Clin Pharm 2-10 - Lung Cancer Treatment 6-27-24 (2).pdf

Lung Malignancy Treatment ME 641 – Clinical Pharmacology II Michael A. Sharma, MPAS, PA-C Emergency Medicine, UT Southwestern Medical Center, Dallas, TX Adjunct Professor, Franklin Pierce Unive...

Lung Malignancy Treatment ME 641 – Clinical Pharmacology II Michael A. Sharma, MPAS, PA-C Emergency Medicine, UT Southwestern Medical Center, Dallas, TX Adjunct Professor, Franklin Pierce University, Austin, TX https://go.oncehub.com/MichaelSharma | [email protected] @michaelsharmapa  What is Cancer? Cells normally die when they grow old or become damaged Cancer is when cells grow uncontrollably This is from some sort of genetic alteration Genes are the instruction manual about how a cell should behave Different genes/“instructions” can be changed, resulting in misbehavior These genes can also be targets of cancer therapies These cancerous (malignant) cells can invade or otherwise damage nearby tissues or travel (metastasize) to other locations  Treatment Strategies Neoadjuvant therapy – giving drugs before surgery or radiation 2022 “Checkmate 816” trial Nivolumab + chemo before surgery – 24% event-free survival & response rate Chemo alone before surgery – 2% event-free survival and response rate Adjuvant therapy – giving drugs after surgery or radiation These therapies can be a combination of different medications Chemotherapy Checkpoint inhibitors Targeted therapies  Traditional Tx of Lung Cancer Platinum-based chemotherapy Cisplatin Carboplatin Oxaliplatin Platinum moieties bind to DNA and interfere with synthesis, leading to cellular apoptosis  Traditional Tx of Lung Cancer Cisplatin resistance: decreasing drug uptake increasing drug efflux inducing drug detoxification DNA repair mechanisms  AEs of Lung Cancer Tx Severe N/V Managed with 5-HT3 receptor antagonists (like ondansetron) Nephrotoxic More important with cisplatin Mitigated by aggressive IV hydration Myelosuppression More important with carboplatin, oxaliplatin Neurotoxic Cold-induced & cumulative neuropathy with oxaliplatin Ototoxic Hypomagnesemia Hypocalcemia Hypokalemia  Immunology Refresher Normally, major histocompatibility complex (MHC) on anti-gen-presenting cells (APCs) present antigens to T-cell receptor (TCR) 2nd signal often required for T-cell activation, like CD80 from APC to CD28 on T-cell Once these 2 signals are received, T-cells are activated To prevent excessive inflammation, activated T-cells bring CTLA-4 and PD-1 to their surface These receptors can be bound by APCs or APC tissue cells and deactivate T-cells  How Cancer Subverts Immunology These receptors are called “checkpoints” against overactive immune response Cancer cells can bind to these inhibitory receptors on T-cells and deactivate them 2011: first approval for immune checkpoint inhibitors (ICIs) Now over 80 FDA-approved uses for over 17 concerns since then They are considered the standard of care in APC modern oncology  Immune Checkpoint Inhibitors 2011: first approval for immune checkpoint inhibitors (ICIs) Now over 80 FDA-approved uses for over 17 concerns since then They are considered the standard of care in modern oncology AE: autoimmune response to normal tissues; treated with corticosteroids APC Activated CD8 cells can attack If tumor expresses a high The antibody tumor cells by recognizing level of PD-L1, this ligand inactivates the abnormal cell surface can bind receptor and receptor making proteins as foreign. trigger cell death in the T- the T-cells cell. unresponsive to PD- L1. The CD8 cell can now exert its cytotoxic effect in the tumor cell.  ICI: PD-1/PD-L1 Inhibitors Nivolumab (Opdivo), PD-1 Pembrolizumab (Keytruda), PD-1 Cemiplimab (Libtayo), PD-1 Atezolizumab (Tecentriq), PD-L1 Durvalumab (Imfinzi), PD-L1 APC  ICI: CTLA-4 Inhibitors Ipilimumab (Yervoy) Tremelimumab (Imjudo) APC  Tyrosine Kinase Inhibitors Gene mutations cause abnormal behaviors in cells affecting cell growth The presence (or absence) of these gene mutations means that patients can be candidates (or not) for certain drugs Tyrosine kinases are a family of 50+ enzymes that are involved in these cell growth processes Each has their own adverse effects, monitoring parameters, and other contraindications  ALK Tyrosine Kinase Inhibitors ALK gene Codes for anaplastic lymphoma kinase (ALK), which is involved in cell growth Increased levels of ALK increase the growth of cancer cells Mutated forms of the ALK gene and protein have been found in non-small cell lung cancer and other kinds of cancer ALK TKIs recommended as first-line therapy in patients with ALK gene mutations, with response rates between 47-83% Alectinib Brigatinib Lorlatinib  EGFR Tyrosine Kinase Inhibitors EGF-R gene Codes for Epidermal Growth Factor (EGF) Receptor on cell surface; binds to EGF, leading the cell to divide Mutations in the gene can cause EGF-R upregulation on the surface of many types of cancer cells These mutated cells may divide excessively in the presence of epidermal growth factor EGFR TKIs recommended as first-line therapy in patients with EGFR gene mutations, with response rates of at least 70% Osimertinib is often recommended as the first-line tx  Final Thoughts Decisions on cancer treatments are ultimately not up to primary care, urgent care, EM, or IM PAs Not unusual for these specialties to see patients suffering from the side effects of these medications Important for us to recognize these drugs, recognize that acute symptoms that a patient is suffering could be an AE of these drugs Lung Malignancy Treatment ME 641 – Clinical Pharmacology II Michael A. Sharma, MPAS, PA-C Emergency Medicine, UT Southwestern Medical Center, Dallas, TX Adjunct Professor, Franklin Pierce University, Austin, TX https://go.oncehub.com/MichaelSharma | [email protected] @michaelsharmapa