Combination immunotherapy with the anti–PD-L1 monoclonal antibody durvalumab and other novel agents outperforms durvalumab alone in the neoadjuvant setting for early-stage non–small cell lung cancer (NSCLC), according to research presented by Cascone et al at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT011).
The multicenter, randomized phase II NeoCOAST clinical trial evaluated neoadjuvant durvalumab alone and in combination with each of the following novel immunotherapies: the anti-CD73 monoclonal antibody oleclumab, the anti-NKG2A monoclonal antibody monalizumab, and the anti-STAT3 antisense oligonucleotide danvatirsen. While the study was not statistically powered to compare arms, all combinations resulted in numerically higher major pathologic response rates than with durvalumab monotherapy.
“This study builds on the growing evidence that combination immunotherapy has a role in the neoadjuvant setting for this patient population,” said Tina Cascone, MD, PhD, Assistant Professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center and lead author of the study. “Ultimately, we want to give patients a chance to live longer without their cancer returning.”
The NeoCOAST trial adds to recent progress in neoadjuvant treatment for NSCLC, including the phase II NEOSTAR study results that Dr. Cascone reported last year, showing nivolumab and ipilimumab together induced higher response rates than nivolumab alone, and the March 2022 approval of nivolumab combined with platinum-based chemotherapy based on the CheckMate 816 study. The durvalumab combinations tested previously in the phase II COAST trial were shown to be effective in unresectable stage III NSCLC, which provided the rationale for testing in earlier-stage disease.
The NeoCOAST study enrolled 84 patients with untreated, resectable (> 2 cm), stage I to IIIA NSCLC, between March 2019 and September 2020. Most patients were male (59.5%) and had a smoking history (89%). The median age was 67.5, and the racial breakdown was 89% White, 6% Black, 2% Asian, and 2% other. A total of 83 patients received one 28-day cycle of neoadjuvant durvalumab alone or combined with another therapy.
The primary endpoint 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.
All combinations had numerically higher rates of major pathologic response and pathologic complete response than monotherapy, and there were no statistically significant differences in responses between the combination arms:
The safety profile in the durvalumab monotherapy arm (treatment-related adverse events in 34.6% of patients) was similar to previously published data for anti–PD-1/anti–PD-L1 antibodies. No new safety signals were identified with any of the combination regimens (treatment-related adverse events seen in 43.8%–57.1% of patients).
Major pathologic response was associated with baseline tumor PD-L1 expression ≥ 1% in the oleclumab and monalizumab combination arms. In the oleclumab (anti-CD73) combination arm, high baseline CD73 expression was associated with pathologic tumor regression, and treatment decreased CD73 expression on tumor cells, as previously observed in other studies. The oleclumab combination also was associated with greater natural killer (NK) and CD8 T-cell density in the tumor center on treatment compared with baseline, suggesting an increased infiltration of effector cells in the tumor microenvironment.
Transcriptome analysis on baseline and posttreatment blood samples revealed distinct immune cell signatures in two combination arms. Patients in the oleclumab combination arm who had a major pathologic response also had upregulation of genes involved in B-cell activation and T-cell/B-cell costimulatory pathways, compared to patients without a major pathologic response. In the monalizumab (anti-NKG2A) combination arm, expression of the chemokines CXCL9 and CXCL11, which are associated with NK-cell and T-cell recruitment, was upregulated in the peripheral blood on treatment.
Implications and Next Steps
“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 said. “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 non–small cell lung cancer.”
Limitations of the study include the exploratory nature of the endpoints, small sample sizes, and investigator-assessed outcomes without central review.
Based on these results and the recent approval of neoadjuvant nivolumab plus chemotherapy, the team has launched a follow-up randomized clinical trial, NeoCOAST-2, with Dr. Cascone serving as the global principal investigator. The trial is now enrolling patients with resectable, stage IIA to IIIA NSCLC to receive neoadjuvant durvalumab combined with chemotherapy and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab.
Disclosure: The study was funded by AstraZeneca. Dr. Cascone reported a consulting/advisory role and contracted institutional support/research consulting for MedImmune/AstraZeneca. For full disclosures of all study authors, visit abstractsonline.com.
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