The Phase II NeoCOAST-2 trial has demonstrated promising efficacy for novel pre-surgical treatment combinations in patients with resectable non-small cell lung cancer (NSCLC), with the antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) showing particularly encouraging results. Led by Tina Cascone, M.D., Ph.D., at MD Anderson Cancer Center, the study represents the first global Phase II trial to report clinical data on an ADC in the neoadjuvant setting for this patient population.
Trial Design and Patient Population
The open-label, multiarm, multicenter platform study randomized 202 patients with stage IIA-IIIB resectable NSCLC across three treatment arms. Patients were enrolled from April 2022 to March 2024, with all participants having no sensitizing EGFR mutations or ALK translocations. The modified intention-to-treat population included 198 patients who received at least one dose of study treatment.
Arm 1 received neoadjuvant durvalumab plus oleclumab plus platinum-doublet chemotherapy, followed by surgery and adjuvant durvalumab plus oleclumab. Arm 2 received durvalumab plus monalizumab plus platinum-doublet chemotherapy, followed by surgery and adjuvant durvalumab plus monalizumab. Arm 4 received durvalumab plus Dato-DXd plus single-agent platinum chemotherapy, followed by surgery and adjuvant durvalumab alone.
Approximately half of the study population had stage IIIA disease and approximately two-thirds had a PD-L1 tumor proportion score ≥1%. Patient characteristics were generally well balanced across the three arms.
Pathological Response Results
The primary endpoint of pathological complete response (pCR) rates showed notable differences across treatment arms. In the final analysis, pCR rates were 20.3% (95% CI, 11.8-31.2) in Arm 1, 25.7% (95% CI, 16.0-37.6) in Arm 2, and 35.2% (95% CI, 22.7-49.4) in Arm 4.
Major pathological response (mPR) rates, defined as ≤10% viable tumor cells, were 41.9% (95% CI, 30.5-53.9) in Arm 1, 50.0% (95% CI, 37.8-62.2) in Arm 2, and 63.0% (95% CI, 48.7-75.7) in Arm 4. Patients in Arm 4 had the lowest median percentage of residual viable tumor at 4.5%, compared with 20.0% in Arm 1 and 10.0% in Arm 2.
PD-L1 Expression and Histology Patterns
In Arms 1 and 2, pCR rates were numerically higher in patients with PD-L1 expression ≥1% versus <1%, with the greatest benefit seen in patients with PD-L1 ≥50%. However, in Arm 4, pCR and mPR rates were generally similar across PD-L1 subgroups (<1%, 1-49%, and ≥50%). The largest relative pCR benefit was observed in patients with tumor cell PD-L1 expression <1%, where Arm 4 achieved a 31.3% pCR rate compared with historical rates of 9% and 17% reported in previous studies.
Across all histological subtypes and treatment arms, pCR rates were numerically higher in patients with squamous cell carcinoma than in those with adenocarcinoma.
Surgical Feasibility and Safety
Surgery remained highly feasible across all arms, with 93.2%, 93.0%, and 94.4% of patients in Arms 1, 2, and 4, respectively, undergoing surgery. Most patients who completed surgery had R0 resections. The median time from last neoadjuvant dose to surgery was 34, 34, and 36 days in Arms 1, 2, and 4, respectively.
Surgical complications occurred in 36.2%, 30.3%, and 29.4% of patients in Arms 1, 2, and 4, respectively, with grade ≥3 surgical complications in 13.0%, 9.1%, and 3.9% of patients in the respective arms.
Safety Profile
The overall safety profile was comparable to currently approved regimens. Grade ≥3 adverse events occurred in 51.4% of patients in Arm 1, 63.4% in Arm 2, and 40.7% in Arm 4. The most common adverse events in the neoadjuvant period were nausea, anemia, and asthenia across all arms, reflecting the safety profile of the cytotoxic agents used.
Adverse events leading to discontinuation of any investigational product occurred in 16.2% of patients in Arm 1, 22.5% in Arm 2, and 11.1% in Arm 4. Treatment-related deaths occurred in one patient in each arm, with causes including intestinal ischemia and septic shock, colonic obstruction, and interstitial lung disease.
For Dato-DXd specifically, the most common adverse events of special interest in the neoadjuvant period were oral mucositis or stomatitis (40.7%), ocular surface events (20.4%), and mucosal inflammation (14.8%), with most events being low-grade.
Clinical Significance
The study builds on findings from recent phase III trials including AEGEAN, CheckMate 816, KEYNOTE-671, and CheckMate 77T, which suggest a strong positive association between pathological response and long-term benefit. While Arms 1 and 2 exhibited similar overall pCR rates compared with current standard-of-care regimens, Arm 4 yielded a numerically higher overall pCR rate compared with both the other study arms and historical standard-of-care rates ranging from 17% to 25%.
The researchers noted that preclinical evidence for Dato-DXd and other TOP1 inhibitor ADCs suggests they could potentiate the effect of immune checkpoint inhibitors by inducing immunogenic cell death, providing a potential mechanism for the improved pathological response rates observed across PD-L1 subgroups in Arm 4.
Future Directions
Additional follow-up is needed to assess long-term benefits and determine whether the numerically higher pathological response rates will translate to improvements in event-free survival and overall survival. Further evaluations of new bispecific monoclonal antibodies targeting both PD-1 and CTLA-4, and both PD-1 and TIGIT in combination with chemotherapy, with or without Dato-DXd, are currently ongoing in the NeoCOAST-2 platform.
