Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer
Abstract
:1. Introduction
2. Antibody–Drug Conjugate
Brentuximab Vedotin
3. Bispecific Antibody
3.1. CD-16 and EGFR
3.2. PD-L1 and 4-1BB
3.3. PD-L1 and CTLA-4
3.4. PD-L1 and VEGF
3.5. CD137 and PD-L1
4. Cellular Therapy
4.1. T-Cell Receptor–Engineered T Cells
4.2. Tumor-Infiltrating Lymphocytes
5. Gut Microbiome
6. Monoclonal Antibodies
6.1. Anti-ILT4 and Anti-ILT3
6.2. Anti-CD27
6.3. Anti-NKG2A
6.4. Anti-Complement Factor H
6.5. Anti-CTLA-4
6.6. Anti-LAG-3
7. Other Molecules
7.1. CXCR2 Antagonist
7.2. TLR 7/8 Agonist
7.3. α/β IL-2R Agonist
8. Vaccines
8.1. CCL21-DC
8.2. PDC*lung01
8.3. CAN-2409
8.4. BNT116
8.5. BI1361849
9. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Drug | Class | Trials | Indications |
---|---|---|---|
Nivolumab | Anti-PD-1 | CHECKMATE-057 [12] CHECKMATE-017 [13] |
|
Nivolumab + Ipilimumab | Anti-PD-1 Anti-CTLA-4 | CHECKMATE-227 [14] CHECKMATE-9LA [15] |
|
Pembrolizumab | Anti-PD-1 | KEYNOTE-010 [16] KEYNOTE-042 [17] KEYNOTE-407 [18] KEYNOTE-189 [19] |
|
Atezolizumab | Anti-PD-L1 | IMpower110 [20] IMpower150 [21] IMpower130 [22] OAK [23] |
|
Durvalumab | Anti-PD-L1 | PACIFIC [24] |
|
Durvalumab + Tremelimumab | Anti-PD-L1 Anti-CTLA-4 | POSEIDON [25] |
|
Cemiplimab | Anti-PD-1 | EMPOWER-LUNG 3 [26] EMPOWER-LUNG1 [27] |
|
Target | Drug | Trial | Phase | Type of Tumor | Preliminary Efficacy | Safety | Comments | Ref |
---|---|---|---|---|---|---|---|---|
Antibody–drug conjugate | ||||||||
CD30 | Brentuximab vedotin | NCT04609566 | II | NSCLC Melanoma | mPFS was 4.1 months (mo) and mOS was 13.9 mo (NSCLC). | Grade ≥ 3 TEAEs in 56%, TESAEs in 42%. Peripheral neuropathy reported in 48% of pts.; 17% of pts discontinued treatment due to TEAEs. | In combination with pembrolizumab Recruiting | [29] |
Bispecific antibodies | ||||||||
CD16A and EGFR | AFM24 | NCT05109442 | I/IIa | NSCLC | 3/15 PR, 1/15 CR, 7/15 SD. | 2/17 Grade 3 toxicity infusion-related reaction. | In combination with atezolizumab EGFR wild type Ongoing study, recruiting | [30] |
PD-L1 and 4-1BB | Acasunlimab | NCT05117242 | II | NSCLC | ORR 13%, 21%, and 22% with 6 mo PFS 0%, 18%, and 33% for monotherapy, pembrolizumab combination therapy q3 week, or pembrolizumab combination therapy q6 week. | Most common grade ≥ 3 TRAEs were asthenia, liver-related events, and anemia. | Patients progressed on ICI Monotherapy and combination therapy with pembrolizumab Active, not recruiting | [31] |
PD-L1 and CTLA-4 | KN046 | NCT04054531 | II | NSCLC | ORR is 46.0%, and the median duration of response is 8.1 mo. The mPFS and mOS are 5.8 and 26.6 mo, respectively. | Grade ≥ 3 TRAEs was observed to be 66.7%. Treatment-related deaths occurred in 4 (4.6%) patients, with one case of immune-related pneumonia attributed to KN046. | First-line In combination with chemotherapy | [32] |
PD-L1 and VEGF | HB0025 | NCT04678908 | I | NSCLC | ORR 25%, DCR 66.7% with 3/12 PR, 5/12 SD, and 4/12 PD. | 11/12 patients experienced TRAE. Grade 3 ≥ TRAEs occurred in 2/12. No DLT. | Monotherapy Included TKI-resistant population with EGFR/ALK mutation | [33] |
PD-L1 and VEGF | PM8002 | NCT05918445 | Ib/Iia | NSCLC | 16/61 PR, 32/61 SD. | 11/61 experienced grade ≥ 3 TRAEs. 5/61 patients discontinued due to TRAEs. | Monotherapy Included TKI-resistant population with EGFR mutation | [34] |
CD137 and PD-L1 | MCLA-145 | NCT03922204 | I | Advanced solid tumors | DCR 37% with monotherapy and 68% with combination. | 6/53 patients receiving monotherapy had DLTs. No DLTs occurred in the patients receiving combination therapy. | Monotherapy or in combination with pembrolizumab | [35] |
Cellular therapy | ||||||||
KRAS | FH-A11KRASG12V-TCR | NCT06043713 | I | mutant KRAS including pancreatic, colorectal, and NSCLC | - | - | Recruiting | [36] |
Tumor-infiltrating lymphocytes (TILs) | GT201 | NCT05729399. | I | Advanced solid tumors | 3/7 patients PR, 2/7 patients SD. In the NSCLC subgroup, disease control was observed in 3/3 patients. | Grade ≥ 3 AEs related to lymphodepleting chemotherapy and IL-2 included decreased lymphocyte count, decreased neutrophil count, and decreased white blood cell count, pyrexia and increased heart rate. | 3/7 patients PR, 2/7 patients SD. In the NSCLC subgroup, disease control was observed in 3/3 patients Recruiting | [37] |
Microbiome-based therapeutics | ||||||||
Gut microbiome | BMC128 | NCT05354102 | I | RCC, melanoma, and NSCLC | 4/8 patients with SD. | No SAEs. | In combination with nivolumab | [38] |
Gut microbiome | hdFMT | NCT05669846 | II | NSCLC | - | - | Patients with R/R NSCLC progressed on prior anti-PD-1-based therapy Not yet recruiting | [39] |
Monoclonal antibodies | ||||||||
anti-ILT3 | MK-0482 | NCT04165798 | II | NSCLC | ORR (95% CI) 4% (1%−15%; 0 CR, 2 PR). PFS was 2.6 (1.4−4.7) mo. | Grade ≥ 3 in 17 patients (38%). | In combination with pembrolizumab | [40] |
anti-ILT4 | MK-4830 | NCT04165798 | II | NSCLC | ORR (95% CI) 11% (4−24%; 1 CR, 4 PR). PFS was 2.4 (1.5−2.7) mo. | Grade ≥ 3 in 20 (44%). | In combination with pembrolizumab | [40] |
anti-NKG2A/CD94 | monalizumab | NCT02671435 | I/II | Advanced solid tumors | 2/20 PR and 6/20 SD. | No DLTs. | In combination with durvalumab | [41] |
CD27 agonist | boserolimab | NCT04165798 | II | NSCLC | ORR (95% CI) was 8% (2−22%; 1 CR, 2 PR). PFS was 2.4 mo. | Grade ≥ 3 in 21 (57%). | In combination with pembrolizumab | [40] |
Complement factor H (CFH) | GT103 | NCT04314089 | Ib | NSCLC | Best treatment response was SD in 9/31 patients. | 3/31 patients experienced grade ≥ g3 TRAEs | Monotherapy | [42] |
Complement factor H (CFH) | GT103 | NCT05617313 | II | NSCLC | - | - | In combination with pembrolizumab Ongoing | |
CTLA-4 | IBI310 | NCT05118334 | II | NSCLC | 2/30 PR, 15/30 SD, 2/20 ORR, 17/30 DCR. | TEAEs leading to treatment interruption of any treatment drug occurred in 7 (7/15, 46.7%) and 9 (9/15, 60%) patients in cohorts A and B, respectively. Three treatment-related deaths. | In combination with sintilimab (anti-PD1) | [43] |
LAG-3 | LBL-007 | NCT05102006 | Ib/II | Advanced solid tumors | Out of 75 efficacy evaluable patients, ORR and DCR were 13.3% and 48.0%, respectively. | Treatment interruption and permanent discontinuation due to TEAEs occurred in 6 (7.5%) patients each. | In combination with toripalimab (anti-PD-1) | [44] |
LAG-3 | Ieramilimab | NCT02460224 | II | Advanced solid tumors | In NSCLC cohort, 3/42 PR, 18/42 with SD, ORR 15%. | In the anti-PD-1/L1 naive and pretreated cohorts, 9.9% and 5.4% of patients, respectively, discontinued study treatment due to AEs regardless of study drug relationship. | In combination with startalizumab (anti-PD-1) | [45] |
Other | ||||||||
CXCR2 | Navarixin | NCT03473925 | II | Advanced solid tumors | mPFS was 1.8–2.4 mo without evidence of a dose–response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. | DLTs occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg. | In combination with pembrolizumab | [46] |
TLR7/8 | EIK1001 | NCT06246110 | II | NSCLC | - | - | In combination with pembrolizumab Recruiting | [47] |
α/β IL-2R | STK-012 | NCT05098132 | Ia/Ib | Advanced solid tumors | 3/38 PR. 17/38 SD. | No DLTs. | Monotherapy | [48] |
Cancer vaccines | ||||||||
CCL21 | IT CCL21-DC | NCT03546361 | I | NSCLC | - | - | Active, not recruiting | [49] |
HLA-A*02:01-restricted peptides | PDC*lung01 | NCT03970746 | I/II | NSCLC | The BOR included 12 PR (63.2%) and 7 SD (36.8%) with ORR of 63.2% (80% CI 45.9–78.2%) and DCR of 94.7%. The mPFS was 10.9 months. | Only 1 severe TRAE occurred, a grade 4 allergic infusion-related reaction, leading to IMP discontinuation. | In combination with pembrolizumab HLA-A*02 positive | [50] |
Tumor associated antigen | CAN-2409 | NCT04495153 | II | NSCLC | mOS of evaluable population was 22.0 mo (n = 44). 64% had systemic clinical response of injected and uninjected lesions. | No DLT. | Refractory or resistant to ICI Injected into tumor followed by oral prodrug (valacyclovir) | [51] |
Tumor associated antigen | BNT116 | NCT05142189 | I | NSCLC | 7/20 (35%) PR, 10/20 (50%) SD. ORR was 35% (95% CI: 15.4–59.2%) and the DCR was 85% (95% CI: 62.1–96.8%). | TEAEs ≥ grade 3, (incidence rate ≥10%). No DLTs within the dose confirmation period or deaths under treatment were observed. | In combination with docetaxel | [52] |
Tumor associated antigen | BI1361849 | NCT03164772 | IB | NSCLC | Arm A had 29% ORR and 71% DCR, median months of 10, 7.3 5.7, and not reached for DOR, irPFS, PFS, and OS, respectively. In contrast, arm B yielded 11% ORR and 53% DCR, median months of 6, 2.5, 2.5 and 10 for DOR, irPFS, PFS, and OS, respectively. | Both arms had comparable TRAEs (56–57%) of a generally low grade and manageable within current guidelines. Both arms had a comparable rate of treatment discontinuation (22–24%). | Arm A: BI1361849 + durvalumab and arm B: BI1361849 + durvalumab+ tremelimumab | [53] |
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Share and Cite
Wolf, E.; Sacchi de Camargo Correia, G.; Li, S.; Zhao, Y.; Manochakian, R.; Lou, Y. Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer. Vaccines 2025, 13, 128. https://doi.org/10.3390/vaccines13020128
Wolf E, Sacchi de Camargo Correia G, Li S, Zhao Y, Manochakian R, Lou Y. Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer. Vaccines. 2025; 13(2):128. https://doi.org/10.3390/vaccines13020128
Chicago/Turabian StyleWolf, Emily, Guilherme Sacchi de Camargo Correia, Shenduo Li, Yujie Zhao, Rami Manochakian, and Yanyan Lou. 2025. "Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer" Vaccines 13, no. 2: 128. https://doi.org/10.3390/vaccines13020128
APA StyleWolf, E., Sacchi de Camargo Correia, G., Li, S., Zhao, Y., Manochakian, R., & Lou, Y. (2025). Emerging Immunotherapies for Advanced Non-Small-Cell Lung Cancer. Vaccines, 13(2), 128. https://doi.org/10.3390/vaccines13020128