EGFR inhibitors

Mechanism & Class Overview

• Class mechanism: Target the EGFR tyrosine kinase domain or the extracellular domain; inhibit downstream signaling (RAS/RAF/MEK/ERK, PI3K/AKT).
• Resistance: KRAS/BRAF mutations (bypass EGFR), ↑ EGFR expression, EGFR resistance mutations (especially T790M to 1st-gen, via ↑ ATP affinity; exon 19 deletion/L858R are highly sensitive to 1st-gen; uncommon G719X, L861Q, S768I are less sensitive, afatinib or osimertinib preferred; T790M is sensitive to osimertinib/3rd-gen), c-MET amplification, HER2/HER3 upregulation.

Class Adverse Effects (all EGFR inhibitors)

• Skin toxicity: acneiform, dry, pustular rash with skin cracks, mainly on face and upper trunk, plus photosensitivity and nail changes (paronychia with long-term use). Manage/prevent with topical clindamycin or erythromycin, or oral doxycycline or minocycline.
• Pulmonary toxicity: cough, shortness of breath, and pulmonary infiltrates from interstitial lung disease (ILD); can exacerbate underlying ILD.
• Metabolism: the majority of anti-EGFR small molecules are CYP3A4 substrates, so know the strong inducers and inhibitors (table below).

Anti-EGFR Monoclonal Antibodies

Cetuximab (Erbitux)

• Mechanism: IgG1 chimeric mAb against the extracellular part of EGFR → ↓ homo- and heterodimerization → ↓ EGFR signaling; induces ADCC. RAS-wild-type restriction applies to cetuximab in CRC, not to its head & neck indications. Also FDA-approved (accelerated, Jun 2024) with adagrasib for previously treated KRAS G12C-mutant mCRC (KRYSTAL-1). Resistance via EGFR mutation (↓ binding), ↓ EGFR expression, mutant KRAS/NRAS/BRAF, ↑ HER2/HER3.
• Indications: CRC (RAS wild-type; BRAF V600E with encorafenib), head & neck cancer.
• Toxicities: Acneiform rash (a marker of clinical activity that correlates with improved survival), infusion reactions (from the chimeric portion; ~20% of patients in the southeastern US have pre-existing IgE antibodies to the drug's oligosaccharide (alpha-gal), raising the rate and severity of infusion reactions; premedicate with diphenhydramine), hypomagnesemia (monitor Mg; supplement if low), diarrhea, fatigue, paronychia (long term), pulmonary toxicity/ILD.

Panitumumab (Vectibix)

• Mechanism: Fully human IgG2 mAb against EGFR (mechanism and resistance similar to cetuximab).
• Indications: CRC (RAS wild-type; KRAS G12C with sotorasib).
• Toxicities: Acneiform rash, hypomagnesemia, diarrhea, fatigue, paronychia (long term), pulmonary toxicity/ILD; infusion reactions less common than with cetuximab (fully human).

Necitumumab (Portrazza)

• Mechanism: Recombinant human mAb against EGFR.
• Indications: Squamous NSCLC (with gemcitabine/cisplatin).
• Toxicities: Rash, hypomagnesemia, thromboembolic events (↑ risk), infusion reactions.

1st Generation EGFR TKIs (Reversible)

Erlotinib (Tarceva)

• Mechanism: Reversible small-molecule TKI; inhibits EGFR tyrosine kinase. Binds EGFR wt and exon 19 deletion/L858R (exon 21) mutations → ↓ antiapoptotic enzymes → ↓ proliferation/angiogenesis.
• Resistance: KRAS mutation, ↑ EGFR expression, EGFR T790M (gatekeeper; ↑ ATP affinity, not ↓ drug binding), BRAF mutation, c-MET, HER2.
• Pharmacokinetics: Hepatic metabolism (CYP3A4); take on an empty stomach. Avoid PPIs/H2 blockers (↑ pH ↓ absorption); PPI separation does not overcome the interaction; for an H2 blocker, take erlotinib 10 h after and ≥ 2 h before the next H2 dose; separate antacids by several hours. Less active in smokers (↑ CYP1A2 metabolism).
• Toxicities: Acneiform rash, nail changes, skin cracks, radiation-recall skin reactions, ↑ hair fragility, hirsutism, ↑ eyelash/eyebrow thickness, alopecia, diarrhea, ↑ LFTs, pulmonary toxicity (ILD: cough, SOB), GI bleed, keratoconjunctivitis.

Gefitinib (Iressa)

• Mechanism: Reversible EGFR TKI (wt and exon 19 deletion/L858R); similar to erlotinib.
• Indications: NSCLC (EGFR-mutant).
• Pharmacokinetics: CYP3A4 metabolism (↑ gefitinib dose if on a strong inducer such as phenytoin); ↑ INR on warfarin; take with or without food; avoid PPIs if possible (if needed, give gefitinib 12 h before or after the PPI); separate H2 blockers and antacids by 6 h.
• Toxicities: Acneiform rash, HTN, ILD (cough, SOB), ↓ appetite, mild N/V, ↑ LFTs, keratoconjunctivitis, weakness.

2nd Generation EGFR TKIs (Irreversible, Pan-HER)

Afatinib (Gilotrif)

• Mechanism: Irreversible pan-HER (EGFR, HER2, HER4) TKI → ↓ ErbB signaling.
• Indications: NSCLC (EGFR-mutant, especially ex19del or L858R).
• Toxicities: Diarrhea (dose-limiting; often severe; loperamide helpful), rash, stomatitis, nail loss, transient ↑ LFTs, hepatotoxicity (rare but severe), keratitis/light sensitivity.

Dacomitinib (Vizimpro)

• Mechanism: Irreversible pan-HER TKI (EGFR with L858R/ex19del, HER2, HER4); not clinically effective against T790M.
• Indications: NSCLC (EGFR ex19del or L858R, first-line).
• Pharmacokinetics: CYP3A4 and CYP2D6 metabolism; no dosage modification for hepatic impairment (Child-Pugh A, B, or C); avoid PPIs; give dacomitinib at least 6 h before or 10 h after an H2 blocker; locally acting antacids are an alternative.
• Toxicities: Diarrhea, rash, nausea, palmoplantar keratoderma (hand-foot syndrome variant), stomatitis, ILD.

3rd Generation EGFR TKIs (T790M-Selective)

Osimertinib (Tagrisso)

• Mechanism: Irreversible EGFR TKI; selective for activating mutations (ex19del, L858R) and the T790M resistance mutation; spares wt EGFR (↓ toxicity vs 2nd-gen). Resistance via ↑ c-MET, BRAF mutation, PI3K/AKT activation.
• Indications: NSCLC (T790M+ after 1st-gen EGFR TKI progression; also first-line for EGFR-mutant; benefits CNS metastases via good brain penetration).
• Toxicities: Rash (less frequent/severe than 1st/2nd-gen), diarrhea (milder), myalgias, nausea, cardiotoxicity (↓ LVEF; baseline TTE; assess LVEF if cardiac signs/symptoms; for asymptomatic decrease ≥10 percentage points from baseline AND to <50%, withhold and reassess (resume if recovers to ≥50% and within 10 points of baseline within 4 wk); permanently discontinue for symptomatic CHF), ↑ QTc (periodic EKG; hold if QTc >500 ms; correct electrolytes), atrial fibrillation, ILD.

Advanced Anti-EGFR Agents

Amivantamab (Rybrevant)

• Mechanism: Bispecific mAb; targets the EGFR extracellular domain + MET; blocks ligand binding, induces ADCC, promotes EGFR/MET receptor degradation, and recruits immune effectors (ADCC, trogocytosis).
• Indications: NSCLC: EGFR exon 20 insertion (1L with carbo/pem; monotherapy after platinum); 1L ex19del/L858R with lazertinib (MARIPOSA); after osimertinib with carbo/pem (MARIPOSA-2).
• Toxicities: Infusion reactions (common; premedicate), rash, ↑ creatinine (reversible; monitor), nausea, fatigue.

Mobocertinib (Exkivity)

• Mechanism: Selective EGFR exon 20 insertion TKI.
• Indications: NSCLC (EGFR exon 20 insertion) progressed on or after platinum-based chemotherapy. Withdrawn from the US market Oct 2023 (EXCLAIM-2 failed); FDA accelerated approval formally withdrawn Jul 15, 2024.
• Toxicities: Diarrhea (dose-limiting; severe), rash, nail changes, stomatitis, ↑ LFTs.

2026 update: 1L EGFR-mutant NSCLC combinations + adjuvant expansion

Osimertinib: expanded roles

• FLAURA2 (Planchard NEJM 2023): 1L osimertinib + carbo/pem vs osimertinib in EGFR-mutant (ex19del or L858R) advanced NSCLC; mPFS 25.5 vs 16.7 mo (HR 0.62). FDA Feb 16, 2024 approved the combination for 1L.
• ADAURA (Wu NEJM 2020; OS update Tsuboi NEJM 2023): 3 yr adjuvant osimertinib after resection of EGFR-mutant stage IB to IIIA NSCLC; DFS HR 0.27; OS HR 0.49 (5-yr OS 88% vs 78%). Standard of care.
• LAURA (Lu NEJM 2024): consolidation osimertinib after concurrent chemoradiation in unresectable stage III EGFR-mutant NSCLC; mPFS 39.1 vs 5.6 mo (HR 0.16). FDA Sep 25, 2024 approval, new SOC (durvalumab consolidation is less effective in EGFR-mutant disease).

Amivantamab: EGFR × MET bispecific mAb (expanded)

• PAPILLON (Zhou NEJM 2023): amivantamab + carbo/pem vs carbo/pem in 1L EGFR exon 20 insertion NSCLC; mPFS 11.4 vs 6.7 mo (HR 0.40). FDA Mar 1, 2024 1L approval, new SOC for ex20ins.
• MARIPOSA (Cho NEJM 2024): amivantamab + lazertinib (3G EGFR TKI) vs osimertinib in 1L EGFR-mutant (ex19del/L858R) advanced NSCLC; mPFS 23.7 vs 16.6 mo (HR 0.70). FDA Aug 19, 2024 combination approved 1L. Trade-offs: more skin/nail/paronychia/DVT vs osimertinib.
• MARIPOSA-2 (Passaro Ann Oncol 2024): 2L amivantamab + carbo/pem after osimertinib progression: mPFS 6.3 vs 4.2 mo (amivantamab + lazertinib + chemo 8.3 mo). FDA Sep 19, 2024 approval covers amivantamab + carbo/pem, not the lazertinib regimen. FDA Sep 19, 2024 2L approval post-osimertinib.
• PALOMA-3: subcutaneous amivantamab non-inferior PK to IV, with fewer infusion-related reactions. FDA Dec 17, 2025 approval (Rybrevant Faspro), a 5-min SC injection replacing the multi-hour IV.

EGFR-TKI resistance: MET amplification

• SAVANNAH (osimertinib + savolitinib) / INSIGHT-2 (osimertinib + tepotinib), MET TKIs, for MET-amplified acquired resistance post-osimertinib; ORR ~56% in the SAVANNAH high-MET population (IHC 3+ in ≥90% and/or FISH ≥10) and ~50% in the INSIGHT-2 FISH-confirmed MET-amplified population. Regulatory decisions pending.
• Telisotuzumab vedotin (Emrelis), a c-Met ADC: FDA May 14, 2025 accelerated for c-Met-overexpressing EGFR-wt NSCLC (LUMINOSITY). First c-Met-directed ADC. Selection by c-Met IHC protein overexpression, not MET amplification; not an EGFR-TKI-resistance therapy.
• Datopotamab deruxtecan (Datroway), a TROP2 ADC: FDA Jun 2025 accelerated approval for EGFR-mutated NSCLC after EGFR-directed therapy and platinum chemo.

Exon 20 insertion (updates)

• Sunvozertinib (Zegfrovy): irreversible EGFR-ex20 TKI. WU-KONG1B → FDA Jul 2, 2025 accelerated approval (WU-KONG6 supported the earlier Chinese approval) for 2L+ EGFR-ex20 NSCLC. Chinese approval preceded.
• Mobocertinib (Exkivity): withdrawn from the US market Oct 2023 after the confirmatory EXCLAIM-2 trial was negative.

KRAS-G12C in NSCLC (adjacent class)

• Sotorasib CodeBreaK 200 (de Langen Lancet 2023): PFS benefit over docetaxel in pretreated KRAS-G12C NSCLC. Adagrasib (Krazati) KRYSTAL-1 (Janne NEJM 2022, mature 2024) with better CNS activity. Adagrasib + pembro in 1L KRAS-G12C PD-L1 ≥50% under study.