Novel Combinations Show Promise in Resectable NSCLC, Led by ADC-Chemo-Immuno Triplet

New findings from the phase 2 NeoCOAST-2 platform study (NCT05061550) offer encouraging data for novel neoadjuvant treatment strategies in patients with untreated, resectable stage IIa to IIIb non–small cell lung cancer (NSCLC). Notably, the arm incorporating datopotamab deruxtecan (Dato-DXd; Datroway), an antibody-drug conjugate (ADC) alongside durvalumab (Imfinzi) and single-agent platinum chemotherapy demonstrated the highest pathological complete response (pCR) rates among the regimens investigated, warranting further exploration of ADCs in this setting.¹

Despite recent advances with neoadjuvant or perioperative immune checkpoint inhibitors, a significant unmet need persists for improved outcomes in resectable NSCLC, with 3-year event-free survival (EFS) rates remaining in the 54% to 60% range. The NeoCOAST-2 study aimed to address this by evaluating durvalumab in combination with various novel agents and chemotherapy in a perioperative setting.

“NeoCOAST-2 is, to our knowledge, the first global phase II study to report clinical data on an ADC in the neoadjuvant setting for patients with resectable NSCLC and the first to report data on neoadjuvant combination regimens (immune checkpoint inhibitor therapy plus chemotherapy plus novel agents) in this patient population,” study authors wrote in the Nature Medicine publication.

Study Design and Key End Points

The NeoCOAST-2 study randomized 202 patients across 3 arms to receive neoadjuvant therapy followed by surgical resection and adjuvant durvalumab with or without the novel agent.

• Arm 1: durvalumab plus oleclumab (a CD73 inhibitor) and platinum-doublet chemotherapy followed by adjuvant durvalumab and oleclumab.
• Arm 2: durvalumab plus monalizumab (a NKG2A inhibitor) and platinum-doublet chemotherapy followed by adjuvant durvalumab and monalizumab.
• Arm 4: durvalumab plus Dato-DXd and single-agent platinum chemotherapy followed by adjuvant durvalumab alone.

Primary end points were pCR rate and safety, with secondary end points including feasibility of surgery and major pathological response (mPR) rate. The modified intention-to-treat (mITT) population, comprising 198 patients, was used for efficacy analyses.

Promising Pathological Response Rates

In the mITT population, the Dato-DXd–containing arm 4 demonstrated the highest pCR rate at 35.2% (95% CI, 22.7%–49.4%). This compared favorably with arm 1, which showed a pCR rate of 20.3% (95% CI, 11.8%–31.2%), and arm 2, with a pCR rate of 25.7% (95% CI, 16.0%–37.6%).

Similarly, mPR rates were highest in arm 4 at 63.0% (95% CI, 48.7%–75.7%). Arm 1 and arm 2 reported mPR rates of 41.9% (95% CI, 30.5%–53.9%) and 50.0% (95% CI, 37.8%–62.2%), respectively. These pCR and mPR rates in arm 4 appear numerically higher than those observed in current standard-of-care perioperative regimens reported in phase 3 trials such as CheckMate 816 (NCT02998528), AEGEAN (NCT03800134), KEYNOTE-671 (NCT03425643), and CheckMate 77T (NCT04025879), where pCR rates typically ranged from 17% to 25% and mPR rates from 30% to 37%.^2-5

Interestingly, in arm 4, pCR and mPR rates were generally consistent across all PD-L1 subgroups (<1%, 1–49%, and ge50%).¹ This contrasts with arms 1 and 2, where higher pCR and mPR rates were observed in patients with PD-L1 expression ge1%, aligning with previous immune checkpoint inhibitor studies. The numerically improved responses in the PD-L1 <1% subgroup in arm 4 (pCR of 31.3% compared with 9% and 17% in AEGEAN and CheckMate 816, respectively) suggest a potential synergistic effect of Dato-DXd with durvalumab, possibly through mechanisms like immunogenic cell death.

Regarding histology, all three arms showed numerically higher pCR and mPR rates in squamous cell carcinoma compared to adenocarcinoma, consistent with prior research.

Surgical Feasibility and Safety Profile

The majority of patients across all arms successfully underwent surgery: 93.2% in arm 1, 93.0% in arm 2, and 94.4% in arm 4. Most resections were R0, indicating complete tumor removal. Surgical complications (Clavien–Dindo grade ge3) were observed in 13.0%, 9.1%, and 3.9% of patients in arms 1, 2, and 4, respectively.

The overall safety profile of the combination regimens was manageable and generally consistent with currently approved perioperative treatments. The incidence of grade ge3 treatment-related adverse events (TRAEs) in the overall study period was 36.5% in arm 1, 40.8% in arm 2, and 20.4% in arm 4. The neoadjuvant period exhibited the highest incidence of grade ge3 AEs across all arms.

Common AEs of any cause in the neoadjuvant period across the three arms largely reflected the known safety profiles of the cytotoxic agents. In arm 4, specific adverse events of interest for Dato-DXd included oral mucositis or stomatitis (40.7%), ocular surface events (20.4%), and mucosal inflammation (14.8%), most of which were low-grade. One patient (1.9%) in arm 4 experienced grade 2 interstitial lung disease (ILD) in the neoadjuvant period, which was deemed not related to study treatment by the treating physician but related by independent adjudication.

Future Directions

The results of NeoCOAST-2, particularly the robust pathological responses observed with the Dato-DXd–containing regimen, provide a strong rationale for further investigation of ADCs in combination with chemo-immunotherapy in the neoadjuvant setting for resectable NSCLC. While the study was not comparative, the numerically higher pCR and mPR rates in arm 4 suggest a potential benefit beyond current standard-of-care approaches. Longer-term follow-up for EFS and overall survival is crucial to confirm these promising pathological response findings.

REFERENCES:

1. Cascone T, Bonanno L, Guisier F, et al. Perioperative durvalumab plus chemotherapy plus new agents for resectable non-small-cell lung cancer: the platform phase 2 NeoCOAST-2 trial. Nat Med. 2025 May 31. doi: 10.1038/s41591-025-03746-z. Online ahead of print.

2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab with Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. doi: 10.1056/NEJMoa2202170. Epub 2022 Apr 11.

3. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer. N Engl J Med. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab with Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. doi: 10.1056/NEJMoa2202170. Epub 2022 Apr 11.

4. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. 2023 Aug 10;389(6):491-503. doi: 10.1056/NEJMoa2302983. Epub 2023 Jun 3.

5. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024 May 16;390(19):1756-1769. doi: 10.1056/NEJMoa2311926.