Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates
Abstract
:1. Introduction and Background
2. Her-2 in Urothelial Cancer: Biological Rationale
3. Anti-Her-2 Drugs in UC: Clinical Results
3.1. Anti-Her-2 Monoclonal Antibodies
3.2. Anti-Her-2 Tyrosine Kinase Inhibitors
3.3. Antibody-Drug Conjugates: A Novel Promising Strategy in Anti-Her-2 Therapy
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinical Trial (Phase) | Agents | Context | N | Her-2 Selection | Age Range (Years) | Outcomes | G3/G4 Adverse Events |
---|---|---|---|---|---|---|---|
Hussain et al. (phase II) [21] | Trastuzumab + carboplatin + paclitaxel + gemcitabine | 1st line (mUC) | 44 | Yes | 37−89 | ORR: 70% (95% CI: 55−83%); CR: 5 (11%); PR: 26 (59%); SD: 5 (11%); DCR: 36 (81%) mPFS: 9.3 m (95% CI 6.7−10.2); mOS: 14.1 m (95% CI 11.5−17.1); mDR: 7.1 m (95% CI 4.8−8.0) | Neutropenia (86%), thrombopenia (70%), anemia (45%), GI AEs (28%), metabolic alterations (16%), neuropathy (14%), CV AEs (14%), fatigue (14%), renal failure (14%), neutropenic fever (13%), hemorrhage (11%), dyspnea (9%), elevated ALT/AST (7%) |
Ourdard et al. (phase II, randomized) [22] | Platinum + gemcitabine +/- trastuzumab | 1st line (mUC) | 61 | Yes | 45−80 | ORR: 19/29 (65.5%) vs 17/32 (53.2%); CR: 20.7% vs 21.9%; PR: 44.8% vs 31.3%; mPFS: 10.2 m (95% CI 4.3−13.4) vs 8.2 m (95% CI 4.6−10.6); mOS: 15.7 m (95% CI 12.2−23.6) vs 14.1 m (95% CI 9.3−28.0) | Neutropenia (75.9% vs 67.7%), thrombopenia (48.3% vs 38.7%), anemia (41.4% vs 38.3%), GI AEs (3.4% vs 3.1%), dyspnea (0% vs 3.1%), neutropenic fever (3.4% vs 9.7%) |
Meric-Bernstam et al. (MyPathway) (basket phase II) [23] | Trastuzumab + pertuzumab | Refractory solid tumors | 258 (22 mUC) | Yes | 23−87 | All tumors: ORR: 60/258 (23.3%) (95% CI 18.2−28.9%) (5 CR, 55 PR); DCR: 115/258 (44.6%) (95% CI 38.4−50.9%); mPFS: 2.8 m (95% CI 2.7−4.0); mDR: 7.9 m (95% CI 6.2−9.3); mOS: 10.9 m (95% CI 9.2−13.8); mUC (KRAS wt): ORR: 15.8% | Anemia (1.6%), diarrhea (1.6%), infusion-related reaction (1.6%) |
Galsky et al. (basket phase II) [24] | Lapatinib | Refractory solid tumors | 32 (9 mUC) | Yes | 39−85 | All Her-2+ tumors: CR: 1/32 (3%); PR: 0/32; SD: 9/32 (28%); mPFS: 78 d (95% CI: 42–118) mUC: ORR: 0%; DCR: 33% (SD) | G3 AEs occurring in >5%: nausea and diarrhea (G3 AEs in <5%: not specified) |
Wülfing et al. (phase II) [25] | Lapatinib | 2nd line (mUC) | 59 | No (25/59 Her-2+) | 41−78 | ORR: 1 (2%) (95% CI 0.04–9.09); PR: 1 (2%); SD: 18 (31%); DCR: 19 (32%) (5/27 Her-2 0/1+ [19%]; 14/30 Her-2 2+/3+ [47%]); mPFS (EGFR/Her-2+): 9.0 w (95% CI 8.1–15.0); mPFS (EGFR/Her-2-): 7.9 w (95% CI 4.3−8.3); mOS (EGFR/Her-2+): 30.3 w (95% CI 17.6−49.9); mOS (EGFR/Her-2-): 10.6 w (95% CI 5.0−17.6) | Vomiting (7%), diarrhea (3%), dehydration (3%), hyponatremia (3%) |
Powles et al. (phase III, randomized) [26] | Lapatinib | Maintenance after 1st line ChT | 232 | Yes (Her-1/2) | 64.2−77.1 (IQR) | mPFS: 4.5 m (95% CI 2.8−5.4) (lapatinib) vs 5.1 m (95% CI 3.0−5.8) (placebo) (HR 1.07; 95% CI 0.81−1.43) (p = 0.63); mOS: 12.6 m (95% CI 9.0−16.2) (lapatinib) vs 12.0 m (95% CI 10.5−14.9) (placebo) (HR 0.96; 95% CI 0.70−1.31) (p = 0.82). | Pain (10.3% vs 5.1%), diarrhea (6.2% vs 1.0%), infection (5.2% vs 4.0%), fatigue (4.1% vs 1.0%), vomiting (3.1% vs 1.0%), constipation (2.1% vs 1.0%), rash (2.1% vs 0.0%), nausea (1.0% vs 1.0%) |
Cerbone et al. (phase I) [27] | Cisplatin + gemcitabine + lapatinib | 1st line (mUC) | 17 | No (5/17 Her-2+) | 49.6−76.9 | ORR: 10/17 (58.8%); DCR: 14/17 (82.4%) (1 CR, 9 PR, 4 SD) | Neutropenia (70.6%), lymphopenia (23.5%), thrombocytopenia (41.2%), neutropenic fever (11.8%), renal failure (11.8%), pulmonary side effects (5.9%), nausea (5.9%) |
Tang et al. (phase II) [28] | Docetaxel + lapatinib | Refractory (mUC) | 15 | No (not specified) | NA | ORR: 1/15 (8%) (1 CR); PR: 0/15; SD: 4/15 (31%); mPFS: 2.0 m (95% CI 1.3–6.6); mOS: 6.3 m (95% CI 2.2−12.7) | Diarrhea (33%), vomiting (26.7%), nausea (26.7%), fatigue (6.7%) |
Choudhury et al. (phase II) [29] | Afatinib | Refractory (mUC) | 25 | No (6/25 Her-2/3+) | 36–82 | ORR Her-2/3+: 5/6 (83.3%) / Her-2/3-: 0/15 (0%) mPFS: 6.6 m for Her-2/3+ vs 1.4 m for Her-2/3- | Fatigue (13%), diarrhea (8.7%), acneiform rash (8.7%), vomiting (8.7%), acute renal failure (4.3%), chronic kidney disease (4.3%), PPS (4.3%), cough (4.3%), pleural effusion (4.3%) |
Font et al. (LUX-Bladder 1) (phase II) [30] | Afatinib | Refractory (mUC) | 42 | Yes | NA | Cohort A (Her-2/3 mutation/amplification): ORR: 2/34 (5.9%); DCR: 17/34 (50%) (2 PR, 15 SD); mDR: 22.7 w (95% CI 15.1−36.1); PFS at 6 m: 4/34 (11.8%); mPFS: 9.8 w (95% CI 7.9−16.0); mOS: 30.1 m (95% CI 17.4−47.0) | Infection (26.2%), connective tissue disorders (23.8%), renal failure (7.1%), nausea (4.8%), pyrexia (4.8%), asthenia (2.4%), pain (2.4%), anemia (2.4%), acute coronary syndrome (2.4%), cardiac failure (2.4%), dysphagia (2.4%), intestinal obstruction (2.4%), cachexia (2.4%), pulmonary embolism (2.4%), ischaemic stroke (2.4%), basal cell carcinoma (2.4%) |
Bedard et al. (basket phase II) [31] | Afatinib | Refractory solid tumors | 40 (4 mUC) | Yes | NA | All tumors: ORR: 1/40 (2.7%) (90% CI 0.14−12.2) (1 PR); PFS at 6 m: 12.0% (90% CI 5.6−25.8) mUC: ORR: 0/4 (0%) | Not specified, most AEs G1/2 |
Hyman et al. (SUMMIT) (basket phase II) [32] | Neratinib | Refractory solid tumors | 141 (18 mUC) | Yes | 30−83 | All Her-2+ tumors: ORR at week 8: 13/141 (9.2%); DCR: 39/141 (27.7%) | Diarrhea (22.0%), anemia (7.1%), dehydration (5.7%), abdominal pain (5.0%), nausea (4.2%), fatigue (3.5%), elevated AST (3.5%), dyspnea (3.5%), constipation (1.4%), hyporexia (0.7%), asthenia (0.7%) |
Her-2+ mUC: ORR: 0%; DCR: 3/16 (18.8%) (95% CI 4.0−45.6) | |||||||
KAMELEON (*) | Trastuzumab emtansine (TDM-1) | Refractory solid tumors | 20 (13 mUC) | Yes | NA | CR: 0/13; PR: 5/13 (38.5%); mPFS 2.2 m (95% CI 1.18−4.30); mOS 7.03 m (95% CI 3.75-NE) | G3: 30.8%; G4: 0%; G5: 23.1% (not specified) |
Banerji et al. (basket phase I) [33] | Trastuzumab duocarmazine | Refractory solid tumors | 146 (16 mUC) | Yes | 47–71 | ORR: 4/16 (25%) (95% CI 7.3−52.4%) DCR: 15/16 (93.8%) (4 PR, 11 SD) mPFS: 4.0 m (95% CI 1.3-NE) | Neutropenia (6%), conjunctivitis (4%), fatigue (3%), lymphopenia (3%), keratitis (2%), thrombopenia (2%), pleural effusion (2%), LVEF decreased (2%) dry eye (1%), decreased appetite (1%), vomiting (1%), infusion-related reaction (1%), vision blurred (1%), hemoptysis (1%), diarrhea (1%), elevated AST (1%), hematuria (1%), dyspnea (1%), anemia (1%), mouth ulceration (1%), rash maculo-papular (1%), elevated ALT (1%), leucopenia (1%), retinal haemorrhage (1%), |
Sheng et al. (RC48C005/RC48C009) [34] | Disitamab vedotin | Refractory (mUC) | 107 | Yes | 40−79 | Overall ORR: 50.5% (95% CI 40.6−60.3%); ORR in IHC 3+ or 2+/FISH+: 62.2%; mPFS: 5.9 m (95% CI 4.2−7.2); mOS: 14.2 m (95% CI 9.7−18.8) | Hypoesthesia (15.0%), neutropenia (12.1%), elevated GGT (5.6%) |
Xu et al. (phase II) [35] | Disitamab vedotin | Her-2 negative refractory (mUC) | 19 | Yes | NA | Overall ORR: 5/19 (26.3%) (95% CI 9.1−51.2%) ORR IHC 0/6; ORR IHC 1+: 5/13 (38.5%) DCR: 18/19 (94.7%) (95% CI 74.0−99.9%) mPFS: 5.5 m (95% CI 3.9−6.8) | Neutropenia (10.5%), white blood cell count decreased (5.3%) |
Zhou et al. (phase Ib/II) [36] | Disitamab vedotin + toripalimab | Refractory (mUC) | 14 | No (not specified) | 52−76 | ORR: 8/10 assessable patients (80%); DCR: 9/10 (90%) (8 PR, 1 SD). Follow-up continues for PFS/OS | Intestinal obstruction attributed to treatment in 1/14 (7%) |
Galsky et al. (phase Ib/II) [37] | Trastuzumab deruxtecan + nivolumab | Refractory (mUC) | 34 | Yes | 41−80 | Overall ORR: 13/34 (38.2%). ORR in IHC 2+/3+: 11/30 (36.7%) (95% CI 19.9−56.1%) (4 CR, 7 PR) mDR: 13.1 m (95% CI 4.1−NE); mPFS: 6.9 m (95% CI 2.7−14.4); mOS: 11.0 m (95% CI 7.2−NE) | G3/G4 AEs >5%: AST increase, fatigue, thrombopenia, pneumonitis |
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Albarrán, V.; Rosero, D.I.; Chamorro, J.; Pozas, J.; San Román, M.; Barrill, A.M.; Alía, V.; Sotoca, P.; Guerrero, P.; Calvo, J.C.; et al. Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates. Int. J. Mol. Sci. 2022, 23, 12659. https://doi.org/10.3390/ijms232012659
Albarrán V, Rosero DI, Chamorro J, Pozas J, San Román M, Barrill AM, Alía V, Sotoca P, Guerrero P, Calvo JC, et al. Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates. International Journal of Molecular Sciences. 2022; 23(20):12659. https://doi.org/10.3390/ijms232012659
Chicago/Turabian StyleAlbarrán, Víctor, Diana Isabel Rosero, Jesús Chamorro, Javier Pozas, María San Román, Ana María Barrill, Víctor Alía, Pilar Sotoca, Patricia Guerrero, Juan Carlos Calvo, and et al. 2022. "Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates" International Journal of Molecular Sciences 23, no. 20: 12659. https://doi.org/10.3390/ijms232012659
APA StyleAlbarrán, V., Rosero, D. I., Chamorro, J., Pozas, J., San Román, M., Barrill, A. M., Alía, V., Sotoca, P., Guerrero, P., Calvo, J. C., Orejana, I., Pérez de Aguado, P., & Gajate, P. (2022). Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates. International Journal of Molecular Sciences, 23(20), 12659. https://doi.org/10.3390/ijms232012659