In the NEOSTAR phase II platform study that evaluated neoadjuvant nivolumab plus chemotherapy and ipilimumab plus nivolumab plus chemotherapy primary endpoint is met in both treatment arms, which exceeded the historical conservative major pathologic response (MPR) rate of approximately 15% produced by neoadjuvant chemotherapy in patients with operable non-small cell lung cancer (NSCLC). Neoadjuvant nivolumab plus chemotherapy produced an MPR rate of 32.1%, whereas ipilimumab plus nivolumab plus chemotherapy resulted in an MPR rate of 50%.
The addition of ipilimumab to nivolumab plus chemotherapy maintained an overall acceptable toxicity and allowed curative intent surgery without adverse postoperative outcomes. Although the study was not directly designed to compare both arms, clinical and pathological findings of potential enhanced activity of ipilimumab plus nivolumab plus chemotherapy are supported by translational analyses demonstrating compositional changes consistent with marked tumour immune infiltration with an antitumour activity phenotype in tumours from the ipilimumab plus nivolumab plus chemotherapy cohort compared with those treated with nivolumab plus chemotherapy. The findings are published by Dr. Tina Cascone of the Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 16 March 2023 in the Nature Medicine.
The authors wrote in the background that immune checkpoint inhibitors have changed the treatment paradigm for patients with NSCLC, but until recently, much of the progress had been confined to the locally advanced and metastatic disease. Considerable effort is focused on how to best leverage adjuvant or neoadjuvant immune checkpoint inhibitors for patients with resectable early-stage NSCLC and to prevent postoperative tumour recurrence. Neoadjuvant studies are based on the premise that an intact tumour immune microenvironment elicits the most robust responses to immune checkpoint inhibitors. These studies have benefited by using MPR or complete pathologic response (pCR) as surrogate endpoints of long-term outcomes.
Studies with neoadjuvant single anti-PD-(L)1 agent have yielded MPR rates between 6.7% and 45%. Adding platinum-based chemotherapy to immune checkpoint inhibitor has proved promising, with initial phase II studies producing MPR and pCR rates of 57–83% and 33–63%, respectively. The CheckMate-816 was the first large-scale phase III randomised study that evaluated neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with resectable stage IB–IIIA NSCLC and demonstrated a pCR rate of 24.0% with nivolumab plus chemotherapy compared to 2.2% with chemotherapy alone, as well as improved event-free survival (EFS).
Another strategy to enhance the efficacy of neoadjuvant anti-PD-(L)1 treatment is to combine it with the anti-CTLA-4 ipilimumab, given that the two inhibitors impact the immune system through two independent, and possibly complementary, mechanisms of action. In the phase II randomised NEOSTAR study, the study team evaluated neoadjuvant nivolumab or nivolumab plus ipilimumab followed by surgery in 44 patients with operable NSCLC. The study investigators found that nivolumab and nivolumab plus ipilimumab produced MPR rates of 22% and 38%. Addition of ipilimumab to nivolumab also resulted in higher pCR rates, less viable tumour and enhanced tumour immune infiltration.
The randomised phase II NEOSTAR study evolved into a platform study of sequential, single-centre, single-arm, phase II studies with a modular design using MPR in each individual arm as the primary endpoint, which was hypothesised to be greater than historical controls of neoadjuvant chemotherapy. In the article published in the Nature Medicine, the authors report the primary efficacy results of NEOSTAR arm C evaluating neoadjuvant nivolumab plus chemotherapy and arm D testing neoadjuvant ipilimumab plus nivolumab plus chemotherapy followed by surgical resection in patients with stage IB–IIIA NSCLC. Select secondary endpoints included radiological responses according RECIST v1.1, pCR, toxicity, surgical resectability and perioperative morbidity/mortality, overall survival and EFS, in alignment with time-to-event analyses performed in other neoadjuvant studies, and tissue immune infiltrate analysis. Exploratory endpoints included tumour molecular, immunological and foecal microbiome biomarkers.
The primary endpoint was met in both arms with MPR rates of 32.1% (80% confidence interval [CI] 18.7–43.1%) in the nivolumab plus chemotherapy arm and 50% (80% CI 34.6–61.1%) in the ipilimumab plus nivolumab plus chemotherapy arm. In patients without known EGFR/ALK alterations, MPR rates were 41.2% and 62.5% in the nivolumab plus chemotherapy and ipilimumab plus nivolumab plus chemotherapy arms. No new safety signals were observed in either arm.
Single-cell sequencing and multi-platform immune profiling underscored immune cell populations and phenotypes, including effector memory CD8-positive T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the ipilimumab plus nivolumab plus chemotherapy cohort. Baseline foecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes.
The authors concluded that neoadjuvant ipilimumab plus nivolumab plus chemotherapy enhances pathologic responses and warrants further study in operable NSCLC. The NEOSTAR platform study design with surrogate endpoints and integrated multi-omic correlates enables the rapid assessment of promising therapeutic strategies and the identification of candidate targets to open new areas of translational investigation in the perioperative setting.
In an accompanied editorial article, Drs. Michael Conroy and Patrick M. Forde of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University in Baltimore, MD, US wrote that the NEOSTAR study is a key step on route to better outcomes, but the best approach is likely to be an individualised one, reflecting the many factors that influence treatment response.
- Cascone T, Leung CH, Weissferdt A, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nature Medicine; Published online 16 March 2023. DOI: https://doi.org/10.1038/s41591-022-02189-0
- Conroy M, Forde PM. Advancing neoadjuvant immunotherapy for lung cancer. Nature Medicine; Published online 16 March 2023. DOI: https://doi.org/10.1038/s41591-023-02246-2