Understanding Precision Medicine Therapeutics

Molecular testing is standard for many cancers, with National Comprehensive Cancer Network guidelines supporting molecular testing in lung, breast, and colorectal cancers, as well as myeloma and leukemia. Some examples of actionable mutations include KRAS for colon cancer, human epidermal growth factor receptor 2 and estrogen receptor for breast cancer, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase for non-small cell lung cancer, and BRAF for malignant myeloma.

Drugs are designed to attach and interfere with specific pathways. Wujcik gave examples of oral agents that target small molecules:

• Tyrosine kinase inhibitors targeting EGFR, vascular EGFR, and others: erlotinib, sunitinib, ponatinib, imatinib, dasatinib, and ibrutinib
• Kinase inhibitors targeting RAF/RAS/MEK: sorafenib, dabrafenib, trametinib, vemurafenib
• Poly ADP ribose polymerase inhibitors: olaparib, rucaparibPI3 kinase inhibitor idelalisib
• Sonic hedgehog pathway inhibitors: sonidegib, vismodegib
• Cyclin dependent kinase 4 and 6 inhibitor: palbociclib.

However, oral therapies are associated with issues, including adherence, potential drug−food and drug−drug responses, symptom management, and proper intake of medications.

Wujcik then discussed IV, subcutaneous, or oral small molecule therapies:

• Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
• Histone deacetylase inhibitors: vorinostat, belinostat, panobinostat
• BCL-2 inhibitor: venetoclax.

Wjucik gave an overview of the naming conventions for medications, which include a prefix, infix (which identifies the target/disease class and source), and suffix (i.e., “mab” refers to monoclonal antibody). For the target/disease class infix, “tu” refers to tumor, “ci” refers to circulatory, and “il” refers to immunomodulator. For the source infix, “mo” refers to mouse models, “xi” refers to chimeric or cross between mouse and human, “zu” means it is humanized, and “u” refers to fully human models.

She then discussed checkpoint inhibitors, which target receptors that promote T-cell proliferation to allow the immune system to recognize tumor antigens. Examples of checkpoint inhibitors include cytotoxic T-lymphocyte-associated antigen-4 (i.e., ipilimumab), programmed cell death (PD) protein (i.e., nivolumab and pembrolizumab), and PD protein ligand 1 (i.e., atezolizumab).

Checkpoint inhibitors carry potentially serious or life-threatening immune related adverse events, including diarrhea; colitis; pneumonitis; interstitial lung disease; thyroid, adrenal, and pituitary issues; hepatitis; nephritis; uveitis; and skin conditions, so providers should be aware and cautious of these.