Although the treatment landscape for patients with advanced non-small-cell lung cancer (NSCLC) has evolved dramatically over the last decade, translation of these therapeutic advances to earlier-stage NSCLC has lagged. However, results of the Phase II NeoCOAST trial show that combination immunotherapy with anti-PD-L1 durvalumab and one of several other immunotherapies appears superior in terms of achieving pathological response compared to durvalumab alone for treating pre-surgical, early-stage non-small-cell lung cancer (NSCLC). The trial’s findings were published in Cancer Discovery.
NeoCOAST is the first Phase II, open-label, randomized, multicenter, multidrug platform, window-of-opportunity study of neoadjuvant therapy for patients with previously untreated, early-stage, resectable NSCLC. The results add to the growing body of evidence that combination immunotherapy provides encouraging results in the neoadjuvant setting for patients with this cancer type.
The trial evaluated neoadjuvant durvalumab 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 (already approved for advanced NSCLC). While the study was not statistically powered to compare arms, all combinations resulted in numerically higher major pathological response (MPR) rates than with durvalumab alone.
“There’s a whole host of novel immunotherapy agents being developed in lung cancer and other tumor types for advanced disease, but the evaluation of those drugs for treatment of earlier-stage disease has been very slow,” notes Patrick Forde, senior study author at the Johns Hopkins Kimmel Cancer Center. The trial demonstrated that patients who received the novel combinations of durvalumab with monalizumab and durvalumab with oleclumab had higher levels of response, where the tumor had regressed by the time of surgery. “We are hopeful that these types of trials will allow us to expedite development of new treatments for earlier-stage lung cancer,” he adds.
The NeoCOAST study enrolled 84 patients at 17 study centers across seven countries with untreated stage I-IIIA NSCLC. Nearly all patients received a single infusion of neoadjuvant durvalumab alone or combined with oleclumab, monalizumab, and danvatirsen prior to surgery.
The primary endpoint was investigator-assessed major pathological response (MPR), defined as ≤10% residual viable tumor cells in the resected tumor tissue and sampled nodes at surgery. The investigators also assessed pathological complete response (pCR), or complete disappearance of viable tumor cells, as a secondary endpoint.
All combinations had statistically higher rates of MPR and pCR than monotherapy, and there were no statistically significant differences in responses between the combination arm. Major pathological response rates were seen in 11.1% of patients receiving durvalumab alone (3 of 27 patients); in 19% of patients receiving durvalumab plus oleclumab (4 of 21 patients); and in 30% of patients receiving durvalumab plus monalizumab (6 of 20 patients). Pathological complete responses were observed in 3.7% of durvalumab-only treated patients, which is comparable to results from other monotherapy studies, 9.5% in those receiving durvalumab/oleclumab, and 10% in durvalumab/monalizumab-treated patients.
Since the trial results were first presented at the AACR meeting in 2022, additional studies on tumor tissues and blood samples revealed new insights into the impact of neoadjuvant treatment on the immune system. Not only did patients with resectable NSCLC achieve improved MPR rates after durvalumab plus oleclumab or monalizumab, but transcriptome analysis on pre- and post-treatment samples showed indicators of an augmented immune response including upregulation of genes associated with cytotoxicity, and tertiary lymphoid structures and lymphocyte recruitment.
Based on these results and the recent approval of neoadjuvant nivolumab plus chemotherapy, the same research team launched NeoCOAST-2, a follow-up, larger randomized trial. The trial is now enrolling patients with resectable, stage IIA-IIIA NSCLC to receive neoadjuvant durvalumab combined with chemotherapy and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab.
