5840 - Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase 2 clinical trial – Updated progression-free survival, overall survival and mechanisms of resistance

Background

ROS1 fusions are found in 1% of lung cancer patients. EUCROSS is the first prospective European trial to evaluate crizotinib in this patient subset. Here we present an updated analysis of the progression-free survival (PFS), overall survival (OS) and molecular characteristics of progression.

Methods

Multi-centre, single arm phase II trial. Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearrangement. Treatment: 250 mg crizotinib BID. Key endpoints of this report: updated PFS (according to RECIST 1.1) and OS and molecular tumour characterization.

Results

Thirty patients were eligible for response evaluation (N = 30; intention-to-treat population, N = 34). Median follow-up was 44.9 months (95% CI, 39.6-47.4). At data-cut off 19 patients (63.3%) discontinued treatment due to progression or death. Investigator-assessed efficacy: ORR, 70% (95% CI, 51–85; 21/30); disease control rate, 90.0% (95% CI, 73.5-97.9; 27/30); median PFS, 19.4 months (95% CI, 10.1-31.2); 24-months-OS probability, 65.5% (95% CI, 48.3-82.9). Prevalence of co-occurring genetic aberrations by hybrid-capture sequencing was 61%. TP53 mutations were most frequent (28%; 5/18). PFS (p = 0.0219) and OS at 24 months (p = 0.015) were significantly shorter in TP53-mutant patients. Tissue or blood samples were collected in six patients at progression. In three (50%) samples, secondary mutations in ROS1 (i.e. p.G2032R (N = 2), p.L2026M (N = 1)) were detected. In one (17%), a PIK3CA mutation (p.E545K) was identified. In the other two patients (33%) aberrations of unknown significance were detected.

Conclusions

Updated PFS and OS results confirm the efficacy of crizotinib in ROS1-rearranged lung cancer patients. Patients with co-mutations in TP53 had significantly worse outcomes compared to TP53 wild-type patients. The most common mechanisms of resistance were mutations in ROS1. Next-generation ROS1 inhibitors or the multi-kinase inhibitor cabozantinib may be promising treatment options for these patients.

Clinical trial identification

NCT02183870.

Editorial acknowledgement

Legal entity responsible for the study

University Hospital of Cologne.

Funding

Pfizer.

Disclosure

S. Michels: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Janssen; Honoraria (self): Roche. B. Massuti Sureda: Honoraria (self): Merck Sharp Dome; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): Pfizer. H. Schildhaus: Honoraria (self): ZytoVision; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Novartis. M. Sebastian: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp Dome; Honoraria (self): Takeda; Honoraria (self): Mediolanum; Honoraria (self): AbbVie; Honoraria (self): Celgene. E. Felip: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Eli Lilly; Honoraria (self): Guardiant; Honoraria (self): Merck Sharp Dome; Honoraria (self): Merck KGa; Honoraria (self): Novartis. M. Reck: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Abbot; Honoraria (self): Celgene; Honoraria (self): Merck Sharp Dome; Honoraria (self): Merck KGa; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche. S. Merkelbach-Bruse: Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Roche; Honoraria (self), Research grant / Funding (institution): Novartis. L. Nogova: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Janssen; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): Celgene. J. Wolf: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Janssen; Honoraria (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Chugay; Honoraria (self): Ignyta; Honoraria (self): Eli Lilly; Honoraria (self): Merck Sharp Dome; Honoraria (self): Roche. All other authors have declared no conflicts of interest.