ErlotinibEdit

Erlotinib is an oral small-molecule anticancer medication that inhibits the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase involved in signaling pathways that promote tumor cell proliferation, survival, and metastasis. Sold under the brand name Tarceva by Genentech and Roche in many markets, erlotinib is a tyrosine-kinase inhibitor (TKI) that specifically targets the ATP-binding site of EGFR, thereby blocking downstream signaling such as the RAS-RAF-MAPK and PI3K-AKT pathways. The drug has become an example of how molecular characteristics of a tumor can guide therapy, though its clinical value varies by cancer type, smoking status, and molecular mutations.

Erlotinib's development and clinical use sit at the intersection of precision medicine, patient access, and pharmacoeconomics. While it can provide meaningful benefit for selected patients, especially those whose tumors harbor certain activating EGFR mutations, its performance in broader, unselected populations has been more modest. The therapy has also highlighted the evolution of cancer treatment from broad cytotoxic regimens to targeted approaches, and it has sparked ongoing discussions about pricing, access, and the real-world value of targeted drugs.

Mechanism of action

Erlotinib binds reversibly to the intracellular tyrosine kinase domain of EGFR (also known as HER1), inhibiting phosphorylation and activation of the receptor. By preventing EGFR autophosphorylation, erlotinib disrupts signaling cascades that drive tumor cell proliferation and survival. Tumors with activating EGFR mutations—such as certain exon 19 deletions or the L858R substitution in exon 21—are particularly susceptible to EGFR inhibition, which can translate into higher response rates and longer progression-free survival in those patients. See also EGFR mutations for details.

Medical uses

Erlotinib is approved for several indications, with its efficacy closely tied to the molecular profile of the tumor.

Non-small cell lung cancer (NSCLC)—In patients with NSCLC whose tumors harbor activating EGFR mutations, erlotinib is an effective targeted therapy and may be used as initial therapy in mutation-positive disease. In broader NSCLC populations without known EGFR mutations, benefit is typically smaller, reflecting ongoing heterogeneity in tumor biology. See non-small cell lung cancer for context.
Pancreatic cancer—Erlotinib in combination with gemcitabine has been used for locally advanced or metastatic pancreatic cancer, offering a modest improvement in survival compared with gemcitabine alone in some settings. See pancreatic cancer for background.

Other uses have been explored in clinical trials, and erlotinib remains a reference point in discussions about targeted agents and companion diagnostics.

Dosing and administration

Erlotinib is taken orally, usually once daily. The standard dose and adjustments depend on liver function, concomitant medications, and tolerance. Because erlotinib is metabolized by liver enzymes, strong inhibitors or inducers of CYP3A4 can affect drug exposure; care is taken to manage potential drug interactions with agents such as certain antifungals, anticonvulsants, and other commonly prescribed drugs. See sections on pharmacokinetics and [drug interactions]] for details.

Adverse effects

As a targeted therapy, erlotinib has a characteristic profile of side effects:

Dermatologic: A common acneiform eruption or rash, often appearing on the face and upper torso, which may reflect EGFR inhibition in skin cells.
Gastrointestinal: Diarrhea, nausea, and decreased appetite are seen in some patients.
Fatigue and weakness: Generalized tiredness can occur and may affect quality of life.
Other risks: Interstitial lung disease (rare but serious), hepatic enzyme elevations, and electrolyte disturbances such as hypomagnesemia can occur in some cases.

The risk–benefit balance of erlotinib is frequently assessed in relation to individual tumor biology, prior therapies, and patient comorbidities.

Pharmacokinetics

Oral bioavailability of erlotinib is influenced by food intake and hepatic metabolism. The drug is primarily metabolized by hepatic enzymes, notably CYP3A4, and drug–drug interactions can significantly alter plasma levels. It has a relatively long half-life that supports once-daily dosing but requires monitoring for hepatic and renal function in long-term use. See pharmacokinetics for a comprehensive overview.

Resistance and limitations

Resistance to EGFR TKIs, including erlotinib, is a recognized issue. Acquired resistance frequently involves secondary mutations in EGFR (for example, disruptions in the binding pocket such as T790M in some settings) or activation of alternative signaling pathways that bypass EGFR dependence. Primary resistance can occur in tumors lacking activating EGFR mutations or with other molecular drivers that override EGFR signaling. Ongoing research aims to overcome resistance through combination therapies and next-generation TKIs.

History and regulatory status

Erlotinib was developed as part of the wave of targeted cancer therapies that emerged in the early 2000s. It received FDA approval in 2004 for locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy and later gained approval for pancreatic cancer in combination with gemcitabine in the mid-2000s. Brand-name Tarceva remain a widely recognized reference product, with manufacturing and distribution by Genentech and Roche in many regions. See FDA for regulatory history and tarceva for the brand name provenance.

The drug’s commercialization has intersected with debates about drug pricing and patient access, as with many targeted therapies. Generics and alternate pricing models have affected availability in various markets, reflecting broader conversations about pharmaceutical innovation, patent life, and therapeutic value. See cost of cancer drugs and generic drug for related topics.

Controversies and debates

Value in unselected populations: While erlotinib shows clear benefit for patients with activating EGFR mutations, its benefit in unselected NSCLC populations is less certain, leading to discussions about the appropriate use of molecular testing and the allocation of resources.
Pricing and access: The introduction of high-cost targeted therapies has prompted ongoing debates about what constitutes fair pricing, how to balance innovation with patient access, and how to structure reimbursement policies. See pharmacoeconomics and cost of cancer drugs for broader context.
Biomarker-driven therapy: The success of erlotinib in mutation-selected subgroups reinforces the push toward companion diagnostics and precision medicine. Critics and proponents alike weigh the costs and practicality of widespread molecular testing in real-world settings. See EGFR mutation and companion diagnostic for related topics.