HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Types of HER2 Alterations
3. Treatment of HER2-Altered NSCLC
3.1. Antibody-Drug Conjugates
3.1.1. Trastuzumab–Deruxtecan (T-DXd)
3.1.2. Ado Trastuzumab–Emtansine (T-DM1)
3.1.3. Summary of Evidence regarding HER2 ADC
3.2. Monoclonal Antibodies
3.2.1. Trastuzumab
Drug | Trial | NSCLC Population (n) | Overall Response Rate | Median PFS (Months) | Median OS (Months) | Ref |
---|---|---|---|---|---|---|
trastuzumab | phase II (HOT1303-B) | HER2 IHC 2/3+ or mutation (n = 10) | 0% | 5.2 | n/a | [24] |
trastuzumab ± docetaxel | phase II | HER2 IHC 2/3+ (n = 13) | Trastuzumab: 0% Trastuzumab + docetaxel: 0% | n/a a | 5.7 | [25] |
trastuzumab + cisplatin/ gemcitabine | phase II | HER2 IHC 1+ or HER2 shed antigen level >15 ng/mL by ELISA (n = 21) | 38% | 36 weeks | n/a | [27] |
trastuzumab + paclitaxel/ carboplatin | phase II (ECOG 2598) | HER2 IHC ≥ 1+ (n = 56) | 24.5% | 3.3 | 10.1 | [26] |
gemcitabine/cisplatin ± trastuzumab | phase II | HER2 IHC 2/3+, HER2/CEP17 ratio ≥ 2, Serum HER2 ECD >15 ng/mL by ELISA (n = 101) | Control arm: 41% (50% in HER2 IHC 3+) Trastuzumab arm: 36% (83% in HER2 IHC 3+) | Control arm: 7.0 Trastuzumab arm: 6.1 | Control arm: n/r Trastuzumab arm: 12.2 | [28] |
pertuzumab + trastuzumab + docetaxel | phase II (IFCT-1703 R2D2) | HER2 exon 20 mutation (n = 45) | 29% | 6.8 | n/a | [29] |
3.2.2. Pertuzumab
3.2.3. Summary of Evidence regarding HER2 Monoclonal Antibodies
3.3. Tyrosine Kinase Inhibitors
3.3.1. Pyrotinib
3.3.2. Poziotinib
3.3.3. Mobocertinib
3.3.4. Tarloxotinib
3.3.5. Afatinib
3.3.6. Neratinib
3.3.7. Dacomitinib
3.3.8. Summary of Evidence regarding HER2 TKIs
3.4. Immunotherapy
3.5. Cytotoxic Chemotherapy
4. Practical Treatment Considerations
5. Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Trial | Tumor Types | NSCLC Population (n) | Overall Response Rate | Median PFS (Months) | Median OS (Months) | Ref |
---|---|---|---|---|---|---|---|
T-DXd | phase I | NSCLC, colorectal, salivary gland, breast, esophageal, endometrial, Paget’s disease, biliary tract, pancreatic, cervical, extraskeletal myxoid chondrosarcoma, small intestine adenocarcinoma | HER2 IHC ≥ 1+ or HER2 mutation (NSCLC n = 18; exon 20 NSCLC n = 8) | Overall NSCLC: 55.6% HER2 mutant: 72.7% | Overall NSCLC: 11.3 HER2 mutant: 11.3 | Overall NSCLC: n/r HER2 mutant: 17.3 | [17] |
T-Dxd | phase II (DESTINY-Lung01) | NSCLC | HER2 IHC 2/3+ (n = 49) | 24.5% | 5.4 | n/a | [18] |
T-DXd | phase II (DESTINY-Lung01) | NSCLC | HER2 mutation (n = 91; exon 20 = 78) | 55% | 8.2 | 17.8 | [19] |
T-DM1 | phase II | NSCLC | HER2 mutation (n = 18; exon 20 = 11) | 44% | 5.0 | n/a | [20] |
T-DM1 | phase II | NSCLC | HER2 (IHC 3+, IHC 2+ and FISH HER2/CEP17 ratio ≥ 2, or exon 20 mutation) (n = 15, IHC/FISH+ n = 8, exon 20 n = 7) | Overall: 6.7% IHC/FISH-positive: 0% Exon 20: 14.3% | 2.0 | 10.9 | [21] |
T-DM1 | phase II | NSCLC | HER2 IHC 2/3+ (n = 49) | IHC 2+: 0% IHC 3+: 20% | IHC 2+: 2.6 IHC 3+: 2.7 | IHC 2+: 12.2 IHC 3+: 15.3 | [22] |
T-DM1 | phase II | NSCLC | HER2 exon 20 mutation (n = 22) | 38.1% | 2.8 | 8.1 | [23] |
Drug | Trial | NSCLC population (n) | Overall Response Rate | Median PFS (Months) | Median OS (Months) | Ref |
---|---|---|---|---|---|---|
pyrotinib | phase II | HER2 exon 20 mutation (n = 15) | 53.3% | 6.4 | n/a | [30] |
pyrotinib | phase II | HER2 mutation (n = 60; HER2 exon 20 mutation n = 56) | 30% | 6.9 | 14.4 | [31] |
pyrotinib | phase II | HER2 mutation (n = 78, HER2 exon 20 mutation = 62) | 19.2% | 5.6 | 10.5 | [32] |
pyrotinib | phase II | HER2 amplification (n = 27) | 22.2% | 6.3 | 12.5 | [33] |
poziotinib | phase II | HER2 exon 20 mutation (n = 30) | 27% | 5.5 | 15 | [34] |
poziotinib | phase II (ZENITH20) | HER2 exon 20 mutation (n = 90) | 27.8% | 5.5 | n/a | [35] |
tarloxotinib | phase II (RAIN-701) | EGFR Exon 20 insertion, HER2 activating mutation, or any solid tumors with NRG1, EGFR, HER2 or HER4 fusion (n = 23; HER2 n = 11) | HER2 cohort: 22% | n/a | n/a | [36] |
afatinib | phase II (NICHE) | HER2 exon 20 mutation(n = 13) | 8% | 15.9 weeks | 56.0 weeks | [37] |
afatinib ± paclitaxel | phase II | EGFR and HER2 (n = 41; HER2 exon 20 mutation n = 7) | afatinib HER2: 0% afatinib + paclitaxel HER2: 33.3% | afatinib HER2: 17 weeks afatinib + paclitaxel (EGFR and HER2): 6.7 weeks | n /a | [38] |
neratinib ± TEM | phase II (PUMA-NER-4201) | HER2 exon 20 mutation (n = 60) | neratinib: 0% neratinib + TEM: 19% | neratinib: 3.0 neratinib + TEM: 4.1 | neratinib: 10.0 neratinib + TEM: 15.8 | [39] |
dacomitinib | phase II | HER2 exon 20 mutation (n = 26) or amplification (n = 4) | HER2 exon 20 mutation: 12% HER2 amplification: 0% | HER2 exon 20 mutation: 3.0 HER2 amplification: n/a a | HER2 exon 20 mutation: 9.0 HER2 amplification: n/a a | [40] |
Drug | Mechanism of Action | Development Phase | Sponsor | NCT Number |
---|---|---|---|---|
Trastuzumab Deruxtecan | ADC | phase III (DESTINY-Lung04) | AstraZeneca | NCT05048797 |
Pertuzumab + Trastuzumab + Docetaxel | Monoclonal antibody | phase II | Intergroupe Francophone de Cancerologie Thoracique | NCT03845270 |
Pyrotinib | TKI | phase III (PYRAMID-1) | Jiangsu HengRui Medicine Co | NCT04447118 |
Pyrotinib + Thalidomide | TKI | phase II | Shanghai Chest Hospital | NCT04382300 |
Pyrotinib | TKI | phase II | Tianjin Medical University Cancer Institute and Hospital | NCT04063462 |
Poziotinib | TKI | phase III (PINNACLE) | Spectrum Pharmaceuticals | NCT05378763 |
Poziotinib | TKI | phase II | MD Anderson Cancer Center | NCT03066206 |
Poziotinib | TKI | phase II | Spectrum Pharmaceuticals | NCT03318939 |
Mobocertinib | TKI | phase I/II | Takeda | NCT02716116 |
BDTX-189 (tuxobertinib) | TKI | phase I/II(MasterKey-01) | Black Diamond Therapeutics | NCT04209465 |
DZD9008 (sunvozertinib) | TKI | phase I/II (WU-KONG1) | Dizal Pharmaceuticals | NCT03974022 |
AST2818 (furmonertinib) | TKI | phase I | ArriVent BioPharma | NCT05364073 |
BAY2927088 | TKI | phase I | Bayer | NCT05099172 |
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Uy, N.F.; Merkhofer, C.M.; Baik, C.S. HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies. Cancers 2022, 14, 4155. https://doi.org/10.3390/cancers14174155
Uy NF, Merkhofer CM, Baik CS. HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies. Cancers. 2022; 14(17):4155. https://doi.org/10.3390/cancers14174155
Chicago/Turabian StyleUy, Natalie F., Cristina M. Merkhofer, and Christina S. Baik. 2022. "HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies" Cancers 14, no. 17: 4155. https://doi.org/10.3390/cancers14174155