ALK inhibitors

Mechanism & Class Overview

• Class mechanism: Inhibit ALK tyrosine kinase with variable off-target activity (c-MET, ROS1, RON); ↓ angiogenesis and ↓ tumor growth (downstream ↓ STAT3 and AKT).
• Resistance: ALK kinase domain mutations (L1196M, G1269A to 1st-gen; G1202R and I1171N/S/T to 2nd-gen; L1198F to lorlatinib), activation of EGFR/ROS1/MET/HGF or MEK/SRC pathways, P-glycoprotein (P170) efflux, and reduced CNS penetration (the brain acts as a sanctuary site).
• Class toxicities: All ALK inhibitors can cause pulmonary toxicity (cough, SOB, infiltrates from ILD/pneumonitis) and can exacerbate underlying ILD. They are CYP3A4 substrates, so know the strong inducers and inhibitors (table below).

1st Generation ALK Inhibitor

Crizotinib (Xalkori)

• Mechanism: Inhibits ALK plus c-MET, ROS1, RON tyrosine kinases.
• Indications: NSCLC (ALK+ or ROS1+; see PROFILE 1014), ALK+ anaplastic large cell lymphoma (pediatric and young adult), ALK+ inflammatory myofibroblastic tumor.
• Pharmacokinetics: Hepatic metabolism (CYP3A4/5; azoles, phenytoin, warfarin interactions). Take with or without food; PPIs have no clinically significant effect. Predominantly hepatic metabolism (CYP3A) with mainly fecal elimination; still dose reduce to 250 mg once daily if CrCl <30 not on dialysis. Half-life ~42h.
• Toxicities: ↑ QTc (monitor EKG), ↑ LFTs (can cause fatal hepatotoxicity; monitor AST/ALT), visual defects (floaters, flashes, blurred/double vision, reduced acuity, photopsia; can cause retinal detachment, refer to ophthalmology, avoid driving/machinery), Grade 3 bradycardia (monitor HR), hypogonadism (↓ testosterone in male patients), peripheral neuropathy, ILD/pneumonitis, N/V/D, peripheral edema, constipation.

2nd Generation ALK Inhibitors (ceritinib, alectinib, brigatinib, ensartinib; lorlatinib is 3rd generation)

Ceritinib (Zykadia)

• Mechanism: ALK TKI (also ROS1, IGF-1R, insulin receptor; unlike crizotinib, does not meaningfully inhibit MET); more potent than crizotinib with some CNS penetration; remains active against L1196M and G1269A. Resistance via other ALK mutations, MEK/SRC activation, P170 MDR phenotype.
• Indications: NSCLC (ALK+, first-line per ASCEND-4, or after crizotinib). Dose 450 mg once daily with food.
• Toxicities: Diarrhea (frequent, severe; antidiarrheals), nausea, vomiting, abdominal pain, ↑ LFTs, fatigue, visual changes, ↑ QT, and hyperglycemia (from IGF-1R blockade).

Alectinib (Alecensa)

• Mechanism: Selective ALK (and RET) TKI → ↓ STAT3 and AKT; excellent CNS penetration (preferred for CNS metastases). Resistance via ALK G1202R/I1171N and ↑ MET/HGF or NRG1-HER3-EGFR pathways.
• Indications: NSCLC (ALK+, first-line or crizotinib-refractory; see ALEX).
• Pharmacokinetics: CYP3A4 metabolism to active M4; high-fat food alters concentration; watch warfarin (may need INR-guided dose adjustment). Half-life ~32h.
• Toxicities: Constipation, myalgia, fatigue, muscle weakness, peripheral edema, ↑ LFTs (↑ bilirubin), bradycardia, rash, ILD/pneumonitis.

Brigatinib (Alunbrig)

• Mechanism: ALK TKI (also IGF-1R, ROS1, FLT3, EGFR); good CNS penetration. Resistance with combined L1196M + G1202R.
• Indications: NSCLC (ALK+ metastatic, first-line per ALTA-1L, or after crizotinib).
• Pharmacokinetics: CYP3A4 and CYP2C8 metabolism.
• Toxicities: Hypertension and bradycardia (no clinically relevant QT prolongation, unlike crizotinib/ceritinib), ↑ LFTs (can be fatal), hyperglycemia (IGF-1R blockade), ↑ amylase/lipase, CPK elevation (myositis; monitor CK), ILD/pneumonitis (an early-onset pulmonary event can occur; rare but severe).

Lorlatinib (Lorbrena)

• Mechanism: Selective ALK (and ROS1) TKI; excellent CNS penetration; active against L1196M, G1202R, and other resistance mutations (resistance via L1198F).
• Indications: NSCLC (ALK+ with or without resistance mutations; first-line or after prior ALK TKIs; see CROWN). Not affected by food.
• Toxicities: Hypercholesterolemia/hypertriglyceridemia (monitor lipids; statin often needed), hypertension, peripheral neuropathy, cardiac conduction effects (↑ PR interval progressing to AV block; obtain baseline EKG), peripheral edema, mood/behavioral/cognitive CNS changes (from strong BBB penetration: confusion, mood changes, hallucinations, seizure), weight gain, ↑ LFTs, ILD/pneumonitis. Teratogenic (use contraception; no breastfeeding).

Ensartinib (Ensacove)

• Mechanism: ALK TKI; covers some resistance mutations.
• Indications: NSCLC (ALK+, ALK-inhibitor-naive, including after chemotherapy; eXalt3 vs crizotinib; FDA Dec 2024).
• Toxicities: Rash, hypertension, GI toxicity, CPK elevation, peripheral neuropathy.

2026 update: adjuvant + long-term outcomes

Alectinib: new adjuvant indication

• ALINA (Wu NEJM 2024): 2 yr adjuvant alectinib vs platinum chemo after complete resection of ALK+ stage IB (≥4 cm) to IIIA NSCLC. 2-yr DFS 93.8% vs 63.0% in stage II to IIIA (HR 0.24; primary endpoint) and 93.6% vs 63.7% in the ITT stage IB to IIIA population (HR 0.24). CNS-DFS also strongly in favor. FDA Apr 18, 2024 adjuvant approval, the first targeted adjuvant for ALK+ NSCLC.

Lorlatinib: 5-year CROWN update

• CROWN 5-yr update (Solomon JCO 2024): 5-yr PFS 60% (lorlatinib) vs 8% (crizotinib) in 1L ALK+ advanced NSCLC; the longest PFS of any ALK-TKI to date. mPFS still not reached at 5 yr. Freedom from intracranial progression ~92% at 5 yr (time to intracranial progression, not CNS PFS). Establishes lorlatinib as a preferred 1L option for many patients (especially brain mets or high-risk).

4th-gen ALK TKI (investigational)

• NVL-655 (neladalkib): macrocyclic ALK TKI selective for TKI-resistant mutations (especially compound mutations) with brain penetration; ALKOVE-1 phase 1/2 ongoing; regulatory filing anticipated.

Long-term class pearls

• Lorlatinib CNS-cognitive/mood AEs are manageable with dose reduction; hyperlipidemia often needs a statin.
• ROS1 splits from ALK: repotrectinib (Augtyro; FDA Nov 15, 2023), ROS1 and TRK (NTRK) inhibitor; approved for ROS1+ NSCLC in both TKI-naive and previously treated disease (TRIDENT-1), not only after crizotinib/entrectinib. Also approved: taletrectinib (Ibtrozi; FDA Jun 2025) and zidesamtinib (Jideytro; FDA Jul 2026, after a prior ROS1 TKI).