Background
Phase I expansion cohort (PROFILE 1001); N=50; ROS1-rearranged advanced NSCLC; mostly previously treated (~80% prior platinum-based chemo, 14% treatment-naïve). Long-term update reported 2019 (Shaw, Ann Oncol, PMID 30980071).
Interventions and follow up
Treatment: Crizotinib 250mg PO twice daily
Primary endpoint: Objective response rate (ORR)
Primary endpoint: Objective response rate (ORR)
Results
ORR: 72%
mDOR: 24.7mo
mPFS: 19.3mo
mOS: 51.4mo
OS rates (12/24/36/48mo): 79% / 67% / 53% / 51%
mDOR: 24.7mo
mPFS: 19.3mo
mOS: 51.4mo
OS rates (12/24/36/48mo): 79% / 67% / 53% / 51%
Adverse events
Ocular: Vision changes 87% (any grade)
GI: Nausea 51%, vomiting 38%, diarrhea 45%
Grade ≥3: Hypophosphatemia 15%, vomiting 4%, elevated LFTs 4%
Labeling warnings: ↑QTc, hepatotoxicity (can be fatal), visual disorders/retinal effects, peripheral neuropathy, pneumonitis/ILD, ↓testosterone
GI: Nausea 51%, vomiting 38%, diarrhea 45%
Grade ≥3: Hypophosphatemia 15%, vomiting 4%, elevated LFTs 4%
Labeling warnings: ↑QTc, hepatotoxicity (can be fatal), visual disorders/retinal effects, peripheral neuropathy, pneumonitis/ILD, ↓testosterone
Conclusions
Crizotinib produced durable responses and prolonged survival in ROS1-rearranged advanced NSCLC, establishing it as an effective targeted therapy for this molecular subset.
Key Limitations
Single-arm, small (N=50), nonrandomized phase I cohort; limited CNS penetration (poor intracranial control vs newer agents); no comparator.
Clinical Context
FDA approved crizotinib for ROS1-positive metastatic NSCLC (Mar 2016); EMA approved 2016. ESMO lists ROS1 TKIs as first-line standard; entrectinib favored when CNS disease present given superior intracranial activity.
References
Shaw AT, et al, NEJM, 2014, PMID: 25264305; Shaw AT et al, Ann Oncol, 2019, PMID: 30980071