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Prospective investigation on cancer-associated venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) during treatment with immune checkpoint inhibitors (ICIs) is lacking.A prospective real-world study using combined computed tomography venography and pulmonary angiography (CTVPA) to screen patients with NSCLC for VTE (cohort A). A retrospective multicenter cohort without additional screening with CTVPA was included as control (cohort B). A model with VTE as a time-dependent event using competing risk analysis model with death as a competing event was used to evaluate outcomes and differences in cumulative VTE incidences.Cohort A (n = 146) and cohort B (n = 426) had median follow-up for VTE of 16.5 months (IQR 6.7-35.6). Cumulative VTE events at 1, 3, 6, and 12 months were 7.5 %, 9.6 %, 13.0 %, 14.4 % for cohort A and 1.9 %, 3.8 %, 4.9 %, 5.6 % for cohort B with SHR 2.42 (CI 95 % 1.37-4.27) p = 0.0024. Recurrent VTE comprised 52 % and 37 %, respectively. In multivariate overall survival analysis, VTE was significantly associated with impaired OS (HR 2.12 CI 95 % [1.49-3.03], p 0.0001). Risk factors for VTE comprised prior VTE and ICI administered in first line.Cumulative VTE incidence in NSCLC patients following palliative ICI may be significantly higher than reported in randomised clinical trials and retrospective real-world reports. VTE development during ICI impair OS significantly. Thus, more focus on VTE during ICI is warranted to optimise both prevention and management of VTE. Whether there is a causal relationship between VTE and ICI remains to be explored.

Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown. Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort. Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment. Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations. Keywords: Osimertinib; uncommon EGFR mutations; circulating tumour DNA (ctDNA); T790M

Background: Comorbidity is an important prognostic marker and a treatment indicator for lung cancer patients. Register-based studies often describe the burden of comorbidity by the Charlson comorbidity index (CCI) based on hospital discharge data. We assessed the association between somatic and psychiatric comorbidity and death within one year in early lung cancer and, furthermore, the burden of comorbidity according to treatment type. Material and methods: We conducted a population-based matched case-control study of stage I lung cancer identifying all treated patients who died (all-cause) within one year after diagnosis (early death group, cases). On the basis of data from the Danish Lung Cancer Registry these patients were then matched with two controls who survived more than one year (survivors). Through a review of the medical records, we validated inclusion criteria and collected data on somatic and psychiatric comorbidity. We assessed the association between comorbidity and early death with multivariate conditional logistic regression. Results: We included 221 cases and 410 controls. The mean CCI score in the early death group was 2.3 vs. 1.3 in the survivor group (p

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC.Methods: Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.Results: Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Sparse data exist on immune checkpoint inhibition (ICI) in NSCLC patients with brain metastasis (BM), especially for those with no local therapy (LT) (whole brain radiation therapy (WBRT), stereotactic RT (SRT) or neurosurgery) preceding ICI. Our aims were to investigate the prevalence of BM, rate of intracranial response (ICR), and survival and quality of life (QoL) in real-life patients with advanced NSCLC undergoing palliative ICI. This was a prospective non-randomized study (NCT03870464) with magnetic resonance imaging of the brain (MR-C) performed at baseline resulting in a clinical decision to administer LT or not. ICR evaluation (MR-C) at week 8–9 (mRECIST criteria) for group A (LT) and group B (untreated) was assessed. Change in QoL was assessed using EQ-5D-5L. Of 159 included patients, 45 (28%) had baseline BM. Median follow-up was 23.2 months (IQR 16.4–30.2). Of patients in group A (21) and B (16), 16/37 (43%) had symptomatic BM. ICR was 8/21, 38% (complete or partial response) for group A versus 8/16, 50% for group B. No statistical difference in median overall survival of patients with BM (group A: 12.3 (5.2-NR), group B: 20.5 months (4.9-NR)) and without (22.4 months (95% 16.2–26.3)) was obtained. Baseline QoL was comparable regardless of BM, but an improved QoL (at week 9) was found in those without BM. Patients with NSCLC and BM receiving ICI had long-term survival comparable to those without BM.

Osimertinib is standard of care forWe identified patients with uncommonOf 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6%Osimertinib demonstrates activity in patients with uncommon

BACKGROUND For decades many patients with small cell lung cancer (SCLC) have been offered prophylactic cranial irradiation (PCI) to prevent brain metastases (BM). However, the role of PCI is debated in the modern era of increased brain magnetic resonance imaging (MRI) availability. BM in SCLC patients may respond to chemotherapy, and if a negative MRI is used in the decision to use of PCI in the treatment strategy, the timing of brain MRI may be crucial when evaluating the effect of PCI. This retrospective study investigates the impact of PCI outcomes in patients with SCLC staged with brain MRI prior to chemotherapy. MATERIALS AND METHODS This study included 245 patients diagnosed SCLC/mixed NSCLC-SCLC treated between 2012 and 2019. The population was analyzed separately for limited disease (LS-SCLC) and extensive disease (ES-SCLC). Patients were divided into groups based on baseline brain MRI prior to chemotherapy and PCI. The primary endpoint was time to symptomatic BM. Secondary endpoints were overall survival (OS), and progression-free survival (PFS). RESULTS In patients with LS-SCLC staged with brain MRI the probability of developing symptomatic BM at one year was 4% vs. 22% (p

Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients.The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8-12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases.Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Introduction: Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. Methods: The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8–12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. Results: Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. Conclusion: This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

OBJECTIVES: Tyrosine kinase inhibitors (TKIs) are first line treatment choices for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, responses vary among patients, therefore good biomarkers predicting better responses are required. EGFR mutations are detected in the blood from patients as circulating tumour DNA (ctDNA). Studies have shown that clearing ctDNA during first line TKI treatment predicts outcomes for first and second generation TKI treatments. We aimed to investigate the effects on outcome measures of ctDNA clearing in subsequent treatment lines to treatment with the third generation TKI osimertinib.METHODS: In total, 225 patients were included in a prospective, multicentre study, where consecutive blood samples were monitored for EGFR mutations during systemic treatment lines, using the Cobas® EGFR mutation test v2. This study focused on EGFR mutations in ctDNA of 82 systemically pre-treated patients receiving osimertinib.RESULTS: Clearing all EGFR mutations from the blood after osimertinib treatment, significantly predicted progression-free survival, objective response rates and disease control rates. Primary sensitising EGFR mutations were found in ctDNA in 70 % of patients, and were accompanied by the T790 M mutation in nearly two thirds of cases. The T790 M mutation was cleared in all cases, while the accompanying sensitising mutations did not necessarily clear. However, T790 M clearing without simultaneously clearing of the primary sensitising mutation did not predict clinical responses. Neither the detection of T790 M before osimertinib treatment, nor the presence of EGFR mutations at the time of osimertinib initiation predicted clinical outcomes.CONCLUSION: The clearing of EGFR mutations in ctDNA after osimertinib treatment initiation in patients with advanced NSCLC is useful as a positive predictor of clinical outcome.

Objectives: Epidermal growth factor receptor (EGFR) mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, a subset of patients has limited or no response. We investigated the initial dynamics of EGFR mutations detected in circulating tumour DNA (ctDNA) during treatment as a predictive marker of outcome. Methods: A total of 225 patients with advanced EGFR mutated NSCLC were included for consecutive blood sampling in this prospective multicentre study. Out of these, 146 patients received first line TKI and had a baseline blood sample available for EGFR mutation testing with the Cobas® EGFR mutation test V2. For examinations on clearing and clinical outcome, 98 patients who had detectable ctDNA at baseline and at least one follow-up blood sample were included. Results: For patients with EGFR mutations present in plasma at baseline, clearing of mutations from the blood during first line TKI served as a positive predictor for objective response rate (p = 0.0008), progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001). This was seen both for patients who cleared the ctDNA within the first 7 weeks of treatment and patients who cleared the ctDNA at a slower pace. Baseline mutation presence was a negative predictor for PFS (p = 0.0069) and OS (p = 0.0340). Conclusion: The current study is the first to confirm, in a sizeable Caucasian cohort, that clearing of EGFR mutations predict outcome to first line TKI in patients with EGFR mutated NSCLC.

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)–rearranged non–small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee–assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Background: To investigate effect and toxicity of immune checkpoint inhibition (ICI) in a Danish real-life non-small cell lung cancer (NSCLC) population. By including patients underrepresented in clinical trials, such as those with brain metastasis (BM), higher age, more comorbidity and poorer performance status (ECOG), comparison of unselected patients to clinical trial populations is possible. Material and methods: Real life data were gathered from 118 consecutive NSCLC patients with incurable NSCLC treated with ICI at the Department of Oncology at the University Hospital of Odense, Denmark from September 2015 to April 2018. Immune-related adverse events (irAEs) grades 3–5 were registered prospectively during the same period. Additional patient related data were obtained retrospectively from patients' files. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan–Meier estimates, the log-rank test and cox regression analysis performed for factors affecting survival. Results: Median age for patients was 66 years (IQR 59–71) and 62 years (range: 55–64) for those with BM. Females 63%; adenocarcinoma (AC)/squamous/others 69%/23%/8%; ECOG ≥ 2 10%; bone/brain/liver metastases 36%/18%/15%; PD-L1 (TPS) p = .005). For patients with BM, the median OS was 8.2 months (HR 1.38, [95% CI: 0.7–2.5], p = .37). Twenty-four percent of patients terminated ICI due to irAE grades 3–5 alone (grade 5, n = 1), which were not associated with higher age or BM. Conclusions: OS and PFS were comparable to clinical trial reports. Long-lasting remission is also possible in patients with BM. Real-life populations have higher rates of irAE grades 3 and 4 than reported in clinical trials, but it does not seem to impact median OS.

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

Background We report an analysis of Asian vs non-Asian pts with CRZ-refractory, ALK+ NSCLC from ALTA (NCT02094573). Methods Pts were stratified by presence of baseline (BL) CNS metastases and best response to prior CRZ and randomized 1:1 to BRG 90mg qd (arm A) or 180mg qd with a 7-day lead-in at 90mg (arm B). Primary endpoint: Investigator-assessed confirmed ORR by RECIST v1.1. Results 222 pts were randomized; 69 Asian (A/B, n=39/30), 153 non-Asian (n=73/80); median age: Asian, 50/56 y; non-Asian, 51/57 y; 85/70% vs 64/66% had BL CNS metastases. As of Sep 2017, median follow-up was 18.4/22.5mo (A/B) in Asians vs 22.3/24.5mo in non-Asians. In Asians, median IRC-assessed PFS (mo) was 9.1 (95% CI 5.6–18.2) in A vs 15.6 (9.2–21.2) in B (HR 0.88 [95% CI 0.48–1.62]; P=0.6808); in non-Asians, PFS (A/B) was 9.9 (9.0–26.3) vs 17.9 (11.6–23.9; HR 0.72 [0.45–1.13]; P=0.1510) (Table). Of 7/2 (A/B) Asian pts with measurable BL CNS metastases, 3/1 had confirmed intracranial objective responses; in non-Asian pts with measurable BL CNS metastases, IRC-assessed iORR was 53/69% (n=19/16). In Asians (A vs B) with any BL CNS metastases, IRC-assessed median iPFS (mo) was 15.6 (5.6–18.4) vs 12.8 (7.3–21.1); in non-Asians, 12.8 (7.4–NR) vs 20.7 (11.1–NR). Most common any-grade TRAEs in Asians (≥20%): increased CPK and amylase; in non-Asians, nausea, diarrhea, and increased CPK. Most common grade ≥3 TRAEs (>3%) in Asians: increased CPK; in non-Asians, increased CPK and lipase, hypertension. Early-onset pulmonary AEs occurred in 3 (4%; 1 grade ≥3) Asian (Korean) and 11 (7%; 6 grade ≥3) non-Asian pts. Dose reductions due to AE: 7.7/30.0% in Asian pts; 7.1/28.8% in non-Asian pts; discontinuations due to AE: 7.7/16.7% in Asian pts; 10.0/20.0% in non-Asian pts.Table1543PTableInvestigator-AssessedIndependent Review Committee (IRC)–AssessedAsian (n=69)Non-Asian (n=153)Asian (n=69)Non-Asian (n=153)Arm A (n=39)Arm B (n=30)Arm A (n=73)Arm B (n=80)Arm A (n=39)Arm B (n=30)Arm A (n=73)Arm B (n=80)Confirmed ORR, %49 (30–67a)67 (45–84a)44 (31–58a)53 (40–65a)56 (40–72b)67 (47–83b)48 (36–60b)53 (41–64b)Median DoR in responders,c mo13.7 (5.6–19.4b)13.8 (10.2–14.8b)9.5 (7.4–NRb)16.6 (9.0–24.0b)16.4 (5.6–24.9b)13.9 (7.4–19.4b)24.6 (7.4–NRb)15.7 (12.6–30.2b)Median PFS,c mo Events, %9.2 (5.6–15.6b) 6915.6 (11.1–15.7b) 609.2 (5.7–11.1b) 6914.7 (10.8–24.0b) 589.1 (5.6–18.2b) 6715.6 (9.2–21.2b) 609.9 (9.0–26.3b) 5317.9 (11.6–23.9b) 45OSc Median, mo 1-y,c % 2-y,c %NR (18.2–NRb) 77 (60–88b) 56 (37–72b)NR (NR–NRb) 92 (73–98b) 79 (57–91b)29.5 (14.5–NRb) 67 (54–76b) 53 (41–64b)34.1 (22.6–NRb) 76 (65–84b) 62 (50–71b)– – –– – –– – –– – –DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. a97.5% CI (primary endpoint); b95% CI; cKaplan-Meier estimate. Conclusions BRG showed comparable efficacy and acceptable safety in Asians and non-Asians in CRZ-refractory ALK+ NSCLC, with nonsignificant, numerically improved PFS at the 180-mg (with lead-in) dose. Clinical trial identification NCT02094573. Editorial acknowledgement Peloton Advantage, LLC, an OPEN Health Company, funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Legal entity responsible for the study ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Funding ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Disclosure D.H. Lee: Honoraria (self): AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChongKunDang, CJ Healthcare, Eli Lilly, Genexine, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, Takeda. D. Kim: Research grant / Funding (institution): Alpha Biopharma, Astrazeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan. D.R. Camidge: Honoraria (self): AstraZeneca, Takeda, Genoptix, G1 Therapeutics [DSMB], Mersana Therapeutics, Roche, Ignyta, Daiichi Sankyo [ILD adjudication committee], Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med; Research grant / Funding (self): Takeda. C.J. Langer: Honoraria (self): Bristol-Myers Squibb, Eli Lilly, Roche/Genentech; Advisory / Consultancy: Abbott, ARIAD, AstraZeneca, Bayer/Onyx, Bristol-Myers Squibb, Cancer Support Community, Celgene, Clarient, Clovis Oncology, Eli Lilly, Merck, Roche/Genentech, Takeda; Research grant / Funding (self): Advantagene, ARIAD, Celgene, Clovis Oncology, GlaxoSmithKline, Inovio, Merck, Roche/Genentech, Stemcentrx; Advisory / Consultancy: Amgen, Lilly, Peregrine Pharmaceuticals, Synta. R.M. Huber: Honoraria (self): ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche; Advisory / Consultancy: Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, Novartis, Roche; Research grant / Funding (self): Pierre Fabre. M. Tiseo: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche. H.L. West: Advisory / Consultancy: AbbVie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Merck, PharmaMar, Roche/Genentech, Spectrum, Takeda; Speaker Bureau / Expert testimony: ARIAD, Bristol-Myers Squibb, Roche/Genentech. H.J.M. Groen: Advisory / Consultancy: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech; Research grant / Funding (self): Eli Lilly, Roche. K.L. Reckamp: Advisory / Consultancy: Amgen, ARIAD, Astellas, Takeda, Tesaro; Research grant / Funding (self): Adaptimmune, ARIAD, BMS, Boehringer Ingelheim, AbbVie, Novartis, Pfizer, Roche/Genentech, Xcovery. M.J. Hochmair: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, Takeda; Advisory / Consultancy: Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Roche, Takeda. N.B. Leighl: Travel / Accommodation / Expenses: AstraZeneca, BMS, MSD, Pfizer. K.H. Hansen: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Roche; Advisory / Consultancy: AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Roche; Travel / Accommodation / Expenses: BMS, Boehringer Ingelheim, MSD, Pfizer, Roche. S.N. Gettinger: Advisory / Consultancy: Alexion Pharmaceuticals, ARIAD, Bristol-Myers Squibb, Pfizer; Research grant / Funding (self): ARIAD, Bristol-Myers Squibb, Incyte, Pfizer, Roche/Genentech. L. Paz-Ares: Honoraria (self), Spouse / Financial dependant: Eli Lilly, MSD, BMS, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint; Officer / Board of Directors: Genomica; Research grant / Funding (institution): MSD, BMS, AstraZeneca, Pfizer. E.S. Kim: Advisory / Consultancy: AstraZeneca, Celgene, Eli Lilly; Honoraria (self): Eli Lilly, AstraZeneca, Celgene. E.F. Smit: Advisory / Consultancy: Eli Lilly; Research grant / Funding (self): AstraZeneca, Bayer, Boehringer Ingelheim, Roche/Genentech. Q. Ni: Full / Part-time employment: Takeda. P. Zhang: Full / Part-time employment: Takeda. M. Ahn: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Lilly, MSD; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Lilly, MSD. All other authors have declared no conflicts of interest.

Background Lung cancer is an increasing problem in the older patient population due to the improvement in life expectation of the Western population. In this study we examine trends in lung cancer incidence and mortality in Denmark from 1980 to 2012 with special focus on the elderly. Material and methods Lung cancer was defined as ICD-10 codes C33-34. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence, and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. Results In 2012, about 50% of lung cancers were diagnosed among persons aged 70 years or more. For men and women older than 75 years the incidence rates have been increasing and for those aged 80-84 years, the rates have doubled since 1980. Due to the poor survival, similar trends were seen in mortality rates. Over the period, the one-year relative survival rates almost doubled in patients aged 70 years or more, but still only 25% of the patients aged 80-89 years survived their lung cancer for one year. Conclusion The incidence of lung cancer is closely linked to the pattern of tobacco smoking with the differences between gender and age groups reflecting smoking behavior in birth cohorts. Elderly patients with lung cancer are a heterogeneous group in whom treatment should be offered according to comorbidity and a geriatric assessment.

e21149Background: PD-L1 testing was established in Denmark (DK) after the approval of Nivolumab (Niv) and Pembrolizumab (Pem) in second line (2L) treatment of Non-Small Lung Cancer (NSCLC) due to t...

9061Background: ALTA (NCT02094573) evaluated 2 doses of the ALK inhibitor BRG post-CRZ. Overall ORR contains both CNS and extra-CNS target lesion data. Methods: In ALTA, stratification included BL CNS disease (+/−). Pts were randomized to BRG 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). To differentiate CNS and extra-CNS efficacy we compared CNS ORR with overall ORR by BL CNS status. Results: 222 pts were randomized (n = 112/110, arm A/B); 71%/67% had BL CNS lesions. Of 247/204 total target lesions in A/B, 38 (15%) and 32 (16%), respectively, were in the CNS; 28 (25%) pts in A and 23 (21%) in B had ≥1 target CNS lesion. Median follow-up was 19.6/24.3 mo. Per independent review, CNS ORR in pts with measurable BL CNS lesions (n = 26/18, A/B) was 50%/67%; in pts with any BL CNS lesions (n = 81/74, A/B), median intracranial PFS (iPFS) was 12.8/18.4 mo. Table shows long-term overall efficacy updates by BL CNS status. Dose reductions or discontinuations due to AEs (A/B): 7%/29% and 4%/11...

Hyponatremia is often seen in SCLC, and is thought to be caused by the paraneoplastic syndrome SIADH. Variable results of the prognostic significance of low P-sodium (P-Na) have been reported. This study was performed to investigate the prognostic value of hyponatremia in SCLC. Data was obtained from files from 453 patients diagnosed with SCLC and treated at Odense University Hospital from 1995 to 2005 in which data on P-sodium was available. The standard chemotherapy was six cycles of carboplatin-etoposide. P-Na was

We wanted to analyse the prevalence of EGFR-mutation, and how EGFR-mutation analysis has influenced the treatment during the first four years of use. In the Danish Lung Cancer Registry we have identified all 929 patients (56% female) from Funen (484,700 inhabitants) with first occurrence of adenocarcinoma or NSCLC not otherwise specified - diagnosed from July 2010 to June 2014. Chart review was updated in February 2015. The median age was 68 years (range 31 – 96 years), 6.4% were never-smokers and 37.5% ex-smokers. EGFR-mutation status has been determined for 683 patients (73.6%), but has not been possible from the available samples in 89 cases. For 156 patients the analysis has not been requested. The prevalence of EGFR-mutation has been 10.4% in women, 5.4% in men, and 39.2% in never-smokers (no gender difference). The EGFR mutations were proven in cytology samples in 75% of the 56 positive cases. In the first two years of the study period, EGFR-mutation analysis had not been requested or had not been possible for 34.3% of the patients at the initiation of primary therapy with palliative intent. This fraction was reduced to 10.9% in the last two years (p < 0.001, Fisher's exact test). Despite this improvement, the median time from start of diagnostics to start of therapy did not increase (29 days vs. 28 days). Of the 56 patients with an EGFR-mutation 37 have until now been treated with a tyrosine kinase inhibitor (TKI). Eleven patients had radical therapy without the later use of a TKI, one had conventional chemotherapy due to an exon 20 mutation, and seven patients have died without having systemic therapy.

e20014 Background: Correct staging of small cell lung cancer (SCLC) in limited disease (LD) or extensive disease (ED) is crucial as it has an impact on the therapeutic decision-making. The staging procedures in SCLC in the late 1990s included chest X-ray, blood samples, abdominal ultrasonography (UL), and iliac crest BMex. The aim of this study was to evaluate the continued eligibility of performing BMex in patients (ptt) with SCLC as a routine staging procedure, and to see how often therapeutic decisions were influenced by a positive BM before and after the PET/CT scan era. Methods: All diagnostic and staging procedures were registered in ptt with SCLC referred to our department from 1995 to 1999 in cohort 1 (C1). Cohort 2 (C2) included SCLC patients referred from 2009 to 2013. In C2 results of PET/CT in terms of bone metastases were related to results of BMex. Results: In C1 194 ptt was referred with 136 (70%) having ED. BMex was omitted in 32 (17%) fragile ptt having known ED while all LD ptt underwent BMex. BM involvement was seen in 37 (23%) of all 162 BMex and 36% of the 104 ED ptt examined. When BM was negative the staging of ED was due to other imaging. The BM had an impact on therapeutic decision-making in 5 (4%) of 136 having ED and 5 (3%) of 162 BMex. In C2 211 ptt of 292 (72%) had ED and 203 (70%) of all ptt underwent BMex. BM biopsy was done in 137 (65 %) ED and in 66 (69 %) LD. Of 137 ED ptt BM involvement was found in 31 (23 %) cases. A PET/CT scan was performed in 13 (42 %) of these ptt of which bone metastases was found in 12 (92 %). One patient (8%) had a PET/CT without bone lesions. Bone metastases were seen at PET/CT scan in 61 ptt in C2, of these 22 (36%) had negative BM, whereas 12 (20%) had BM involvement and in 3 ptt (5%) BMex were inconclusive. No BMex was performed in 24 ptt (39%). BMex had an impact on therapeutic decision-making in 3 (1.4%) of 211 having ED and 5 (2.5%) of 203 BMex. Conclusions: Due to staging by PET/CT and CT scan in SCLC ptt the impact of BMex in the therapeutic decision-making has decreased and fewer ptt are undergoing BMex. Though a negative PET/CT cannot exclude BM involvement BMex may be considered omitted.

e20503 Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]

9007Background: We report the first results of a pivotal ph 2 trial of BRG in pts with ALK+ NSCLC. BRG, an investigational oral tyrosine kinase inhibitor (TKI) with preclinical activity against rea...

Hyponatremia is often seen in SCLC, and is thought to be caused by the paraneoplastic syndrome SIADH. Variable results of the prognostic significance of low P-sodium (P-Na) have been reported. This study was performed to investigate the prognostic value of hyponatremia in SCLC. Data was obtained from files from 453 patients diagnosed with SCLC and treated at Odense University Hospital from 1995 to 2005 in which data on P-sodium was available. The standard chemotherapy was six cycles of carboplatin-etoposide. P-Na was125 mEq/L in 47 patients (11%) and 126-135 mEq/L in 151 (33%), and 255 patients (56%) showed normal values. The median survival was 11.2 months in patients with normal P-Na, and 7.1 months in patients with subnormal values (p=0.0001). In a Cox multivariate analysis of the 402 patients treated with carboplatin-etoposide, hyponatremia was associated with poorer prognosis. Other independent prognostic factors included LDH, gender, age, performance status, stage, and low value of albumin. Treatment prior to year 2000 was of border line significance, while in-significant factors included hemoglobin level, WBC and alkaline phosphatase. In 61 patients with P-Na130 mEq/L receiving two or more cycles of chemotherapy, only 15 of the 61 patients (25%) normalized the value of P-Na to 136 mEq/L or above at the time of the second cycle of chemotherapy. The patients who did not fully regain normal values of P-Na, had poorer survival compared with the patients who did in a univariate analysis (p=0.027), and in a Cox multivariate analysis. In conclusion, hyponatremia was a significant prognostic factor associated with poor prognosis and so was failure to normalize P-Na within the first two cycles of chemotherapy.

18107 Background: Brain metastases (BM) is a major problem in NSCLC. To evaluate the influence on survival in locally advanced NSCLC treated with radical RT, a retrospective analyses was performed of the patients treated at our institution. Methods: From June 1995 to Dec. 2003 200 patients with non-resectable NSCLC stage IIB-IIIAB received radical 3-D conformal radiotherapy with a planned dose =60Gy/30 F. Data on brain metastases were retrospectively obtained from the patient files. All patients were followed to death except in few cases in which data was obtained from other hospitals. End points were occurrence of BM and BM free survival (BM-RFS). A Cox multivariate analysis was performed including possible prognostic factors. Results: Stage at RT: IIB 8 (4%), IIIA 66(33%), IIIB+recurrent disease 126 (63%). Male/female ratio was 126 /74. The median survival was 15.5 months. The 2 yrs. survival was 34%. 42 (21%) cases of BM were observed. The median time to BM was 8.5 ms. with 86% occurring within 2 yrs. In 28 (67%) of the cases BM was the first site of failure, and in 10 (24%) BM remained the only site of failure. More women than men experienced BM 25 (34%) vs. 17 (14%), p= 0.0013. The survival after diagnosis of BM was 2.8 ms. The patients having BM as and these had better prognosis then patients experiencing BM at a later stage 5.3 vs 1.9 ms. (p No significant financial relationships to disclose.

No previous reports on 3-D conformal radiotherapy of Danish patients with inoperable local advanced non-small-cell lung cancer have been published.From 1995 to 2003, 158 patients with inoperable non-small-cell stage III lung cancer received radical radiotherapy in doses of 60-66 Gy in 30-33 fractions. Neoadjuvant chemotherapy was administered to 77 patients.The median survival time was 15.8 months. The one, two-, three-, four-, and five-year survival rates were 61%, 35%, 23%, 19% and 17%, respectively. Gender and age had no influence on survival, while patients in performance status 2 tended to have poorer survival rate than patients in performance status 0-1. The lung function as evaluated byh FEV1 and FVC declined by 8-9% during the first year and was reduced by 9-13% after three years. The cause of death in 90% of the cases was lung cancer. In 50% of all cases, a loco-regional relapse was found, and in 41% distant metastases existed.These results show that a significant number of stage III patients treated with modern radiotherapy with curative intent will be long-term survivors.

7091 Background: Hyponatriemia is very often seen in SCLC due to the paraneoplastic syndrome SIADH. Hyponatriemia has been found to be associated with poorer outcome in some but not in the majority of published studies. This study was performed to investigate the prognostic value of hyponatriemia in SCLC. Methods: Data from the patient files from 468 patients diagnosed with SCLC and treated at Odense University Hospital 1995 to 2005. In the 444 cases data on the initial S-Na was available. A Cox multivariate analysis was performed including possible prognostic factors. Results: Stage: Extensive disease (ED) 283 (64%), limited disease (LD) 161 (36%). The standard chemotherapy was 6 cycles of carboplatin-etoposide. 70% of the patients with LD received thoracic radiotherapy, usually in a dose of 45 Gy/22–30 F and 49% received PCI usually as 25 Gy/11F. Median survival in ED 7.2 months with a 1 and 2-year survival rate of 21% and 6%. In LD the figures was 15.2 months, 65%, 31% and a 5-year survival rate of 16%. S-Na was [Table: see text] No significant financial relationships to disclose.