adjuvant immunotherapy-based therapy as an approach to reduce viable tumor in surgery and improve outcome in NSCLC. The combination has also been associated with an increase in immune cell infiltration and proper gut microbiome composition.
The current study reports to the two most recent arms of the NEOSTAR trial, evaluating the neoadjuvant chemotherapy nivolumab plus chemotherapy (dual combination) and neoadjuvant ipilimumab plus nivolumab and chemotherapy (triple combination). Both treatment arms met a predefined primary endpoint limitation of six or more patients achieving MPR, defined as 10% or less residual viable tumor (RVT) in a tumor sample resected at surgery, a candidate surrogate endpoint for survival outcome on Improved survival from previous studies.
In the intent-to-treat population, the triple combination resulted in an MPR rate of 50%, while 32.1% of patients achieved an MPR after dual therapy. Both treatment arms also exceeded the historical MPR rates of 15% achieved by neoadjuvant chemotherapy alone.
“The results we’re seeing with the new dual immunotherapy and chemotherapy are very encouraging,” said corresponding author Tina Cascon, MD, PhD, assistant professor of thoracic/head and neck oncology. “This is a treatable group of patients who need more effective treatment strategies to reduce their risk of disease relapse and improve their outcome. The NEOSTAR platform provides us with a quick read-out of potentially effective regimens and allows us to perform translational analyzes and correlative work before and after treatment.”
Of the patients diagnosed with NSCLC, approximately 30% have resectable disease, which means the tumor can be surgically removed. While many of these patients can be treated with surgery, it is estimated that more than half of them will recur without further treatment. Unfortunately, chemotherapy given before or after surgery provides only a small survival benefit. Previous reports from the NEOSTAR trial showed that the new adjuvant nivolumab plus ipilimumab caused higher MPRs compared to historical controls on chemotherapy and nivolumab alone and resulted in greater immunological memory relative to nivolumab monotherapy.
The triple combination reduces viable tumor, and enhances markers of immune activation. Each arm enrolled 22 patients with surgically resectable stage IB to IIIA NSCLC between December 2018 and December 2020. In the dual arm, participants were 86% White, 14% Asian, and 45% Asian. % male; In the three-component arm, the participants were 82% white, 5% Asian, 14% black, and 68% male.
The NEOSTAR trial was not designed for direct comparisons between the two arms, but an exploratory analysis of clinical and pathological outcomes showed that adding a single dose of ipilimumab resulted in an increase in infiltration of beneficial neoplastic immune cells and a reduction in RVT at surgery.
Patients treated with the triple combination had an average of 4.5% RVT at surgery, compared to 50.5% RVT in patients treated with the dual combination. All patients who achieved MPR in the triple group group and 86% of those who achieved MPR in the double group group had <5% RVT at surgery. All patients treated with the dual combination and 91% of those treated with the triple combination underwent surgery. No new safety signals were observed in both treatment arms.
Further analyzes showed that triple combination therapy led to an increase in tumor-infiltrating lymphocytes – including subtypes of CD8+ T cells and B cells and in markers of specialized immune cell populations called tertiary lymphocyte structures, as well as a decrease in infiltrating immunosuppressive cells, all of which It could be signs of an enhanced antitumor response.
When analyzing the gut microbiomes in patients who received MPR, the researchers found a richness in beneficial bacteria previously linked to positive responses to immunotherapy in lung cancer, melanoma and other cancers, along with a lower abundance of potentially pathogenic microbes.
The NEOSTAR platform is an effective strategy for rapidly testing new therapies. Interestingly, the exploratory comparison indicates that some results from the double arm of the NEOSTAR trial are generally similar to those seen in the recent Checkmate-816 trial. This global, randomized, phase III study evaluated the neoadjuvant chemotherapy nivolumab plus chemotherapy compared to chemotherapy alone in patients with resectable NSCLC, and the results of the study led to the first new FDA-approved treatment for NSCLC.
Checkmate-816 and NEOSTAR showed similar overall MPR rates and event-free survival benefits from adding nivolumab neoadjuvant to chemotherapy. The similarity between the two trials suggests that the NEOSTAR platform may offer a viable strategy for rapidly evaluating newer adjuvant therapies.
“The modular platform for the NEOSTAR experiment provides an opportunity to test promising systems and quickly make a ‘go’ or ‘no-go’ decision,” said Cascone. “This experience is an incredible testament to the scientific environment of the team at MD Anderson. Our clinical and multiscale analyzes are made possible by the collaborative efforts of physicians, surgeons, pathologists, scientists, bioinformatics experts and statisticians across many departments that investigate the many features of these patients, their tumors and samples Others. Thanks to their amazing work, we are able to achieve rapid results that can guide the next generation of trials to improve patient outcomes even further.”
The results of these two latter arms of the study support the addition of a neoadjuvant CTLA-4 blockade to nivolumab in addition to chemotherapy prior to resection of NSCLC to improve outcomes and suggest that this combination merits further investigation.