The anti–PD-L1 monoclonal antibody durvalumab in combination with other immuno-oncology agents may outperform treatment with durvalumab alone in the neoadjuvant setting for patients with early-stage non–small cell lung cancer (NSCLC), according to a recent study published by Cascone et al in Cancer Discovery.
Background
The NeoCOAST trial adds to recent progress in neoadjuvant treatment for NSCLC—including recent findings demonstrating that nivolumab and ipilimumab combination therapy induced higher responses than nivolumab alone, and the March 2022 approval of nivolumab combined with platinum-based chemotherapy. The durvalumab combinations tested previously in the phase II COAST trial were shown to be effective in unresectable stage III NSCLC, providing rationale for testing in earlier-stage disease.
“This study builds on the growing evidence that combination immunotherapy has a role in the neoadjuvant setting for this patient population,” highlighted lead study author Tina Cascone, MD, PhD, Assistant Professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “Ultimately, we want to give patients a chance to live longer without their cancer returning,” she added.
Study Methods and Results
In the new multicenter, randomized phase II NeoCOAST trial (ClinicalTrials.gov identifier NCT03794544), the researchers enrolled 84 patients with a median age of 67.5 years who had untreated, resectable, stage I to IIIA NSCLC and randomly assigned 83 of them to receive neoadjuvant durvalumab in combination with the anti-CD73 monoclonal antibody oleclumab (n = 21), the anti-NKG2A monoclonal antibody monalizumab (n = 20), or the anti-STAT3 antisense oligonucleotide danvatirsen (n = 16) or alone (n = 26).
They reported that 59.5% of the patients were male and 89% of them had a smoking history. Further, 89% of the patients were White, 6% of them were Black, 2% of them were Asian, and 2% of them were another race.
The primary endpoint of the trial was investigator-assessed major pathologic response, defined as ≤ 10% residual viable tumor cells in the resected tumor tissue and sampled nodes at surgery. The investigators assessed pathologic complete response as a secondary endpoint. Exploratory endpoints included tumor, fecal, and blood biomarkers.
The researchers found that although the study was not statistically powered to compare arms, all of the durvalumab combinations resulted in numerically higher major pathologic response and pathologic complete response rates compared with durvalumab monotherapy. Among the findings were:
- Major pathologic response and pathologic complete response occurred in 11.1% and 3.7%, respectively, of the patients who received durvalumab monotherapy, comparable to results of other monotherapy studies.
- The major pathologic response rates for the combination therapy ranged from 19% in the oleclumab combination arm to 31.3% in the danvatirsen arm, whereas the pathologic complete response rates ranged from 9.5% in the oleclumab arm to 12.5% in the danvatirsen arm. For combination therapy with monalizumab, the major pathologic response rate was 30% and the pathologic complete response rate was 10%.
The safety profile in the durvalumab monotherapy arm—with treatment-related adverse events occurring in 34.6% of patients—was similar to previously published data for anti–PD-1 and PD-L1 antibodies. The researchers identified no new safety signals with any of the combination regimens, reporting treatment-related adverse events in 43.8% to 57.1% of the patients.
Major pathologic response was associated with baseline tumor PD-L1 expression of ≥ 1% in the oleclumab and monalizumab combination arms. High baseline CD73 expression was associated with pathologic tumor regression in the patients assigned to the oleclumab combination arm, and treatment decreased CD73 expression on tumor cells as observed in previous studies. Further, the oleclumab combination was associated with greater natural killer and CD8 T-cell density in the tumor center after treatment compared with baseline, suggesting an increased infiltration of effector cells in the tumor microenvironment.
Updated translational studies on tumor tissues and blood samples revealed the impact of neoadjuvant treatment on the immune system. Transcriptome analysis on pre- and posttreatment samples showed an upregulation of genes associated with cytotoxicity, tertiary lymphoid structures, and lymphocyte recruitment—all indicators of an activated immune response.
The number of patients with no detected circulating tumor DNA (ctDNA) increased progressively from pre-to posttreatment and postsurgery follow-up, highlighting the relationship between decreasing ctDNA levels and improved patient outcomes. Notably, surgery was the most effective intervention to result in clearance of ctDNA. The researchers also found an enrichment of beneficial bacteria in the gut microbiome of patients who achieved major pathologic response. These bacteria were previously associated with a favorable immunotherapy response across several cancer types.
Conclusions
“Our study is a testament to how clinical trials designed with translational findings in mind can support the rapid advancement of novel immune-based combinations to larger scale studies,” Dr. Cascone underscored. “I’m encouraged by these early findings as we work toward reducing the risk of recurrence and increasing cure rates for patients with early-stage [NSCLC],” she emphasized.
Based on the results of the new trial and the recent approval of neoadjuvant nivolumab plus chemotherapy for patients with NSCLC, the researchers have launched the follow-up NeoCOAST-2 trial (NCT05061550). The researchers are currently seeking the enrollment of patients with resectable, stage IIA to stage IIIA NSCLC, who will receive neoadjuvant durvalumab combined with chemotherapy and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab.
Disclosure: The research in this study was funded by AstraZeneca. For full disclosures of the study authors, visit aacrjournals.org.
