Summary of clinical trials (2020–2025) in lung cancer nanomedicine.
| Nanomedicine platform | Clinical stage/population | Findings | Reference(s) |
|---|---|---|---|
| Telisotuzumab vedotin (Teliso-V)—c-MET-targeted ADC | Phase II (LUMINOSITY) in advanced NSCLC with high c-MET overexpression (EGFR wild-type); FDA ACC 2023. | ORR 35% (all PR) in c-MET IHC 3+ patients; median DOR 7.2 months. Responses enriched in c-MET high (e.g., ~54% ORR in IHC 3+ subgroup). Common AEs: nausea, fatigue, hematologic toxicity (mostly Grade 1–2). First c-MET-directed ADC approved in lung cancer, addressing an unmet need in c-MET-overexpressed NSCLC. | [88] |
| Datopotamab deruxtecan (Dato-DXd)—TROP2-targeted ADC | Phase III (TROPION-Lung01) in metastatic NSCLC post-1L (TROP2-expressing); results 2023–2024. | Met primary PFS endpoint (significant improvement vs. docetaxel). In non-squamous NSCLC: OS 14.6 vs. 12.3 mo (HR 0.84, trend); higher ORR and longer DOR than chemo (data pending publication). Grade ≥ 3 TRAEs 26% vs. 42% (less toxicity vs docetaxel). First TROP2 ADC to show survival benefit trend in NSCLC. | [91] |
| HER3-DXd—HER3-targeted ADC | Phase II (HERTHENA-Lung01) in EGFR-mutant NSCLC after EGFR TKI ± chemo; phase III trial ongoing. | Phase II: ORR ~30% in heavily pretreated EGFR TKI-resistant patients (including ~33% ORR in those with brain metastases); median PFS ~5.5 mo, OS ~11.9 mo. Early phase III data (HERTHENA-Lung02) vs. chemo show improved PFS (5.8 vs. 5.4 mo, HR 0.77) and ORR (35% vs. 25%) but no OS difference (16.0 vs. 15.9 mo). High rate of Grade ≥ 3 AEs (~65%) observed with monotherapy. Demonstrated intracranial activity and efficacy across diverse resistance mechanisms; further combination strategies under investigation. | [76, 92] |
| T-DXd—HER2-targeted ADC | Phase II (DESTINY-Lung01) in advanced HER2-mutant NSCLC after chemo; FDA-approved under ACC. | ORR ~55%, median PFS ~8.2 mo, OS ~17.8 mo. Notable toxicity: ILD in 26% (Grade ≥ 3 in ~10%, 2 % fatal). First HER2-directed therapy in lung cancer, showing high efficacy in HER2-mutant NSCLC. | [93] |
| Disitamab vedotin (RC48) | Advanced HER2-mutant NSCLC (phase II, China). | Demonstrated encouraging efficacy in patients with HER2-mutant or overexpressing NSCLC, showing an ORR of 45.5% and a median PFS of 7.5 mo. In subgroups treated with platinum-based chemo ± bevacizumab, ORR improved to 71.4%. Treatment was generally well tolerated with mostly mild-to-moderate adverse events. | [94] |
| Rovalpituzumab tesirine (Rova-T) | Phase III in DLL3-high SCLC (TAHOE trial). | Failed to improve OS vs. topotecan (6.3 vs. 8.6 mo). Associated with significant toxicity, including pleural and pericardial effusions, leading to early termination of the trial due to futility. | [95] |
| EGFR-targeted bacterial nanocell (EDVTM)—biomimetic | Phase I/IIa (2025, EGFR-positive refractory solid tumors, including NSCLC; ≥ 2L basket trial). | Earlier phase I studies showed acceptable safety for EDV nanocells in advanced cancers. A new multicenter trial is underway delivering EGFR-targeted EDVTM loaded with a “super-cytotoxic” drug (PNU-159682) plus an immunostimulant (α-GalCer) to EGFR-expressing tumors. Will evaluate safety/efficacy in patients who have exhausted standard 2L therapies (including NSCLC). (No efficacy results yet; prior EDV trials in other cancers reported minimal side effects and signs of overcoming drug resistance.) | [95, 96] |
| mRNA-lipid nanoparticle (mRNA-LNP) vaccine—BNT116 | Phase I (LuCa-MERIT-1) in advanced NSCLC; fixed six-antigen mRNA vaccine, as monotherapy or with chemo/immunotherapy. | Immunogenicity demonstrated: vaccine-induced CD8+ and CD4+ T-cell responses to multiple tumor antigens in patients. In combination (with docetaxel or anti-PD-1), early signs of efficacy were observed (including some partial responses in heavily pretreated patients). Safety profile was acceptable: mostly low-grade cytokine release symptoms and injection-site reactions; no dose-limiting toxicities. Represents the first-in-human mRNA cancer vaccine in NSCLC, showing feasibility and preliminary anti-tumor activity. | [97, 98] |
| NBTXR3 hafnium oxide nanoparticle—radioenhancer (intratumoral) | Phase I (MD Anderson) in inoperable, locally recurrent NSCLC (with re-irradiation ± anti-PD-1). | Feasible CT-guided intratumoral injections; established recommended phase II dose with a favorable safety profile (no dose-limiting toxicities). The ongoing expansion phase is evaluating efficacy; preliminary signals indicate local tumor control and potential immune activation (abscopal effects reported in other NBTXR3 studies). First-in-class inorganic nanotherapeutic activating radiotherapy, aiming to improve outcomes in radioresistant lung tumors. | [99] |
| Hafnium-oxide nanoparticles (NBTXR3)—stimuli-responsive radioenhancer | Phase I (ongoing; stage III NSCLC unsuitable for surgery, intratumoral NBTXR3 + radiotherapy ± anti-PD-1). | A novel inorganic nanoparticle that amplifies radiotherapy effects. Preliminary findings (2025 ELCC) show intratumoral NBTXR3 (activated by radiation) can enhance local tumor control without increasing systemic toxicity. Early safety data in thoracic tumors are encouraging (few ≥ Grade 3 AEs, mainly procedure-related, e.g., one pneumothorax) and demonstrate the feasibility of intratumoral injections in lung lesions. Moreover, abscopal responses have been documented in trials—untreated lesions regressing post-therapy—suggesting NBTXR3 plus hypofractionated radiation may stimulate systemic anti-tumor immunity. | [100] |
| Nab-paclitaxel (albumin-bound) vs. docetaxel | Advanced NSCLC, 2L vs. docetaxel (Phase III, 503 pts). | Median OS ~16 months in the nab-paclitaxel arm, non-inferior to docetaxel. Notably, severe neutropenia was much lower with nab-paclitaxel (febrile neutropenia 2% vs. 22% on docetaxel), indicating a significantly improved safety profile at similar efficacy. | [11] |
| NALIRI(vs. topotecan) | Phase III (RESILIENT) in 2L SCLC. | ORR was significantly higher with NALIRI (44.1% vs. 21.6%), but no significant improvement in OS or PFS. Hematologic toxicities were less frequent in the liposomal arm, supporting a more favorable safety profile. | [101] |
| Pm-Pac—cremophor-free micellar taxane | Phase III (open-label) in untreated advanced NSCLC (Pm-Pac + cisplatin vs. solvent paclitaxel + cisplatin). | Pm-Pac arm achieved higher ORR (by independent review) and longer median PFS (6.4 vs. 5.3 mo, HR 0.63, p = 0.0001). No OS difference. Safety improved: serious AEs 9% vs. 18%; significantly less Grade ≥ 3 neutropenia (1% vs. 23%). Validated nanoparticle delivery (no CrEL solvent) improves efficacy and tolerability in first-line NSCLC. | [73] |
| Inhalable lipid-polymer hybrids; sapanisertib + telaglenastat | Phase I in advanced NSCLC; phase I in NSCLC with KEAP1/NFE2L2 mutations. | Safe lung-specific delivery, minimal systemic exposure; ORR 12.5%; 1 PR in squamous NRF2-mutant patient. Well tolerated. | [44] |
| NALIRI—PEGylated liposome SN-38 | Phase II (dose exploration) in relapsed small-cell lung cancer (2L after platinum)—China. | ORR 32% (21/66 pts; 95% CI 21–44) across doses; median PFS 4.0 mo, OS 9.7 mo. Recommended dose 80 mg/m2 had the best risk-benefit (ORR 37%, manageable diarrhea). Grade ≥ 3 TRAEs in 47% (mostly neutropenia 27%, leukopenia 24%, anemia 15%). Demonstrated activity of nanoparticle irinotecan in SCLC, though phase III (RESILIENT) showed no OS benefit vs. topotecan. | [72] |
| Oncoprex (REQORSA)—TUSC2 gene-loaded liposome | Phase I/II in advanced NSCLC (monotherapy or combined with EGFR-TKI/ICI) | First-in-human systemic delivery of tumor suppressor gene via nanoparticle. Phase I showed safety and early efficacy (PR/stable disease). Ongoing phase II evaluating combinations. | [102] |
| CRISPR-edited PD-1 knockout T cells | Phase I in NSCLC (China) | Established the feasibility of CRISPR-edited T cell therapy in solid tumors. No cytokine release syndrome observed. Edited cells persisted in circulation and showed early signs of immune activity. | [103] |
MET: mesenchymal-epithelial transition; ADC: antibody-drug conjugate; NSCLC: non-small cell lung cancer; EGFR: epidermal growth factor receptor; ACC: accelerated approval; ORR: objective response rate; PR: partial response; IHC: immunohistochemistry; DOR: duration of response; AEs: adverse events; TROP2: trophoblast cell surface protein 2; PFS: progression-free survival; OS: overall survival; HR: hazard ratio; mo: month; chemo: chemotherapy; TRAEs: treatment-related adverse events; HER3: human epidermal growth factor receptor 3; TKI: tyrosine kinase inhibitor; ILD: interstitial lung disease; DLL3: delta-like ligand 3; SCLC: small cell lung cancer; 2L: second-line; Pm-Pac: polymeric micellar paclitaxel; CrEL: cremophor el solvent; PEG: polyethylene glycol; ICI: immune checkpoint inhibitor.