In the multiarm phase II NeoCOAST-2 trial, neoadjuvant treatment with datopotamab deruxtecan (Dato-DXd) plus the monoclonal antibody durvalumab and single-agent platinum chemotherapy led to promising rates of pathologic complete and major pathologic responses in patients with early-stage non–small cell lung cancer (NSCLC). The findings were reported at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.1
Tina Cascone, MD, PhD
“This is the first global phase II study showing encouraging pathologic response rates for Dato-DXd in the neoadjuvant setting for patients with resectable NSCLC,” said Tina Cascone, MD, PhD, Associate Professor Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston. -“Dato-DXd in combination with durvalumab and single-agent platinum chemotherapy as neoadjuvant treatment demonstrated a manageable safety profile, with similar rates of adverse events of special interest as compared with historical Dato-DXd monotherapy data.”
Dato-DXd is a TROP2-directed antibody-drug conjugate that showed significant benefits vs docetaxel in the phase III TROPION-Lung01 trial.2 Perioperative anti–PD-(L)1 therapies plus neoadjuvant chemotherapy have also improved event-free survival outcomes and rates of pathologic complete response vs chemotherapy alone in several phase III trials. The phase II NeoCOAST-2 platform study evaluated the efficacy and tolerability of novel perioperative treatment combinations in patients with resectable NSCLC.
NeoCOAST-2 Design and Key Outcomes
In NeoCOAST-2, patients with stage IIA to IIIB resectable NSCLC and no EGFR mutations or ALK rearrangements were randomly assigned to one of the following four regimens:
- Arm 1: Neoadjuvant oleclumab (anti-CD73 monoclonal antibody) plus durvalumab plus platinum-doublet chemotherapy, followed by surgery and adjuvant oleclumab and durvalumab (n = 76)
- Arm 2: Neoadjuvant monalizumab (anti-NKG2A agent) plus durvalumab plus platinum-doublet chemotherapy followed by surgery and adjuvant monalizumab plus durvalumab (n = 72)
- Arm 3: Neoadjuvant volrustomig (PD-1/CTLA-4 bispecific antibody) plus chemotherapy followed by surgery and volrustomig (n = 70; data not presented in this report)
- Arm 4: Neoadjuvant Dato-DXd plus durvalumab plus single-agent platinum chemotherapy followed by surgery and adjuvant durvalumab (n = 54).
Dr. Cascone presented findings for arms 1, 2, and 4; those for arm 3 will be presented at a later date. The study was not powered to make direct statistical comparisons between arms, and because of small cohort sizes, the results should be interpreted with caution, she said. The primary intent was to look for preliminary efficacy signals by calculating pathologic complete response rates.
For arms 1, 2, and 4, most patients had adenocarcinoma histology (61%–66%) and PD-L1 (tumor proportion score [TPS]) ≥ 1% (67%–76%); approximately half (46%–53%) had stage IIIA tumors. Approximately three-fourths of all arms completed neoadjuvant therapy, and more than 90% underwent surgery.
The rates of pathologic complete response and major pathologic response with the novel neoadjuvant combinations were encouraging, Dr. Cascone said, especially the combination of Dato-DXd and durvalumab plus single-agent platinum chemotherapy; with this combination, the pathologic complete response rate was 34.1%, exceeding that seen in the phase III AEGEAN trial of durvalumab plus chemotherapy, which was 17%.2 She reported these rates from NeoCOAST-2:
- Dato-DXd/durvalumab/chemotherapy: pathologic complete response rate, 34.1%; major pathologic response rate, 65.9%
- Oleclumab/durvalumab/chemotherapy: pathologic complete response rate, 20.0%; major pathologic response rate, 45.0%
- Monalizumab/durvalumab/chemotherapy: pathologic complete response rate, 26.7%; major pathologic response rate, 53.3%.
Rates of pathologic complete response generally rose in accordance with PD-L1 level (TPS), but Dr. Cascone cautioned these sample sizes are small for final interpretation. For the Data-DXd plus durvalumab cohort, pathologic complete responses were observed in 41.2% of patients with a TPS ≥ 50%, 37.5% of patients with a TPS ≥ 1%, and 25.0% with a TPS < 1%. For the oleclumab plus durvalumab cohort, these rates were 32.0%, 20.9%, and 17.6%, respectively. For the monalizumab plus durvalumab cohort, these rates were 35.0%, 32.5%, and 15.0%, respectively.
Safety profiles were manageable in all three arms, she said. The most common adverse events included nausea, anemia, asthenia, and neutropenia. With Dato-DXd, durvalumab, and single-agent platinum chemotherapy, grade ≥ 3 treatment-related adverse events occurred in 18.5% of patients in the neoadjuvant setting and led to treatment discontinuation in 7.4%, but none occurred thereafter.
“In perioperative NSCLC therapy, these novel combinations showed promising efficacy, with numerically higher pathologic complete response and/or major pathologic response rates compared with historical benchmarks,” Dr. Cascone said. “All three study arms demonstrated manageable safety profiles and surgical rates comparable to those of currently approved regimens.”
EXPERT POINT OF VIEW
Nan Wu, MD
“Novel immuno-oncology combinations, with or without chemotherapy, showed promising efficacy and safety data in the perioperative setting,” said Nan Wu, MD, of Peking University Cancer Hospital, China, who was invited to discuss the results of NeoCOAST-2. “The significance of NeoCOAST-2 is that it’s the first global phase II study exploring novel combinations in the perioperative setting.”
Putting Findings Into Context
The study’s aim was to determine whether adding novel drugs to an established durvalumab-based perioperative regimen might improve upon current outcomes. Indeed, the results were encouraging, he said, putting them into context with previous studies.
In the historical comparator for NeoCOAST-2—the phase III AEGEAN trial—perioperative durvalumab plus chemotherapy yielded a pathologic complete response rate of 17.2% and a major pathologic response rate of 33.0%.2 In two recent studies of nivolumab plus chemotherapy, pathologic complete response rates were 24% with adjuvant nivolu-mab plus chemotherapy in CheckMate 8163 and 25% with perioperative nivolumab plus chemotherapy in CheckMate 77T.4 In NeoCOAST-2, he noted, datopotamab deruxtecan plus durvalumab and single-agent chemotherapy, in particular, yielded a 34.1% pathologic complete response rate and a 65.9% major pathologic response rate.
“We saw that the novel combination with the TROP2-directed antibody-drug conjugate had the potential for high responses in all subgroups. Upgrading of the combination and treatment duration maintained a similar safety profile, comparable with other combinations in the platform,” he explained. “Of course, direct comparisons of novel combinations with durvalumab plus chemotherapy in a randomized controlled trial are needed.” To this end, several phase II studies are underway evaluating novel regimens that include durvalumab and also some other checkpoint inhibitors (eg, tislelizumab-jsgr).
DISCLOSURE: Dr. Cascone has received speaker fees/honoraria from The ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medicals, PeerView, Physicians’ Education Resource, and Targeted Oncology; advisory role/consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, and Regeneron; and institutional research funding from AstraZeneca and Bristol Myers Squibb. Dr. Wu reported no conflicts of interest.
REFERENCES
1. Cascone T, Florian G, Bonanno M, et al: Neocoast-2: Efficacy and safety of neoadjuvant durvalumab (D) + novel anticancer agents + CT and adjuvant D ± novel agents in resectable NSCLC. 2024 World Conference on Lung Cancer. Abstract PL02.07. Presented September 8, 2024.
2. Heymach JV, Harpole D, Mitsudomi T, et al: Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med 389:1672-1684, 2023.
3. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 386:1973-1985, 2022.
4. Cascone T, Awad MM, Spicer JD, et al: Perioperative nivolumab in resectable lung cancer. N Engl J Med 390:1756-1769, 2024.
