Lung Cancer Treatment - Clinical Pharmacology II

What is Cancer?

• Cancer is when cells grow uncontrollably due to genetic alterations.
• These alterations affect genes, which are the instruction manual for cell behavior.
• Cancerous cells can invade or damage nearby tissues or travel to other locations.

Treatment Strategies

• Neoadjuvant therapy: giving drugs before surgery or radiation.
• Adjuvant therapy: giving drugs after surgery or radiation.
• Combination therapies can include chemotherapy, checkpoint inhibitors, and targeted therapies.

Traditional Treatment of Lung Cancer

• Platinum-based chemotherapy: Cisplatin, Carboplatin, and Oxaliplatin.
• Platinum moieties bind to DNA, interfering with synthesis, leading to cellular apoptosis.

Cisplatin Resistance

• Decreasing drug uptake
• Increasing drug efflux
• Inducing drug detoxification
• DNA repair mechanisms

Adverse Effects of Lung Cancer Treatment

• 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 and oxaliplatin
• Neurotoxic: cold-induced and cumulative neuropathy with oxaliplatin
• Ototoxic, hypomagnesemia, hypocalcemia, and hypokalemia

Immunology Refresher

• MHC on antigen-presenting cells (APCs) presents antigens to T-cell receptor (TCR)
• 2nd signal often required for T-cell activation, like CD80 from APC to CD28 on T-cell
• Activated T-cells bring CTLA-4 and PD-1 to their surface to prevent excessive inflammation

How Cancer Subverts Immunology

• Cancer cells can bind to inhibitory receptors on T-cells and deactivate them
• Immune checkpoint inhibitors (ICIs) target these receptors to prevent deactivation

Immune Checkpoint Inhibitors

• 2011: first approval for ICIs
• Over 80 FDA-approved uses for over 17 concerns
• Considered the standard of care in modern oncology
• AE: autoimmune response to normal tissues, treated with corticosteroids

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

CTLA-4 Inhibitors

• Ipilimumab (Yervoy)
• Tremelimumab (Imjudo)

Tyrosine Kinase Inhibitors

• Gene mutations cause abnormal cell behaviors
• Tyrosine kinases are involved in cell growth processes
• Each has their own adverse effects, monitoring parameters, and contraindications

ALK Tyrosine Kinase Inhibitors

• ALK gene codes for anaplastic lymphoma kinase (ALK), involved in cell growth
• Mutated forms of ALK gene and protein found in non-small cell lung cancer
• ALK TKIs recommended as first-line therapy in patients with ALK gene mutations, with response rates between 47-83%

EGFR Tyrosine Kinase Inhibitors

• EGF-R gene codes for Epidermal Growth Factor (EGF) Receptor on cell surface
• Mutations in the gene can cause EGF-R upregulation on cancer cells
• EGFR TKIs recommended as first-line therapy in patients with EGFR gene mutations, with response rates of at least 70%

Final Thoughts

• Decisions on cancer treatments are ultimately not up to primary care, urgent care, EM, or IM PAs
• Recognize these drugs and their potential adverse effects, which can be acute symptoms seen in patients

A quiz on lung malignancy treatment, covering clinical pharmacology concepts, taught by Michael A. Sharma from UT Southwestern Medical Center and Franklin Pierce University.