The 2024 World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC), is currently in full swing in San Diego, USA.  Oncology Frontier invited domestic lung cancer experts to analyze key research data from the conference. This article presents Dr. Shengxiang Ren's review of the NeoCOAST-2 study results (Abstract PL02.07) from Shanghai Pulmonary Hospital.

The Phase II NeoCOAST-2 open-label platform trial (NCT05061550) evaluated several combination therapies involving durvalumab for resectable early-stage non-small cell lung cancer (NSCLC) patients in the perioperative setting. At WCLC 2024, data were released on three new combinations used for perioperative treatment. NeoCOAST-2 enrolled EGFR/ALK wild-type, ECOG PS 0 or 1, and stage IIA-IIIB resectable NSCLC patients. The primary endpoints were pathological complete response (pCR) rate and safety/tolerability, with key secondary endpoints including major pathological response (mPR) rate, event-free survival (EFS), and surgical feasibility. The primary goal of NeoCOAST-2 was to assess efficacy signals via pCR rate, with no direct statistical comparisons between groups. Patients were randomized to receive one of four neoadjuvant regimens (every three weeks for four cycles): (1) anti-CD73 oleclumab + durvalumab + platinum-doublet chemotherapy (Group 1), (2) anti-NKG2A monalizumab + durvalumab + platinum-doublet chemotherapy (Group 2), (3) volrustomig + chemotherapy (Group 3), or (4) TROP2 antibody-drug conjugate (ADC) Dato-DXd + durvalumab + monotherapy platinum chemotherapy (Group 4). All patients subsequently underwent surgery and received adjuvant therapy (excluding chemotherapy) for up to one year. Data for Group 3 were not reported at WCLC 2024. Baseline characteristics of patients in Group 1 (n=76), Group 2 (n=72), and Group 4 (n=54) were balanced, with most patients being Caucasian (63.2% vs. 59.7% vs. 68.5%), ECOG PS 0 (61.6% vs. 69.0% vs. 66.7%), with adenocarcinoma histology (65.8% vs. 63.9% vs. 61.1%), and PD-L1 TPS ≥1% (68.4% vs. 66.7% vs. 75.9%). Completion rates of neoadjuvant treatment were 74.3%, 76.1%, and 72.1%, respectively, with surgery performed in 92.2%, 92.1%, and 95.8% of patients, and adjuvant therapy received by most (83.6%, 74.1%, and 83.3%).

Among the intention-to-treat population, pCR rates were 20.0% for Group 1 (n=60), 26.7% for Group 2 (n=60), and 34.1% for Group 4 (n=44), while mPR rates were 45.0%, 53.3%, and 65.9%, respectively. “Group 4 achieved the highest pCR and mPR rates. All treatment groups demonstrated manageable safety profiles and high surgical rates, comparable to currently approved regimens,” stated Tina Cascone of MD Anderson Cancer Center in her report.

In each group, patients with PD-L1 tumor proportion score (TPS) ≥50% had higher pCR rates than those with TPS 1%-49% and TPS <1%. Caution is needed when interpreting these results due to the small sample sizes in each subgroup. Specifically, pCR rates in Group 1 were 17.6%, 5.6%, and 32.0% for PD-L1 TPS <1% (n=17), 1%-49% (n=18), and ≥50% (n=25), respectively; in Group 2, pCR rates were 15.0%, 30.0%, and 35.0% for TPS <1% (n=20), 1%-49% (n=20), and ≥50% (n=20), respectively; in Group 4, pCR rates were 25.0%, 33.3%, and 41.2% for TPS <1% (n=12), 1%-49% (n=15), and ≥50% (n=17), respectively.

Adverse Events (AEs)

In Group 1, the incidence of grade 3 or higher treatment-related adverse events (TRAEs) during neoadjuvant therapy (n=74), postoperative therapy (n=59), and adjuvant therapy (n=46) was 31.1%, 0.0%, and 4.3%, respectively. The rates of AEs leading to treatment discontinuation were 8.1%, 1.7%, and 6.5%. Grade ≥3 treatment-emergent adverse events (TEAEs) during neoadjuvant therapy included anemia, fatigue, neutropenia, arthralgia, and decreased appetite. Additionally, three patients died due to severe AEs—two during postoperative recovery from lobectomy-related respiratory failure, and one due to chemotherapy-related intestinal ischemia during neoadjuvant therapy.

In Group 2, 29.6% of patients (n=71) during neoadjuvant therapy, 1.7% during postoperative therapy (n=58), and 12.5% during adjuvant therapy (n=40) experienced grade ≥3 TRAEs. TEAEs during neoadjuvant therapy included anemia, neutropenia, alopecia, diarrhea, and thrombocytopenia. AEs led to treatment discontinuation in 12.7%, 0.0%, and 7.5% of patients. Four patients died from serious AEs—three during postoperative recovery (sepsis following pneumonectomy, septic shock following lobectomy, and renal failure following bilobectomy), and one during adjuvant therapy from cardiopulmonary arrest related to durvalumab and monalizumab.

In Group 4, grade ≥3 TRAEs occurred only during neoadjuvant therapy (n=54) in 18.5% of patients. AEs led to discontinuation of treatment during the neoadjuvant phase in 7.4% of patients. Grade ≥3 TEAEs during neoadjuvant therapy included anemia, fatigue, neutropenia, alopecia, thrombocytopenia, nausea, vomiting, mucositis, and fatigue. One patient died postoperatively due to idiopathic pulmonary fibrosis, which was deemed unrelated to the treatment, pending independent adjudication (the patient had a history of idiopathic pulmonary fibrosis, which was an exclusion criterion for the study).

Dr. Shengxiang Ren：The NeoCOAST-2 study results presented at WCLC 2024 suggest that durvalumab combined with novel agents (particularly Dato-DXd) in the perioperative setting can increase pCR rates in resectable NSCLC. NeoCOAST-2 builds upon findings from the AEGEAN study, the first global Phase III trial to report positive results for a “neoadjuvant immunotherapy + surgery + adjuvant immunotherapy” (“sandwich” model) for stage IIA-IIIB(N2) (AJCC 8th edition) resectable NSCLC patients without EGFR or ALK mutations, which has been conditionally approved by the FDA.

In NeoCOAST-2, 92.2%, 92.1%, and 95.8% of patients in Groups 1, 2, and 4 underwent surgery, with pCR rates of 20%, 26.7%, and 34.1%, and mPR rates of 45%, 53.3%, and 65.9%, respectively. Group 4 had the highest pCR rate, and safety was generally acceptable. TRAE rates during the neoadjuvant phase were 94.6%, 90.1%, and 96.3% for Groups 1, 2, and 4, respectively, with grade ≥3 TRAEs reported in 31.1%, 29.6%, and 18.5% of cases. These promising efficacy and controllable safety results suggest that these novel perioperative regimens may further improve the prognosis of resectable NSCLC patients.

NeoCOAST-2 is the first global Phase II trial to demonstrate the safety and efficacy of combining ADC, CD73, and NKG2A antibodies in neoadjuvant treatment for resectable NSCLC patients, confirming the feasibility of integrating novel anti-cancer drugs into neoadjuvant and perioperative treatment to enhance clinical benefit.

Reference

1. Cascone T, Guisier F, Bonanno L, 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: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract PL02.07.

2. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med 2023.

Dr. Shengxiang Ren

Chief Physician, Professor, Doctoral Supervisor Department of Oncology, Shanghai Pulmonary Hospital, Tongji University Administrative Director Member of the Education Committee of IASLC Secretary-General of the Thoracic Oncology Branch, China Medical Promotion Association Vice Chair of the Clinical Research Subcommittee on Oncology Drugs, China Anti-Cancer Association Vice Chair of the Oncology Branch, Shanghai Medical Association Vice Chair of the Lung Cancer Molecular Targeted Immunotherapy Committee, Shanghai Anti-Cancer Association Vice Chair of the Translational Research Committee, Shanghai Anti-Cancer Association Vice Chair of the Molecular Targeting Subcommittee, Shanghai Medical Association Executive Member of the Non-Small Cell Lung Cancer Committee, CSCO Executive Member of the Youth Committee, CSCO Executive Member of the Immunology Expert Committee, CSCO Member of the Geriatric Oncology Prevention and Treatment Expert Committee, CSCO Executive Member of the Oncology Specialty Committee, China Association of Geriatric Medicine Executive Member of the Oncology Bronchoscopy Specialty Committee, Shanghai Anti-Cancer Association