Alectinib or lorlatinib as first-line?

Both are FDA-approved first-line. Lorlatinib showed the deepest PFS in CROWN (median not reached at 5 years) and superior CNS efficacy, but it carries a sharper neurocognitive and metabolic AE profile (mood changes, hypercholesterolemia). Alectinib remains a strong choice with a more tolerable profile. Patient comorbidities and CNS disease guide the call.

What about crizotinib?

Crizotinib was the original ALK TKI and has been largely displaced by alectinib, brigatinib, and lorlatinib as first-line due to superior efficacy and CNS penetration. Crizotinib remains an option in specific contexts where access or AE profile favors it.

Does ALK fusion testing need to be done up front?

Yes. Current NCCN guidance recommends molecular testing for all stage IV non-squamous NSCLC, including ALK, EGFR, ROS1, KRAS G12C, BRAF, HER2, MET, RET, NTRK. Up-front comprehensive NGS is the most efficient path. (NCCN content is licensed; UNMIRI does not paraphrase NCCN guidelines in product output.)

Are ALK-positive patients candidates for immune checkpoint monotherapy?

No. ALK fusion-positive NSCLC responds poorly to single-agent PD-1 / PD-L1 inhibitors. Combinations have raised toxicity concerns. Targeted therapy with an ALK TKI is the standard, with immunotherapy reserved for after TKI exhaustion in select contexts.

Variant cheat sheet · NSCLC

ALK fusions in non-small cell lung cancer

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

ALK fusion-positive NSCLC is AMP/ASCO/CAP Tier I-A. First-line standard is alectinib or lorlatinib, both with FDA-approved companion diagnostics. Lorlatinib has the deepest CNS penetrance and the longest progression-free survival in CROWN, but a sharper neurocognitive AE profile. ALK G1202R is the dominant resistance allele on second-generation TKIs; lorlatinib covers it.

Biology

ALK (Anaplastic Lymphoma Kinase) fusions arise from inversions or translocations on chromosome 2 that fuse the ALK kinase domain to a partner gene (most commonly EML4). The resulting fusion protein is a constitutively-active receptor tyrosine kinase that drives MAPK, PI3K/AKT, and JAK/STAT signaling. Fusions are mutually exclusive with EGFR, KRAS, and most other oncogenic drivers in NSCLC.

Epidemiology

ALK fusions occur in roughly 3-7% of NSCLC, enriched in adenocarcinoma, never-smokers or light-smokers, and younger patients. EML4-ALK is the most common partner (~80%), with multiple variants (v1, v3, etc.) that have modest prognostic differences on TKI sensitivity.

Detection

IHC (Ventana ALK D5F3): high sensitivity, often used as screen.
FISH (Vysis ALK Break Apart): companion diagnostic for crizotinib.
RNA NGS or DNA NGS with fusion calling: comprehensive vendor panels (Foundation Medicine F1CDx, Tempus xT, Caris MI Profile) report fusion partner and breakpoint.
Plasma circulating tumor DNA detection improving; tissue remains gold standard.

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Alectinib	First-line ALK+ metastatic NSCLC	1L	I-A
Lorlatinib	First-line ALK+ metastatic NSCLC (CROWN); also post-second-gen-TKI	1L / later-line	I-A
Brigatinib	ALK+ NSCLC, including post-crizotinib	1L / 2L	I-A
Ceritinib	ALK+ NSCLC, post-crizotinib	2L	I-A
Crizotinib	Historical 1L, largely displaced by 2nd/3rd-gen TKIs	Historical	I-A

Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.

Resistance pathways

ALK G1202R: dominant on-target resistance allele after second-generation TKIs. Lorlatinib retains activity.
ALK L1196M, F1174L, I1171N/T: secondary kinase-domain mutations, partner- and TKI-specific.
Bypass-track activation (MET amplification, EGFR pathway): more common in later-line settings. Triggers combination strategies.
Lineage plasticity / small-cell transformation: rare but documented; requires re-biopsy.

Pharmacogenomics

ALK TKIs interact with CYP3A4. Lorlatinib is a CYP3A4 inducer (auto-induction of its own metabolism). Co-administration of strong CYP3A4 inhibitors (ketoconazole, ritonavir) or inducers (rifampin, St. John's wort) is contraindicated or requires dose modification. No CPIC-level pharmacogenomic guideline currently mandates germline testing before ALK TKI initiation.

Caveats

Cheat-sheet content is current to AMP/ASCO/CAP 2017 tiering and FDA-approved labels at time of last update. Clinical decision-making must factor patient-specific comorbidities, CNS disease status (lorlatinib's CNS efficacy is a major decision lever), and tolerability. Synthetic data — educational use only.

Frequently asked questions

Alectinib or lorlatinib as first-line?: Both are FDA-approved first-line. Lorlatinib showed the deepest PFS in CROWN (median not reached at 5 years) and superior CNS efficacy, but it carries a sharper neurocognitive and metabolic AE profile (mood changes, hypercholesterolemia). Alectinib remains a strong choice with a more tolerable profile. Patient comorbidities and CNS disease guide the call.
What about crizotinib?: Crizotinib was the original ALK TKI and has been largely displaced by alectinib, brigatinib, and lorlatinib as first-line due to superior efficacy and CNS penetration. Crizotinib remains an option in specific contexts where access or AE profile favors it.
Does ALK fusion testing need to be done up front?: Yes. Current NCCN guidance recommends molecular testing for all stage IV non-squamous NSCLC, including ALK, EGFR, ROS1, KRAS G12C, BRAF, HER2, MET, RET, NTRK. Up-front comprehensive NGS is the most efficient path. (NCCN content is licensed; UNMIRI does not paraphrase NCCN guidelines in product output.)
Are ALK-positive patients candidates for immune checkpoint monotherapy?: No. ALK fusion-positive NSCLC responds poorly to single-agent PD-1 / PD-L1 inhibitors. Combinations have raised toxicity concerns. Targeted therapy with an ALK TKI is the standard, with immunotherapy reserved for after TKI exhaustion in select contexts.