Durable efficacy of first-line necitumumab plus pembrolizumab in PD-L1–high advanced NSCLC: Final results of the phase II K-TAIL-202 study.

8573 Background: Pembrolizumab is a standard 1st line treatment for advanced non–small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score TPS ≥50%); however, durable benefit is achieved in only a subset of patients. Prior pembrolizumab-based combination strategies (e.g., anti-TIGIT) have inconsistently improved outcomes over pembrolizumab monotherapy in this setting. Epidermal growth factor receptor (EGFR) signaling may promote immune evasion by stabilizing PD-L1 expression and shaping an immunosuppressive tumor microenvironment, providing a rationale for combining the anti-EGFR antibody necitumumab with pembrolizumab. We therefore evaluated the efficacy and safety of necitumumab plus pembrolizumab in treatment-naive patients with PD-L1–high advanced NSCLC. Methods: K-TAIL-202 (jRCT2031200248) was an open-label, multicenter, single-arm phase II study conducted in Japan. Eligible patients were aged ≥20 years with unresectable stage III/IV or recurrent NSCLC, PD-L1 TPS ≥50% (22C3), ECOG PS 0–1, and ≥1 measurable lesion. Patients received necitumumab 800 mg IV on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 every 3 weeks for up to 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study assumed an expected ORR of 54.8% and a threshold ORR of 39.0% (one-sided α = 0.10; 80% power), requiring enrollment of 50 patients. Results: Between December 2020 and March 2023, 50 patients were enrolled (median age, 72 years). The ORR was 68.0% (95% CI, 53.3–80.5) and the disease control rate was 78.0% (95% CI, 64.0–88.5). Complete response, partial response, stable disease, progressive disease, and not evaluable status were observed in 2.0%, 66.0%, 10.0%, 12.0%, and 10.0% of patients, respectively, meeting the primary endpoint. Median PFS was 16.0 months (95% CI, 9.0–24.0), with a 24-month PFS rate of 35.9%. Median OS was not attained (95% CI, 38.0 months–not estimable), and the 24-month OS rate was 71.3%. The most treatment-emergent adverse events included acneiform dermatitis (66.0%), hypomagnesemia (60.0%), and pneumonitis (12.0%). One grade 5 cardiac arrest occurred in 1 patient (2.0%), for which a causal relationship to study treatment could not be ruled out. Conclusions: At final analysis, first-line necitumumab plus pembrolizumab demonstrated durable antitumor activity and encouraging long-term survival as a chemotherapy-free regimen in patients with PD-L1–high advanced NSCLC. Toxicities were consistent with the known profiles of EGFR-targeted antibodies and PD-1 inhibitor therapy, underscoring the need for careful monitoring. These findings warrant further confirmation in a randomized phase III clinical trial. Clinical trial information: jRCT2031200248.