4899 - Secondary ROS1 mutations and lorlatinib sensitivity in crizotinib-refractory ROS1 positive NSCLC: results of the prospective PFROST trial

Background

Lorlatinib, an ALK/ROS1 inhibitor, showed activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

Methods

The PFROST trial included ROS1+ NSCLCs refractory to crizotinib. Eligible patients received lorlatinib 100 mg daily until disease progression. Primary end point was response rate (RR). For all patients, pre-lorlatinib tumor tissue or blood sample collection was mandatory. At lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

Results

From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N = 8; 36.4%), PS1 (N = 14; 63,6%); The majority had brain metastases at baseline (N = 15; 68.1%), were never smokers (N = 13; 59.1%) and received lorlatinib as third-line therapy (N = 16; 72.7%). In all cases crizotinib was the last therapy before lorlatinib. Accrual is completed and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N = 1) or partial (N = 6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N = 1 ROS1^S1861I, N = 1 ROS1 ^V2054A, N = 3 ROS1^G2032R). All patients harboring the ROS1^G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of of lorlatinib failure.

Conclusions

In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals harbouring crizotinib-induced secondary ROS1 mutations.

Clinical trial identification

EudraCT Number: 2016-001259-34.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Ricerca Traslazionale.

Funding

Has not received any funding.

Disclosure

L. Landi: Advisory / Consultancy: Pzifer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Boehringer Ingelheim. M. Tiseo: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Otsuka; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre. D.L. Cortinovis: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. A. Delmonte: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Boehringer Ingelheim. D. Galetta: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. R. Chiari: Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Novartis. L. Crinò: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca. F. Cappuzzo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. All other authors have declared no conflicts of interest.