PI3K inhibitors

Definition and Clinical Importance
PI3K inhibitors are a targeted class of anticancer agents that interfere with the phosphoinositide 3-kinase (PI3K) signaling pathway, a crucial regulator of cell proliferation, survival, metabolism, angiogenesis, and immune response. PI3Ks are lipid kinases that phosphorylate phosphatidylinositol lipids in the cell membrane, leading to activation of downstream pathways such as AKT (Protein kinase B) and mTOR (mechanistic target of rapamycin).

Aberrations in the PI3K/AKT/mTOR axis are implicated in many cancers—including breast cancer, lymphomas, and leukemias—making PI3K an important molecular target for anticancer therapy. Several PI3K inhibitors have gained FDA and EMA approval, especially in hematologic malignancies, and others are in clinical development.

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1. Classification of PI3K Inhibitors

PI3K inhibitors are broadly classified based on their specificity for PI3K isoforms:

A. Pan-PI3K Inhibitors

• Inhibit all class I PI3K isoforms: p110α, p110β, p110γ, p110δ

• Example: Copanlisib

B. Isoform-Selective PI3K Inhibitors

• Target a specific isoform of class I PI3K

• Sub-classified into:

  • PI3K-δ inhibitors: Idelalisib, Umbralisib

  • PI3K-α inhibitors: Alpelisib

  • PI3K-γ/δ dual inhibitors: Duvelisib

C. Dual PI3K/mTOR Inhibitors

• Simultaneously inhibit PI3K isoforms and mTOR kinase

• Mostly under investigation

D. Experimental Allosteric or Covalent Inhibitors

• Bind outside the ATP-binding site or irreversibly inhibit specific isoforms (e.g., nemiralisib)

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2. Mechanism of Action

PI3K inhibitors block the catalytic activity of class I PI3K enzymes, preventing the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3).

Downstream effects include:

• Reduced activation of AKT (protein kinase B)

• Inhibition of mTOR, leading to decreased protein synthesis

• Disruption of cell cycle progression and metabolism

• Enhanced apoptosis and reduced angiogenesis

• Modulation of immune cell activity, particularly B-cell and T-cell signaling

Each isoform plays a distinct role:

• p110α: Frequently mutated in solid tumors (e.g., breast, colon)

• p110δ: Predominant in leukocytes; target in hematologic cancers

• p110γ: Implicated in macrophage and T-cell signaling

• p110β: Functions in PTEN-deficient tumors

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3. Therapeutic Indications

Currently approved PI3K inhibitors are mostly used in hematological malignancies and selected solid tumors. Indications may differ by regulatory agency (e.g., FDA vs EMA).

A. Approved Indications

Drug	Approved Indications
Idelalisib	Relapsed CLL, follicular lymphoma, small lymphocytic lymphoma (SLL)
Copanlisib	Relapsed follicular lymphoma (after ≥2 prior therapies)
Duvelisib	Relapsed/refractory CLL or SLL, follicular lymphoma (withdrawn in US)
Umbralisib	Withdrawn in US (was used for MZL and FL)
Alpelisib	HR+/HER2− PIK3CA-mutated advanced breast cancer (with fulvestrant)

B. Investigational or Off-label Use

• PTEN-deficient cancers (prostate, endometrial)

• Triple-negative breast cancer (TNBC)

• Glioblastoma

• Pancreatic cancer

• Non-Hodgkin lymphoma (various subtypes)

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4. Generic Drug Names and Brand Examples

Generic Name	Brand Name	Isoform Targeted	Administration
Idelalisib	Zydelig	PI3K-δ	Oral
Copanlisib	Aliqopa	PI3K-α and PI3K-δ	Intravenous
Duvelisib	Copiktra	PI3K-δ and PI3K-γ	Oral
Alpelisib	Piqray	PI3K-α	Oral
Umbralisib	Ukoniq (withdrawn)	PI3K-δ and CK1ε	Oral

5. Pharmacokinetics

Drug	Tmax	Half-life	Metabolism	Excretion
Idelalisib	1–2 hrs	~8.2 hrs	CYP3A4	Feces (~78%), urine
Copanlisib	1 hr (IV)	~39 hrs	Mainly CYP3A4	Feces (~64%), urine
Duvelisib	1–2 hrs	~5 hrs	CYP3A4	Feces (~79%), urine
Alpelisib	2–4 hrs	~8–9 hrs	Hydrolysis + CYP3A4	Feces (~81%), urine

6. Adverse Effects

Common Across Class:

• Diarrhea/colitis

• Rash

• Fatigue

• Hyperglycemia (especially with alpelisib)

• Nausea and vomiting

• Stomatitis

• Elevated liver enzymes

• Myelosuppression

Immune-mediated Toxicities:

• Pneumonitis

• Hepatitis

• Severe colitis

• Infections (due to immunosuppression, particularly with PI3K-δ inhibitors)

Black Box Warnings (Idelalisib, Duvelisib):

• Serious and fatal infections

• Severe diarrhea/colitis

• Hepatotoxicity

• Pneumonitis

Unique:

• Alpelisib: Hyperglycemia due to PI3K-α inhibition of insulin signaling

• Copanlisib: Transient hyperglycemia and hypertension (due to PI3K-α inhibition in vasculature and metabolism)

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7. Contraindications

• Hypersensitivity to drug components

• Uncontrolled infections

• Active or latent TB (caution)

• Severe hepatic impairment (drug-dependent)

• Concurrent use with strong CYP3A4 inducers (e.g., rifampin) may reduce efficacy

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8. Precautions and Monitoring

Parameter	Monitoring Frequency
Liver function tests	Baseline, then every 2–4 weeks
Blood glucose (for alpelisib)	Weekly for 4 weeks, then monthly
CBC with differential	Baseline and periodically
Renal function	Baseline and periodically
Signs of infection	Throughout treatment
Pulmonary symptoms	Monitor for interstitial pneumonitis

9. Drug Interactions

Interacting Agent	Effect
CYP3A4 inhibitors (ketoconazole, ritonavir)	↑ plasma levels → toxicity
CYP3A4 inducers (rifampin, phenytoin)	↓ plasma levels → reduced efficacy
Hyperglycemic agents (e.g., insulin, metformin)	Dose adjustment may be needed with alpelisib
QT-prolonging drugs	Use caution with PI3K inhibitors that affect electrolytes

10. Clinical Considerations

• Alpelisib is only indicated in PIK3CA-mutated HR+/HER2− breast cancer; mutation must be confirmed via companion diagnostic (e.g., FoundationOne).

• Due to severe immune-mediated toxicities, PI3K inhibitors in hematology are increasingly restricted to patients who have exhausted other options.

• Duvelisib and Umbralisib were withdrawn from the US market due to toxicity concerns and limited benefit.

• Copanlisib’s IV route and reduced risk of diarrhea may make it preferable in select hematologic cancers.

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11. Summary of Key Agents

Drug	Target	Cancer Type	Key Toxicity
Idelalisib	PI3K-δ	CLL, FL, SLL	Colitis, hepatotoxicity
Duvelisib	PI3K-δ/γ	CLL, FL	Infections, diarrhea
Copanlisib	PI3K-α/δ	Follicular lymphoma	Hyperglycemia, hypertension
Alpelisib	PI3K-α	PIK3CA+ breast cancer (HR+/HER2−)	Hyperglycemia, rash
Umbralisib	PI3K-δ, CK1ε	Withdrawn	Hepatotoxicity, colitis