Combination of durvalumab with novel agents increases pathological responses in patients with resectable NSCLC

Results of the phase II NeoCOAST-2 study demonstrate that datopotamab deruxtecan (Dato-DXd) in combination with durvalumab and single-agent platinum chemotherapy as neoadjuvant therapy results in encouraging pathological response rates for patients with resectable non-small cell lung cancer (NSCLC).

Building further on data from the NeoCOAST and AEGEAN studies, the open-label, multicentre, phase II NeoCOAST-2 multi-arm platform study evaluates durvalumab plus chemotherapy plus novel agents as neoadjuvant therapy, followed by durvalumab with or without novel agents as adjuvant therapy in patients with resectable NSCLC. At WCLC 2024, preliminary safety and efficacy data were presented.

Study design

NeoCOAST-2 enrolled patients with untreated, histologically confirmed, resectable stage IIA-IIIB NSCLC, who are EGFR and ALK wild-type and have an ECOG performance status of 0 or 1. Patients were stratified by PD-L1 expression (<1% vs. ≥1%) and randomised to Arm 1: neoadjuvant durvalumab (D) + platinum-doublet chemotherapy (CT) + oleclumab (anti-CD73 monoclonal antibody), Arm 2: D + platinum-doublet CT + monalizumab (anti-NKG2AmAb), or Arm 4: D + single-agent platinum CT + datopotamab deruxtecan (Dato-DXd, TROP2 directed antibody-drug conjugate [ADC]). Neoadjuvant therapy was given Q3W for four cycles prior to surgery, followed by adjuvant treatment with D plus the respective novel agents until disease progression per RECIST v1.1 or for up to one year. Primary endpoints of the study were pathological complete response (pCR) rate, safety and tolerability.

Results

In total, 202 patients were included and randomised to Arm 1 (n=76), Arm 2 (n=72) or Arm 4 (n=54). Baseline characteristics were well-balanced between study arms. Among those, respectively 92.2%, 92.1% and 95.8% of patients in Arms 1, 2 and 4 underwent surgery. The pCR rates were 20%, 26.7%, and 34.1% for Arms 1, 2, and 4, respectively, with corresponding major pathological response (mPR) rates of 45%, 53.3%, and 65.9%. As such, treatment with Dato-DXd resulted in the highest pCR rate. Treatment-related adverse events (TRAEs) occurred in 94.6% of patients in Arm 1, 90.1% in Arm 2, and 96.3% in Arm 4, with grade ≥3 TRAEs reported at 31.1%, 29.6%, and 18.5%, respectively. Treatment discontinuation due to TRAEs were reported in 7.4% of patients in Arm 4. Of note, there was no increase in adverse events of special interest for Dato-DXd when combined with immunotherapy, compared with historical data. In total, 77.8% of patients in Arm 4 achieved R0 after surgery.

Conclusion

In perioperative NSCLC, novel combinations demonstrated promising pathological responses compared to historical benchmarks. The NeoCOAST-2 study is the first global phase II platform trial that provides evidence that the combination of durvalumab with novel agents, particularly Dato-DXd, yields high rates of pCR. However, treatments in all arms led to improvements in mPR rates, along with a manageable safety profile and surgical rates comparable to currently approved neoadjuvant and perioperative immunotherapy-based regimens.

Reference

Cascone T, et al. Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents + CT and Adjuvant D + Novel Agents in Resectable NSCLC. Presented at WCLC 2024; Abstract 3310.