The SENECA trial showed similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients (pts) treated with second-line ...docetaxel/nintedanib, regardless relapsing-time from end of first-line chemotherapy and docetaxel schedule employed (weekly or q3wks) presented at AIOM 2018. Because of the lack of data about optimal therapeutic algorithms for nsNSCLC pts and the evidence of a strong biologic rationale for using both antiangiogenic drugs and immunotherapy (IT), aim of the present analysis is to investigate post progression survival of SENECA pts, exploring if third-line IT may be positively influenced from prior nintedanib use.
SENECA enrolled 212 nsNSCLC pts treated with docetaxel and oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on those 64 pts receiving a third-line treatment and aims to compare who underwent IT with the remaining ones. PFS2 and OS2 (time from start of docetaxel/nintedanib to progression during third-line or death, respectively) are investigated. Comparisons between Kaplan Meier curves of the two groups are made with Log Rank test. Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are also reported.
Pts treated with third-line (39 with IT, 25 with other agents) correspond to 30.2% of the entire study population; they were 40 males and 24 females, mainly current or former-smokers, with ECOG-performance status 0 in 79.7% of cases and average age of 62.2 years. At the cut-off date (April 29th, 2019), after 39.5 months follow-up, no significant differences appear between pts who received IT after SENECA progression and the other ones in terms of PFS2 (10.78 vs 7.91 months; HR 0.602 95% CI 0.342-1.058, p-value=0.0821), while there are in terms of OS2 (14.33 vs 11.32 months; HR 0.537 95% CI 0.292-0.987, p-value=0.0161).
Despite the small sample size, this analysis shows a higher post progression survival for nsNSCLC pts treated with docetaxel/nintedanib and third-line IT, postulating a synergism between the two regimens. Being this topic extremely attractive for development of new therapeutic algorithms, this report could be the basis for further investigations.
EudraCT: 2014-005016-42.
The authors.
Boehringer Ingelheim.
E. Capelletto: Advisory / Consultancy: Boehringer Ingelheim ; Advisory / Consultancy: AstraZeneca. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. F. Grossi: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Amgen. V. Scotti: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. D. Galetta: Honoraria (self): Boehringer Ingelheim ; Honoraria (self): Roche; Honoraria (self): MSD. S. Novello: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AbbVie. All other authors have declared no conflicts of interest.
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.
...The PFROST trial included ROS1+ NSCLCs refractory to crizotinib. Eligible patients received lorlatinib 100mg 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.
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 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of of lorlatinib failure.
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.
EudraCT Number: 2016-001259-34.
Fondazione Ricerca Traslazionale.
Has not received any funding.
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.
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