PD-L1 negative

P2, N=51, Active, not recruiting, The Methodist Hospital Research Institute | N=39 --> 51 | Trial completion date: Dec 2025 --> Dec 2028

P3, N=750, Recruiting, Amgen | Trial completion date: Jun 2031 --> Jun 2032 | Trial primary completion date: Jun 2026 --> Jun 2027

The standard first-line treatment for patients with driver mutation-negative non-small cell lung cancer (NSCLC) is chemotherapy and immunotherapy, including chemotherapy plus anti-programmed death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody (C + PD-1/PD-L1) or anti-PD-1 antibody (nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) (C + NI)...In the C + PD-1/PD-L1 group, platinum doublets were administered for up to four cycles, with pemetrexed maintenance permitted when the initial regimen included pemetrexed, whereas in the C + NI group, platinum doublets were limited to a maximum of two cycles with no maintenance chemotherapy...C + NI did not demonstrate superior effectiveness compared with C + PD-1/PD-L1 treatment across the PD-L1 TPS subgroups and was associated with increased toxicity, suggesting no clear clinical advantage of prioritizing C + NI in routine practice. C + NI should be reserved for selected cases in which the potential benefits outweigh the risks.

P1/2, N=132, Recruiting, Antengene Biologics Limited | Not yet recruiting --> Recruiting

Additional studies with larger cohorts are warranted for comprehensive translational research on PD-L1-negative TNBC, aiming to validate the efficacy and elucidate the mechanisms of action of various ICIs. This case highlights that dual-targeted therapy may provide a promising therapeutic option for patients with PD-L1-negative TNBC.

Next-generation IMVs directed against ARG1 and TGF-β aim to address immune exclusion and desmoplastic stroma and are being developed across peptide- and mRNA-based platforms with favorable safety profiles that support evaluation in earlier-stage settings. Beyond oncology, analogous microenvironment antigens are induced in chronic and acute infections, suggesting that IMV principles may generalize to settings where regulatory circuits constrain pathogen clearance.

Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution.

However, these findings should be interpreted cautiously given the non-randomized design, baseline imbalances between groups, and the limited sample size of the CT alone cohort. Tolerability of CT + IO was consistent with that observed in clinical trials.

Benmelstobart plus anlotinib showed longer progression-free survival than pembrolizumab plus placebo and no unexpected safety signals were reported, suggesting benmelstobart plus anlotinib as a potential first-line option in driver gene-negative, PD-L1-positive, advanced NSCLC. Longer term follow-up is needed to establish effects on overall survival.

NRG1 fusions were identified in 0.8% of NSCLC, exceeding historical estimates and underscoring the importance of RNA-based NGS for fusion detection. The clinical and molecular profile mirrored prior reports, with predominant female patients, IMA histology, PD-L1 negativity, and low TMB. Outcomes were poor in metastatic patients lacking access to targeted therapy, supporting the need for broader implementation of RNA sequencing and access to anti-HER3 agents.

P2, N=20, Recruiting, University of Washington | Not yet recruiting --> Recruiting

P2, N=54, Active, not recruiting, The Netherlands Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Jun 2026