Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small...

Area of Science:

• Oncology
• Molecular Diagnostics
• Thoracic Surgery

Background:

• ALK rearrangement detection via FISH is standard for identifying non-small cell lung cancer (NSCLC) patients eligible for ALK inhibitor therapy.
• Recent studies indicate ALK protein expression, assessed by immunohistochemistry (IHC), has predictive value in resectable NSCLC.

Purpose of the Study:

• To evaluate tumor response and survival rates in advanced NSCLC patients treated with crizotinib.
• To compare the efficacy of dichotomous IHC staining versus FISH for detecting ALK activation.

Main Methods:

• Patients with stage IV NSCLC treated with crizotinib were analyzed.
• ALK rearrangements were detected using both FISH and Ventana ALK (D5F3) CDx assay (IHC).
• Validation was performed using external cohorts of ALK-FISH-positive NSCLC patients.

Main Results:

• Dichotomous ALK-IHC outperformed ALK-FISH in predicting tumor response (AUC, 0.86 vs. 0.64) and survival (PFS AUC 0.86 vs. 0.36; OS AUC 0.78 vs. 0.41).
• ALK-IHC-positive patients showed response to crizotinib, except for three with primary resistance.
• No tumor response was observed in ALK-FISH-positive but ALK-IHC-negative patients, confirmed in validation cohorts.

Conclusions:

• Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA for predicting response and survival to crizotinib in advanced NSCLC.
• Clinical guidelines should be adapted to use dichotomous ALK-IHC as a standard companion diagnostic test for patient selection in ALK-targeting therapy.