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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 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. 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. 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. Crino: 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.

The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non-squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC.

Aim: Novel molecularly targeted agents such as small molecule kinase inhibitors and antibodies targeted against immune check-point inhibitors have begun to erode the dominant position held by platinum-based chemotherapy in the treatment of NSCLC. While in some cases, activating kinase mutations appear to be mutually exclusive (EGFR and KRAS), there are many overlapping molecular subsets within NSCLC. As we continue to develop novel drugs, it is important that we develop a greater understanding of the prevalence, overlap, and prognostic significance of drug targets including activating mutations, signaling pathways, and tumor immune markers, as this will aid in trial design and predictive biomarker development for drug combinations or sequential treatment regimens. Methods: Seven biomarkers - TTF1, p63, EGFR mutation, KRAS mutation, MET immunohistochemistry [IHC], PDL1 IHC, NaPI2B IHC- across two sample sets (Set 1, n = 561; Set 2, n = 310) were tested. Set 1 contained surgically resected cases obtained at MD Anderson Cancer Center (MDA) during 2003-2005. Samples from Set 2 were part of a collaboration between the University of Colorado Cancer Center (UofC), USA and The Norwegian Radium Hospital, and contained surgically-resected NSCLC tissues collected from 2006–2011. Results: The prevalence, overlap, and prognostic significance of each biomarker were compared between the two cohorts. Most endpoints were consistent between the cohorts. However, significant differences in prevalence were observed within adenocarcinomas for MET (50% vs. 34%, MDA vs. UofC; p 67% of patients in both cohorts were positive for more than one biomarker and >33% were positive for at least three biomarkers. Correlations with patient characteristics and outcomes will be described in further detail. Conclusions: These data suggest that the biomarker landscape in NSCLC is complex with most patients having multiple targetable alterations. Thus, the treatment landscape for NSCLC will become increasingly complex as more experimental agents approach pivotal testing. Disclosure: D. Shames, M. Kowanetz, Y. Xiao, Y. Choi, H. Koeppen, R. Firestein, Y. Wang, S. Mocci, C. Bowden and L.C. Amler all declare that: I am an employee of Genentech Inc. I own stock in Roche Holdings. All other authors have declared no conflicts of interest.

Aim: NaPi2b belongs to the type II family of sodium-dependent phosphate co-transporters, physiologically expressed in type II pneumocytes of lung and on the brush border membrane of small intestine. Increased expression of NaPi2b was recently described in ovary, thyroid and breast cancer. The aim of this study was to evaluate NaPi2b expression in lung cancer. Methods: Immunohistochemistry using the 10H1 primary antibody (Genentech) was performed on two cohorts of treatment naive resected NSCLC patients collected at MD Anderson, University of Texas, USA (training cohort, N = 415) and University of Oslo, Norway (testing cohort, N = 350). Moreover, 67 lung cancer cell lines were analyzed (51 non-small cell and 16 small cell lung cancer). EGFR and KRAS mutations were evaluated with the SnapShot assay. NaPi2b protein expression was scored using the H-score method (0-300). Expression was defined as high or low according to a H-score cut-off value of 200. Results: Patient characteristics did not differ significantly in the two cohorts. In the training and testing cohorts high levels of NaPi2b were detected in 48.4% and 64% of patients, respectively. Adenocarcinomas (AC) were found to express significantly higher levels of NaPi2b than squamous cell carcinoma (SqCC) (AC vs SqCC median H-score: 248 vs 11, p Conclusions: NaPi2b is a prognostic marker in NSCLC and is strongly associated with important clinicopathological and biological variables such as histology and driver mutation status. Further studies are warranted to clarify the role of NaPi2b in tumor development and progression, as well as its association with driver mutations. Disclosure: O.T. Brustugun received research funding from Roche, Astrazeneca and GlaxoSmithKline; Y. Xiao is a Genentech employee and owns stock in Roche Holdings; Y. Choi is en amployee of Genetech Inc and owns stock in Roche Holdings; Y. Wang is an employee of Genentech Inc and owns stock in Roche Holdings; R. Firestein is an employee of Genentech Inc and owns stock in Roche Holdings; A. Helland received research funding from Roche, AstraZeneca and GlaxoSmithKline; F.R. Hirsch received research funding from Celgene, Genentech, Ventana, Lilly, Imclone and Amgen, and received compensation from Genentech/Roche, Novartis, Pfizer, Brystol-Meyers Squibb, Amgen and Lilly for partecipating in their advisory boards; D. Shames is an employee of Genetech Inc and owns stock in Roche Holdings. All other authors have declared no conflicts of interest.

Background FGFR1 belongs to a family of five different receptors often dysregulated in human malignancies, including lung cancer. Recent studies showed that gene amplification is one of the mechanisms potentially responsible for FGFR dysregulation. Although FGFR1 gene amplification has been reported in up to 20% of lung cancer patients with squamous-cell carcinoma (SCC), prognostic effect is unknown. Aim of the present study was to assess the prognostic role of FGFR1 gene copy number (GCN) in pure lung SCC. Methods A total of 378 patients were included in the present study. Pure SCC was defined as a tumor positive for P40 and negative for TTF1 using immunohistochemistry. FGFR1 was evaluated by fluorescence in situ hybridization (FISH) in tissue microarray sections from primary lung tumors. All cases with an FGFR1/centromere ratio ≥ 2 were considered as amplified (FGFR1 FISH+). Results Among patients included onto the study, FGFR1 FISH analysis was successfully performed in 304 and 32 (10.5%) were FGFR1 FISH+. FGFR1 amplification was significantly associated with P40 positive status (p = 0.002) and with lack of TTF1 expression (p = 0.005). In the whole population, no difference in disease-free survival (DFS) and overall survival (OS) was detected between FGFR1 FISH positive and negative patients (DFS: 17.2 versus 17.0 months, p = 0.98; OS: not reached in both groups, p = 0.2). In the group of patients p40 + /TTF1 negative (N = 66), 14 (21.2%) displayed FGFR1 gene amplification. No difference in survival was detected between FGFR1 FISH+ and negative patients in p40+ versus p40 negative (OS not reached versus 46.2 months, p = 0.41 in FGFR1 FISH + /p40+ versus any negative), nor in TTF1 negative versus TTF1+ (OS not reached versus 41.8 months in FGFR1 FISH + /TTF1 negative versus other subgroups) nor in FGFR FISH + /p40 + /TTF1 negative versus FGFR negative/p40 + /TTF1 negative (37.3 months versus not reached, p = 0.77). Conclusions FGFR1 is amplified in 21% of pure lung SCC with no prognostic effect. The high percentage of gene amplification detected further support anti-FGFR1 strategies in individuals with pure SCC. Disclosure All authors have declared no conflicts of interest.

Background Although lung adenocarcinoma harboring activating Epidermal Growth Factor Receptor (EGFR) mutations respond dramatically to reversible EGFR tyrosine kinase inhibitors (TKI), all patients (pts) inevitably develop acquired resistance. Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated some activity in Non-Small-Cell Lung Cancer (NSCLC) pts progressing after at least 3 months of EGFR-TKI therapy. Materials and methods We analyzed 44 advanced lung adenocarcinoma pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg in three Italian centers. The drug was given as compassionate use. Results Pts included had a median age of 61.6 year, the majority was female (N = 23/52%), never/former smoker (N = 41/93%), with good PS (0-1; N = 37/84%) and pretreated with > 3 therapy lines (N = 36/81%). EGFR status was assessed in all cases and 35 pts (80%) harbored a mutation in exon 18 (N = 3/8.6%), in exon 19 (N = 19/54,3%), in exon 20 (T790M; N = 2/5.7%) and in exon 21 (N = 11/31.4%). Among the 42 pts evaluable for toxicity, 58% had skin rash (G3 = 4.7%) and 18% diarrhea (G3 = 2.3%). Among the 35 pts evaluable for efficacy, response rate (RR) was 11%, disease control rate (RR+ stable disease) was 65%, median progression free-survival and overall survival were 3.5 months and 4.8 months respectively. EGFR resulted mutated in 3 of 4 responders including 1 pt with T790M mutation. In 4 pts in which tumor biopsy was repeated before starting Afatinib therapy only 1 pt had T790M mutation, with no evidence of response. Conclusions In “real life” experience Afatinib showed encouraging activity in pretreated NSCLC with manageable toxicity profile. Disclosure All authors have declared no conflicts of interest.