Table 1.
List of Posttranslational Protein Modifications and FDA-Approved Agents as Anticancer Agents
| Agent | Target | Disease Site | Clinical Results | Year FDA Approval |
|---|---|---|---|---|
| Tyrosine kinase inhibitors | ||||
| Trastuzumab | HER2 | Metastatic HER2 + gastric cancer | OS improved 11.7 to 13.1 mo | 2010 |
| Adjuvant therapy for HER2 +, LN + breast cancer | DFS HR 0.48 | 2006 | ||
| Metastatic HER2 + breast cancer | TTP improved 4.6 to 7.6 mo | 1998 | ||
| Imatinib | BCR-ABL c-Kit | Adjuvant therapy for GIST | Improved OS with 36 mo vs 12 mo HR 0.45 | 2008/2012 |
| Unresectable or metastatic GIST | ORR 38% | 2002 | ||
| CML | Hematologic response 88% (chronic phase) | 2001 | ||
| Gefitinib | EGFR | NSCLC | ORR 10.6% | 2003 |
| Two failed clinical trials | Revoked 2005 | |||
| Bevacizumab | VEGFR | Metastatic cervical cancer | OS improved 12.9 to 16.8 mo | 2014 |
| Platinum-resistant ovarian cancer | PFS improves 3.4 to 6.8 mo | 2014 | ||
| Renal cell carcinoma | PFS improved 5.4 to 10.2 mo | 2009 | ||
| Refractory high-grade glioma | No phase III data with non–bevacizumab-containing arm | 2009 | ||
| Metastatic renal cell carcinoma | PFS improved 5.4 to 10.2 mo | 2009 | ||
| Metastatic breast cancer | PFS improved 5.8 to 11.3 mo | 2008 | ||
| No survival benefit | Revoked 2011 | |||
| Nonsquamous NSCLC | OS improved 10.3 to 12.3 mo | 2006 | ||
| Second-line metastatic colorectal cancer | OS improved 10.8 to 13.0 mo | 2006 | ||
| First-line metastatic colorectal cancer | ORR improved 35% to 45% | 2004 | ||
| Cetuximab | EGFR | K-ras wild type, EGFR-expressing metastatic colorectal cancer | OS improved 19.5 to 23.5 mo in K-ras wild-type tumors | 2012 |
| Metastatic head and neck cancer | Improved OS 18.2 to 19.1 mo | 2012 | ||
| Head and neck cancer with radiation therapy | OS improved 29.3 to 49.0 mo | 2006 | ||
| EGFR-expressing metastatic colorectal cancer | ORR 23% combined with irinotecan | 2004 | ||
| Erlotinib | EGFR | Metastatic NSCLC with EGFR mutation | Improved PFS 5.2 to 10.4 mo | 2013 |
| Maintenance treatment of NSCLC | Improved PFS HR 0.71 | 2010 | ||
| Unresectable pancreatic cancer | OS improved 6.0 to 6.4 mo | 2005 | ||
| Refractory NSCLC | OS improved 4.7 to 6.7 mo | 2004 | ||
| Dasatinib | Multityosine kinase inhibitor | Chronic-phase CML, Philadelphia chromosome positive (Ph +) | Complete cytogenic response improved 66.2% to 76.8% | 2010 |
| Refractory CML and ALL, Ph + | No phase III data | 2006 | ||
| Panitumumab | EGFR | EGFR-expressing metastatic colorectal cancer | PFS improved 60 to 96 d | 2006 |
| Sunitinib | Multikinase (VEGFR, PDGFR, KIT, FLT3, RET) | Pancreatic neuroendocrine tumor | PFS improved 5.4 to 10.2 mo | 2011 |
| Renal cell carcinoma | ORR 25.5%-36.5% | 2006 | ||
| GIST | TTP improved 6 to 27 wk | 2006 | ||
| Lapatinib | HER-2 | ER/PR +, HER2 + breast cancer | PFS improved 13 to 35 wk | 2010 |
| HER2 + breast cancer | TTP improved 18 to 24 wk | 2007 | ||
| Pazopanib | VEGFR | Advanced soft tissue sarcoma | PFS improved 1.6 to 4.6 mo | 2012 |
| Advanced renal cell carcinoma | PFS improved 4.2 to 9.2 mo | 2009 | ||
| Vandetanib | VEGFR, EGFR | Medullary thyroid cancer | ORR improved 1% to 44% | 2011 |
| Crizotinib | c-Met, anaplastic lymphoma kinase (ALK) | ALK-positive NSCLC | PFS improved 3.0 to 7.7 mo | 2011/2013 |
| Axitinib | VEGFR | Renal cell carcinoma | Improved PFS 4.7 to 6.7 mo | 2012 |
| Bosutinib | Bcr-Abl, Src-family kinases | CML/ALL Ph + | No phase III data | 2012 |
| Cabozantinib | Pan-tyrosine kinase inhibitor | Metastatic medullary thyroid cancer | PFS improved 4.0 to 11.2 mo | 2012 |
| Ponatinib | Multikinase inhibitor | CML/ALL Ph + | Phase III trial stopped | 2012 |
| Regorafenib | Multikinase inhibitor | GIST | PFS improved 0.9 to 4.8 mo | 2013 |
| Refractory metastatic colorectal cancer | Improved OS 5.0 to 6.4 mo | 2012 | ||
| Afatinib | EGFR, HER2, HER4 | Metastatic NSCLC with mutant EGFR | PFS improved 6.9 to 11.1 mo | 2013 |
| Ibrutinib | Burton’s tyrosine kinase | CML | ORR 58.3% | 2014 |
| Mantle cell lymphoma | ORR 69% | 2013 | ||
| Ceritinib | ALK | ALK-positive metastatic NSCLC | ORR 54.6% | 2014 |
| Ramucirumab | VEGFR | Gastric cancer | OS improved 3.8 to 5.2 mo | 2014 |
| Metastatic NSCLC | OS improved 9.1 to 10.6 mo | 2014 | ||
| Serine/threonine kinase inhibitors | ||||
| Vemurafenib | BRAFV600E | Melanoma V600E mutant | PFS improved 1.6 to 5.3 mo | 2011 |
| Trametinib | MEK1, MEK2 | Melanoma BRAF V600E/V600K mutant | PFS improved 1.5 to 4.8 mo | 2013 |
| Dabrafenib | BRAF, CRAF | Melanoma BRAF V600E mutant | PFS improved 2.7 to 5.1 mo | 2013 |
| Other kinase inhibitors | ||||
| Sorafenib | Multikinase inhibitor (BRAF, VEGFR, PDGFR, FLT3, KIT) | Differentiated thyroid cancer | PFS improved 5.8 to 10.8 mo | 2013 |
| Hepatocellular carcinoma | OS improved 7.9 to 10.7 mo | 2007 | ||
| Renal cell carcinoma | PFS improved 84 to 167 d | 2005 | ||
| Temsirolimus | mTOR | Renal cell carcinoma | Improved PFS 3.1 to 5.5 mo | 2007 |
| Everolimus | mTOR | HER2-negative breast cancer | PFS improved 3.2 to 7.8 mo | 2012 |
| Pancreatic neuroendocrine tumor | PFS improved 4.6 to 11.0 mo | 2011 | ||
| Renal cell carcinoma | PFS improved 1.9 to 4.9 mo | 2009 | ||
| Idelalisib | Phosphoinositide-3 kinase | Relapsed CLL | PFS HR 0.18 | 2014 |
| SLL | ORR 58% | |||
| Follicular NHL | ORR 54% | |||
| HDAC inhibitors | ||||
| Vorinostat | HDAC | Cutaneous T-cell lymphoma | ORR 30% | 2006 |
| Romidepsin | HDAC | Cutaneous T-cell lymphoma | ORR 34-35% | 2009 |
| Belinostat | HDAC | Refractory peripheral T-cell lymphoma | ORR 25.8% | 2014 |
| Panobinostat | HDAC | Refractory multiple myeloma | PFS improved 5.8 to 10.6 mo | 2015 |
| Proteasome inhibitors | ||||
| Bortezomib | Proteasome | Mantle cell lymphoma | PFS improved 14 to 25 mo | 2014 |
| Multiple myeloma | ORR 28% | 2003 | ||
| Carfilzomib | Proteasome inhibitor | Multiple myeloma | ORR 23% | 2012 |
| PARP inhibitors | ||||
| Olaparib | PARP | Ovarian cancer with germline BRCA mutation | ORR 34% | 2014 |
DOR: duration of response; ORR: overall response rate; PFS: progression-free survival; TTP: time to progression.
HR = Hazard Ratio DFS = Disease Free Survival OS = Overall Survival.