Targeted Agents -- Solid Tumor Malignancies

The 9 classes of drugs we look at for Solid Tumor Malignancies (targeted agents)

1. EGFR Inhibitors

2. HER2 inhibitors

3. ALK inhibitors

4. VEGF inhibitors

5. MEK inhibitors

6. BRAF inhibitors

7. PARP inhibitors

8. CDK4/6 inhibitors

9. Immune checkpoint inhibitors

EGFR inhibitors classes that we look at (two of them)

1. Monoclonal Antibodies (Cetuximab)

2. Small molecule inhibitors (Erlotinib (Tarceva))

Common Uses:

• NSCLC

• he’s and neck

• Colorectal

• Pancreatic

EGFR Inhibitors (Cetuximab/Erlotinib) MOA

• Binds to EGFR at the ATP binding site —→ Blocks phosphorylation of Tyrosine Kinase —→ Inhibits downstream signaling pathways (PIKC3, SRC) —→ Cell apoptosis

  • TARGETS EGFR mutation

  • KRAS wild type??

Resistance?

• T790M mutation —→ steric hindrance for EGFR binding leads to resistance!!!

EGFR inhibitors class wide toxicities!!

Acneiform rash!!!!

Memory tip for EGFR inhibitor toxicity

EGFR - EpiDERMal = Acneiform rash!

HER2 inhibitors Agents/classes

ADCs and mAbs !!

• mAbs = Trastuzumab (Herceptin)

Common uses:

• Breast cancer

• Gastric cancer

• Endometrial cancer

HER2 inhibitors MOA

• HER2 can be overepxressed on the tumor cell surface (gene amplification causes OR mutation)

• mAbs MOA

  • Bind EXTRACELLULARLY and Interfere with DIMERIZATION —→ Receptor internalizes and degrades —→ reduced cancer cell growth and survival

  • ADCC activates Natural Killer cells —→ causes cancer cell lysis

How do TKIs work in relation to the HER2 receptors on the outside of cancer cells?

They bind to the intracellular domain of HER2 receptors and BLOCK DOWNSTREAM signaling

HER2 inhibitors (Trastuzumab) class wide toxicities AND RBS

Common

• Fatigue, HA, NVD, weakness

RBS

• Cardiomyopathy - Type II (reversible)

  • Risk factors: anthracyclines, prior radiation, advanced age, smoking, DM, etc

• Infusion related reactions (mABs)

• Birth defects

Trastuzumab toxicities

• Pulmonary toxicity

• Renal toxicity

• NOT interchangeable with other trastuzumab forms

Anaplastic Lymphoma Kinase (ALK) inhibitors agents

• Crizotinib

Common uses

• NSCLC

ALK inhibitors (Crizotinib) MOA

• How does ALK normally work?

  • Translocation/mutations within the ALK gene —→ expression of oncogenic fusion protein —→ increased cancer cell growth and survival

• How do ALK inhibitors work?

  • Bind INTRACELLULARLY —→ inhibit downstream signaling pathways —→ reduces cell proliferation/growth

ALK inhibitors (Crizotinib) Common toxicities AND RBS

Common

• Moderate-High emetic risk

• Diarrhea/constipation

• Anorexia

• Fatigue, Vision problems

RBS

• Hepatotoxicity

• Bradycardia

• Interstitial lung disease

• QTc prolongation

VEGF inhibitors Agents

• Bevacizumab

Common uses

• Colorectal, Renal cell, GYN, CNS tumors, Thyroid, Sarcoma, GI stromal, Neuroendocrine

How does VEGF relate to angiogenesis? (Creation of new blood vessels)

Tumors can secrete VEGF —→ which increases blood vessel expression and movement to the tumor cell —→ Tumor has increased blood supply

VEGF inhibitors (Bevacizumab) MOA

• Tumors have unregulated VEGF

• VEGF inhibitors work by BINDING AND NEUTRALIZING VEGF —→ inhibits new vessel growth and causes regression of newly formed tumor vessels

VEGF class wide toxicities AND RBS

Common

• Hypertension

• Proteinuria

• Hemorrhage

RBS

• VTE (embolisms!!!!)

• Heart Failure

• GI perforation!!

• Wound healing complications

• HFS and Hepatotoxicity

BRAF inhibitors and MEK inhibitors Agents

BRAF

• Dabrafenib

MEK inhibitors

• Trametinib

Common uses

• Melanoma

• NSCLC

• Thyroid

BRAF inhibitors (Dabrafenib) class wide toxicities AND RBS

Common

• Dermatologic toxicity (Hyperkeratosis, rash, photosensitivity)

• Arthralgia

• Alopecia

• Fatigue, HA

RBS (think Skin)

• Secondary Malignancies (Cutaneous SCC, Melanoma, SCC head and Neck cancers)

• QTc prolongation

• Ocular toxicitiy

BRAF - “BE RASH”

MEK inhibitors (Trametinib) class wide toxicities and RBS

Common

• Dermatologic toxicity (Like BRAF)

• Diarrhea

RBS

• Cardiomyopathy (Monitor LVEF)

• HTN

• Hemorrhage

• Hepatotoxic

• Ocular toxicity

Poly ADP ribose polymerase (PARP) Inhibitors Agents

• Olaparib

Common uses

• GYN (BRCA +)

• Breast (BRCA +)

• Prostate (BRCA +)
  Pancreatic (BRCA +)

PARP inhibitors (Olaparib) MOA

• Inhibits PARP enzyme that is involved in repair of single and double strand DNA breaks of the following:

  • Base excision repair // homologous recombination // NHEJ and MMEJ

  • Germline/somatic mutations in BRCA and other enzymes impair homologous recombination + added PARP inhibition - can lead to “synthetic lethality”

• Inhibiting the DNA repair enzyme (PARP) leads to cell death by DNA damage of cancer cells

PARP inhibitors (Olaparib) class wide toxicities and RBS

Common

• Fatigue, NV

RBS

• Myelosuppression

  • Anemia, thrombocytopenia, Neutropenia (grade 3 = 10%)

• Secondary Malignancy (MDS/AML)

CDK 4/6 inhibitors agents

• Palbociclib

Common uses

• Breast cancer

CDK 4/6 inhibitors (Palbociclib) MOA + common toxicities/RBS

• Inhibits CDK 4/6 which prevents phosphorylation of retinoblastoma (Rb) —→ arrests cell cycle —→ Reduces cell proliferation

Common

• Fatigue, HA

RBS

• Myelosuppression, Infections, diarrhea, hepatotoxic

Immune Checkpoint Inhibitors Agents

• PD-1 inhibitors (Nivolumab (opdivo))

• PD-L1 inhibitors

• CTLA-4 inhibitors

• Dual-target

What is the Immunoediting hypothesis?

The immune system can either protect the host against tumor cells and suppress tumor growth (anti-inflammatory environment / prevent viral-induced tumors) OR promote tumor progression (selects more fit cells, Establishes tumor microenvironment)

Immune system shapes tumor immunogenicity

The ELIMINATION vs ESCAPE concepts

Elimination vs Escape concepts in regard to immunotherapy /cancers

Tumor cells can express antigens that activate T cells which can kill the cancer cells

OR/AND

Tumor can recruit immunosuppressive cells/cytokines and express negative co-stimulatory molecules —→ Tumors circumvent/avoid the immune system destruction

Immune Checkpoint Inhibitors MOA (Nivolumab - PD-1 inhibitor)

• PD-1 ligands on cancer cells normally bind to PD-1 receptors on T-cells and inhibit T cell proliferation/Cytokine production —→ causes cancer cell to survive BC T-cell surveillance of tumor cells fails

• Nivolumab binds to the PD-1 receptor —→ blocks PD-1 ligand Binding —→ Increases Anti-tumor T cell activity

Immune Checkpoint Inhibitors (Nivolumab - PD-1 inhibitor) class-wide toxicities AND RBS

Common

• fatigue, cough

RBS

• Infusion related reactions (18%)

• Immune related Adverse Events

  • Dermatitis, Endocrinopathies, colitis, nephritis, hepatitis, Pneumonitis

  • Treat with Corticosteroids

What Acronym can be used to remember Immune Checkpoint Inhibitor therapy Adverse effects? (REMEMBER - Spell it backwards for chronological Side effect timeline)

LEGS!!

• L = Liver (hepatitis) / Lungs (pneumonitis)

• E = Endocrine (Hypothyroidism/Hypophysitis)

• G = GI (colitis)

• S = Skin (Dermatitis)
  
  

SGEL is CHRONOLOGICAL ORDER