Discussion
NSCLC, tumor, NEOSTAR, toxicity, cancer, Tumors, Nivo+CT, tumors
TUMOR, INFILTRATION, CANCER, METASTATIC DISEASE, TUMORS, NSCLC, TUMORS
Until now, the pathologic and immunologic consequences of adding the CTLA-4 checkpoint inhibitor Ipi to neoadjuvant combined Nivo+CT for patients with resectable NSCLC have not been investigated. The NEOSTAR phase 2 platform trial evaluating neoadjuvant Nivo+CT and Ipi+Nivo+CT met its primary endpoint in both treatment arms, which exceeded the historical conservative MPR rate of approximately 15% produced by neoadjuvant CT. Neoadjuvant Nivo+CT produced an MPR rate of 32.1%, whereas Ipi+Nivo+CT resulted in an MPR rate of 50%. The addition of Ipi to Nivo+CT maintained an overall acceptable toxicity and allowed curative-intent surgery without adverse postoperative outcomes. Although the trial was not directly designed to compare both arms, our clinical and pathological findings of potential enhanced activity of Ipi+Nivo+CT are supported by our translational analyses demonstrating compositional changes consistent with marked tumor immune infiltration with an anti-tumor activity phenotype in tumors from the Ipi+Nivo+CT cohort compared with those treated with Nivo+CT.MPR was selected as the primary outcome measure in our study owing to the low pCR rates achieved by CT alone in historical neoadjuvant trials and as demonstrated in the control CT arm of the CheckMate-816 studyOur scRNA-seq analysis demonstrated marked differences in the immune landscape between tumors and uninvolved normal tissues in both treatment arms. Tumors were characterized by increased fractions of CD4The tumor PD-L1 expression analysis was limited by the number of pre-therapy samples available for evaluation and the unexpected, particularly high incidence of tumors lacking PD-L1 expression on malignant cells in this dataset. This limited our ability to make firm conclusions regarding the association between this marker and therapeutic responses. Nevertheless, this cohort provided a unique opportunity to investigate the impact of treatment on responses in tumors lacking PD-L1 expression on cancer cells. Our findings suggest that Ipi may be particularly relevant to the treatment of PD-L1-negative tumors in which MPR was seen in 22.2% of patients treated with Nivo+CT and 40% of patients treated with Ipi+Nivo+CT. In patients with metastatic disease, the CheckMate-227 study (evaluating first-line Ipi+Nivo)The gut microbiome remains a strong tumor-extrinsic factor associated with anti-tumor response across various cancer histologies and treatment modalities. In this study, we observed different fecal microbiome structures and compositions between patients with MPR and those without MPR by treatment arm, suggesting a distinct association among treatment, response and gut microbiome composition. Notably, patients achieving MPR in both arms had fecal microbiomes enriched in In conclusion, our findings further support the role of neoadjuvant chemoimmunotherapy before NSCLC resection and expand on the standard-of-care neoadjuvant Nivo+CT by incorporating CTLA-4 blockade to this treatment regimen. The dual immune checkpoint therapy plus CT produces numerically higher MPR rates, is overall safe and tolerated, enhances anti-tumor immune activity and mitigates an immunosuppressive phenotype in exploratory analyses. The NEOSTAR platform trial 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. The addition of CTLA-4 blockade to PD-(L)1 inhibition plus CT deserves further investigation for patients with resectable NSCLC.