bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracranial anti-tumor activity of lazertinib in patients with advanced NSCLC who progressed after prior EGFR TKI therapy: Data from a phase I/II study.
Authors: Kim Sang-We , Ahn Myung-Ju , Han Ji-Youn , Lee Ki Hyeong , Cho Eun Kyung , Lee Yun-Gyoo , Kim Dong-Wan , Kim Joo-Hang , Lee Jong-Seok , Lee Gyeong-Won , Shim Byoung Yong , Kim Jin-Soo , Chun Sang Hoon , Lee Sung Sook , Min Young Joo , Shin Sang Won , Lee Young Joo , Lee Dae Ho , Lee Hana , Cho Byoung Chul 
Published: May 2020

9571 Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. Brain metastasis (BM) are common in patients (pts) with advanced NSCLC. Lazertinib showed a high blood-brain barrier penetration profile in preclinical studies. We report intracranial response data in pts with advanced NSCLC from a Phase I/II study of lazertinib (NCT03046992). Methods: Pts with advanced NSCLC, who had progressed after prior EGFR-TKI therapy, were enrolled in an open-label, multicenter, phase I/II study with dose-escalation, dose-expansion and dose-extension phases. Brain MRI was done in all pts at baseline. Pts with asymptomatic BM were eligible for enrollment. Intracranial anti-tumor activity of lazertinib was analysed in pts with BM present on baseline brain scan. Pre-defined intracranial endpoints included objective intracranial response rate (OIRR) and intracranial progression-free survival (IPFS) by independent central review (ICR). The brain metastasis full analysis population included pts with measurable and/or non-measurable BM lesion present on baseline brain scan; the brain metastasis population evaluable for response included only pts with measurable BM lesion. Results: As of 30 Sep 2019, a total of 181 pts received at least one dose of lazertinib 20-320 mg across 7 dose levels. Of those, 64 pts (56% female, median age 63, 86% T790M mutation positive by central testing) were included in the brain metastasis full analysis population; Intracranial disease control rate (IDCR) was 90.6% (58/64; 95% CI 83.5, 97.8) and median IPFS was not reached (95% CI 14.0, NR). In the brain metastasis population evaluable for response, a total of 22 pts were included; OIRR and IDCR were 54.5% (12/22; 95% CI 33.7, 75.4) and 90.9% (20/22; 95% CI 78.9, 100), respectively. In 13 pts (7.2%) out of 181 pts, brain was the first site of disease progression by existing and/or new lesions. Conclusions: Lazertinib demonstrated clinically meaningful activity against BM, aligned with preclinical data. Clinical trial information: NCT03046992 .
Efficacy and safety of lazertinib 240 mg as the clinical dose in patients with EGFR T790M mutant NSCLC: Data from a phase I/II study.
Authors: Lee Ki Hyeong , Ahn Myung-Ju , Han Ji-Youn , Kim Sang-We , Cho Eun Kyung , Lee Yun-Gyoo , Kim Dong-Wan , Kim Joo-Hang , Lee Jong-Seok , Lee Gyeong-Won , Shim Byoung Yong , Kim Jin-Soo , Chun Sang Hoon , Lee Sung Sook , Min Young Joo , Shin Sang Won , Hong Min Hee , Sun Jong-Mu , Byun Hae Mi , Cho Byoung Chul 
Published: May 2020

9572 Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the efficacy and safety results of lazertinib 240 mg as recommended phase 2 dose (RP2D) from a phase I/II study of lazertinib (NCT03046992). Methods: Patients (pts) with advanced NSCLC, who had progressed after prior EGFR-TKI therapy were enrolled in an open-label, multicenter, phase I/II study with dose-escalation (20-320 mg), dose-expansion (40-240 mg) and dose-extension phases. Pts were assessed for safety, tolerability, pharmacokinetics and efficacy. For dose-expansion and extension phases, tumors had to be T790M mutation-positive (T790M+). Of all 78 pts assigned to lazertinib 240 mg dose level across all phases, 76 pts with centrally confirmed T790M+ were included for efficacy analysis. Results: As of 30 Sep 2019, a total of 78 pts (49% female, median age 62) received at least one dose of lazertinib 240 mg. The median duration of follow-up was 9.6 months and 44 pts were ongoing at data cut-off. Of 78 pts, 76 pts with centrally confirmed T790M+ showed the objective response rate (ORR) 57.9% (95% CI 46.8, 69.0), the disease control rate (DCR) 89.5% (95% CI 82.6, 96.4), the median progression-free survival (PFS) 11.0 months (95% CI 5.6, 16.4) and the median duration of response (DoR) 13.8 months (95% CI 9.6, NR) by independent central review (ICR), respectively. Two pts (3%) experienced a confirmed complete response. The investigator-assessed ORR, DCR, median PFS and median DoR were 72.4% (95% CI 62.3, 82.4), 94.7% (95% CI 89.7, 99.8), 13.2 months (95% CI 9.6, not reached) and 11.8 months (95% CI 8.4, not reached), respectively. The most common treatment-emergent adverse events (TEAEs) at the 240 mg dose regardless of its causality were rash (35%), pruritus (33%) and paraesthesia (32%), which were mostly mild (Grade ≥3 rash: 1%; no Grade ≥3 pruritus or paraesthesia). TEAEs leading to dose reduction and dose discontinuation were observed in 13% (10/78) and 8% (4/78), respectively. Drug related TEAEs of grade ≥3 were observed in 6% (5/78). Conclusions: Lazertinib 240 mg has a favorable safety profile, and exhibits promising anti-tumor activity in pts with EGFR T790M+ NSCLC. Clinical trial information: NCT03046992 .
Study of anlotinib combined with icotinib as the first-line treatment in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations (ALTER-L004).
Authors: Huang Dingzhi , Zhong Diansheng , Zhang Cuiying , Zhang Yan , Shang Yanhong , Wang Liuchun 
Published: May 2020

9573 Background: Anti-angiogenic monoclonal antibodies plus EGFR TKIs have previously shown to prolong PFS in patients with EGFR-mutated NSCLC (JO25567 and NEJ026). Unlike bevacizumab, anlotinib is more convenient with orally administered and can inhibit more targets. Monotherapy using anlotinib has significantly prolonged median PFS and OS compared with the placebo values for third-line treatment or beyond in advanced NSCLC. We conducted a study to investigate the activity of anlotinb combined with icotinib, an oral EGFR TKI. Methods: This is a prospective, single-arm, multicenter clinical trial. Patients with locally advanced and/or metastatic IIIB, IIIC or IV non-squamous NSCLC are enrolled. Patients with EGFR exon 19 deletion and/or exon 21 L858R mutation who have not received prior therapies are eligible. The regimen consists of anlotinib (12 mg p.o, qd, day 1 to 14 every 21-day cycle) and icotinib (125mg p.o, tid). The primary endpoint is PFS. Secondary endpoints are OS, ORR, DCR and safety. Results: Between Jul 2018 and Dec 2019, 35 patients were enrolled in five centers and treated with anlotinb and icotinib. At data cutoff (Jan 7, 2020), patients were followed up for a median of 6.01 months.32 tumors were analyzed with 30 evaluable. Preliminary efficacy results: ORR was 59% (0 CR, 19 PR), DCR was 88% (0 CR, 19 PR, 9 SD). 26 patients are still receiving treatment and the longest exposure was 14 cycles. 10 (67%) of 15 patients with exon 19 deletions and 9 (53%) of 17 patients with L858R mutations achieved an objective response. 18 patients harbored aberrations in additional oncogenic drivers (PIK3CA or AKT1) and/or tumor suppressors (TP53, RB1, and PTEN) with an ORR of 72%. Upon analyses, AEs were observed in 97% (34/35) of patients. No Gr 5 AEs were reported. The most common Grade 3 AEs were hypertension (6 [ 17% ]), hypertriglyceridemia (2 [6% ]), diarrhea (1 [ 3% ]), hyperuricemia (1 [ 3% ]), hand and foot skin reaction (1 [3%]), asthenia (1 [3%]), and acute coronary syndrome (1 [ 3% ]). Hypertriglyceridemia was the only grade 4 AE (2 [ 6% ]). Three patients had to adjust treatment dosage. Conclusions: The strategy of anlotinib plus icotinib showed encouraging efficacy for previously untreated, EGFR-mutated advanced NSCLC patients. The combination was well tolerated and the AEs were manageable. The follow-up time is not sufficient and the PFS and OS outcomes need further evaluation. Clinical trial information: NCT03736837 .
Nazartinib (EGF816) in patients with treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC): Updated phase II results.
Authors: Tan Daniel Shao-Weng , Leighl Natasha B. , Yang James Chih-Hsin , Riely Gregory J. , Sequist Lecia V. , Toyozawa Ryo , Wolf Juergen , Felip Enriqueta , Kim Sang-We , Ponce Aix Santiago , Smit Egbert F. , Hida Toyoaki , Grohé Christian , Ghebremariam Samson , O’Sullivan-Djentuh Leslie , Belli Riccardo , Giovannini Monica , Kim Dong-Wan 
Published: May 2020

9574 Background: Prior data from a phase I/II study showed durable responses, including efficacy in brain lesions, and a tolerable safety profile with nazartinib in treatment (tx)-naïve patients (pts) with EGFR-mutant (mut), locally advanced (adv)/metastatic NSCLC. Here we report updated phase II results, including overall survival (OS). Methods: Tx-naïve adult pts with activating EGFR-mut (L858R or ex19del), stage IIIB/IV adv NSCLC with neurologically stable and controlled brain metastasis (BM) received oral nazartinib 150 mg once daily (continuous schedule). Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1; secondary endpoints: disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), OS, and safety. Results: At data cut-off (Nov 1, 2019), 45 pts were enrolled (median [range] age: 64 [28–83] years; 26 pts [58%] ECOG PS 1; 18 pts [40%] had baseline BM). EGFR mutations: 56% ex19del, 40% L858R, 4% other. 26/45 pts (58%) discontinued tx, with the primary reason being progressive disease in 19 pts (42%); 2 pts (4%) discontinued tx due to AEs. Median (range) follow-up for OS: 25 (0–33) months (mo); and for PFS: 17 (0–33) mo. ORR by BIRC: 69%; median PFS by BIRC: 18 mo; median OS was NE and at 33 mo, 56% of pts were alive (Table). BIRC results by baseline BM are shown in the Table. Median (range) duration of exposure: 24 (0–34) mo. Most frequent AEs (≥20% all grade, all causality): diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough and stomatitis (27% each), decreased appetite and pruritus (24% each), and dermatitis acneiform (22%). Most frequent grade 3/4 AEs (≥10%, all causality): maculopapular rash (5 pts [11%]; all grade 3) and increased lipase (5 pts [11%]; 1 pt with grade 4; no clinical pancreatitis AE was observed). Conclusions: After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Clinical trial information: NCT02108964 . [Table: see text]
FOXO3 polymorphisms were correlated with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.
Authors: Guan Shaoxing , Chen Xi , Huang Min , Zhang Li , Wang Xueding 
Published: May 2020

9578 Background: Drug-induced liver injury (DILI) is one of the most safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, drug discontinuation and further treatment failure, however, the mechanism of gefitinib-induced hepatotoxicity remains unclear. AKT1/FOXO3 regulates expression of genes involved in multiple biological/pathological processes in liver cells, including apoptosis, oxidative stress, and cell-cycle transition, as well as expression of autophagy-related (Atg) genes. Therefore, we investigated the correlation between single nucleotide polymorphisms (SNP) in AKT1/ FOXO3 and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 172 advanced NSCLC patients with activating EGFR mutations were enrolled and administered with gefitinib 250mg daily. 22 tag SNPs in AKT1/FOXO3 were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between polymorphisms of AKT1/FOXO3 and gefitinib-induced hepatotoxicity were analyzed by Chi square test. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: FOXO3 rs4946935 and FOXO3 rs75544369 were found to be associated with gefitinib-induced hepatotoxicity in NSCLC patients. FOXO3 rs4946935 AA carriers have higher risk of developing gefitinib-induced hepatotoxicity than those with FOXO3 rs4946935 AG/GG. ( P = 0.018, OR = 12.414, 95%CI (1.53-100.711)). Patients with FOXO3 rs75544369 GA have higher risk of developing hepatotoxicity with P of 0.0002 (OR = 5.241, CI%(1.85-14.851)), or developing severe hepatotoxicity with P of 0.033 (OR = 2.963, 95%CI (1.090-8.059)), than those with FOXO3 rs75544369 GG. Conclusions: FOXO3 rs4946935 and FOXO3 rs75544369 are predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. The mechanism underlying the association between FOXO3 polymorphisms and gefitinib-induced hepatotoxicity are worth investigating in further studies. Clinical trial information: NCT01994057 .
Indirect comparison of TAK-788 vs real-world data outcomes in refractory non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions.
Authors: Horn Leora , Lin Huamao Mark , Padda Sukhmani Kaur , Aggarwal Charu , McCoach Caroline Elizabeth , Zhu Yanyan , Yin Yu , Lin Jianchang , Li Shuanglian , Feng Zhongling , Neal Joel W. 
Published: May 2020

9580 Background: Currently approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are ineffective in patients (pts) with EGFR exon 20 insertion NSCLC. TAK-788 is an EGFR TKI with potent and selective preclinical inhibitory activity against EGFR exon 20 insertions, and has demonstrated preliminary efficacy in a single-arm phase 1/2 clinical trial (NCT02716116). We performed an indirect comparison of real-world outcomes with clinical trial data for this subset of pts to determine whether TAK-788 provides superior efficacy over standard treatment options. Methods: We compared efficacy in pts with refractory NSCLC with EGFR exon 20 insertions treated with TAK-788 160 mg qd (1–7 prior lines) from the ongoing clinical trial (data cut Mar 1, 2019) vs real-world data (RWD) in the second-line setting from the US Flatiron Health electronic health record–derived database (Jan 2011‒Jun 2018). This analysis was conducted using an unadjusted data set, as well as by applying propensity score modeling with inverse probability of treatment weighting (IPTW) to adjust for group differences in key baseline characteristics. Progression-free survival (PFS) and objective response rate (ORR) were compared between groups. Results: A total of 99 pts were included, n=28 TAK-788 and n=71 RWD; mean age 62/65 y; male 25%/46%; Asian 18%/10%; former smoker 39%/45%; brain metastases 43%/34%. In the RWD, there was no consistent regimen for second-line treatment (including 29.6% immuno-oncologic agents, 25.4% EGFR TKI, 10% docetaxel). Baseline characteristics were comparable after weighting. PFS and ORR showed statistically significant improvements with TAK-788 vs RWD (Table). Specifically, after weighting, median PFS for TAK-788 vs RWD is 7.3 vs 3.5 mo, and ORR is 43% vs 13%. Conclusions: Despite a more heavily pretreated pt population, the efficacy of TAK-788 in pts with refractory NSCLC with EGFR exon 20 insertions appears better than other second-line treatment options used in the real-world setting. Clinical trial information: NCT02716116 . [Table: see text]
SPRING: A Worldwide Innovative Network (WIN) Consortium phase I study of triple therapy (avelumab, axitinib, and palbociclib) in advanced non-small cell lung cancer (NSCLC) with genomic and transcriptomic correlates.
Authors: Solomon Benjamin Maurice , Callejo Ana , Bar Jair , Berchem Guy J. , Bazhenova Lyudmila , Saintigny Pierre , Raymond Eric , Girard Nicolas , Sulaiman Raed , Prouse Bruce , Bresson Catherine , Wunder Fanny , Lee J. Jack , Raynaud Jacques , Rubin Eitan , Lazar Vladimir , Felip Enriqueta , Onn Amir , Leyland-Jones Brian , Kurzrock Razelle 
Published: May 2020

9581 Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm in order to predict treatment response by comparing tumor and normal tissue biopsies on both genomic and transcriptomic platforms. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC (no EGFR or ALK alterations; no ROS1 alterations if tested; PD-L1 unrestricted; ≤2 prior therapy lines) were treated with avelumab, axitinib, and palbociclib (3+3 dose escalation design). Tumor and normal endobronchial mucosal biopsies were obtained on all patients for retrospective SIMS algorithm validation. Results: Fifteen patients were treated: 6 at dose level 1 (DL1); 6, dose level 2 (DL2); 3, dose level 3 (DL3). Three dose-limiting toxicities (DLTs) at least possibly drug-related occurred: 1 DLT at DL2 (Grade 3 (G3) infusion reaction); 2 patients with DLTs at DL3 (1 with G3 hand/foot syndrome and G3 fatigue and 1 with G5 respiratory failure). Among 14 evaluable patients, the partial response (PR) rate was 28.6% (4/14 patients including 2/6 patients at DL1; two PRs in patients who failed prior pembrolizumab; two PRs in patients with PD-L1 < 1%). The maximum tolerated dose was avelumab 10 mg/kg IV q2weeks, axitinib 5 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle (DL2). DL2 was above the recommended phase II dose (RP2D), since 5/6 patients treated at DL2 required later treatment delays and/or dose reductions, mostly due to neutropenia. To further evaluate DL1, 3 patients were added to this cohort (total of 6). Since no DLTs were seen at DL1, and 5 of 6 patients did not require dose reduction, DL1 (avelumab 10 mg/kg IV q2weeks, axitinib 3 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle) is the RP2D. Conclusions: The RP2D was determined to be dose level 1. This triplet showed antitumor activity in patients with NSCLC, including those progressing on prior pembrolizumab. SIMS algorithm correlates of response are being assessed. Clinical trial information: NCT03386929 .
A phase Ib study of a novel c-MET, AXL and VEGFR-2 inhibitor ningetinib and gefitinib combination therapy in Chinese EGFR-TKI resistant NSCLC with T790M negative.
Authors: Zhao Hongyun , Liu Lianke , Ma Yuxiang , Fang Jian , Fang Wenfeng , Ma Haiqing , Zhang Yang , Feng Guosheng , Hong Shaodong , Zeng Shan , Xie Bo , Ren Jun , Lin Xiaoyan , Zhang Yingjun , Xi Ning , Jiang Yingzhi , Wu Yanjun , Kang Ning , Li Su , Zhang Li 
Published: May 2020

9583 Background: Ningetinib is a novel tyrosine kinase inhibitor, targeted at c-Met, Axl, VEGFR-2, Mer and Flt3. This phase Ib trial (NCT03758287) evaluated the safety, determined the recommended phase II dose (RP2D), and further explored the pharmacokinetic and efficacy of Ningetinib + Gefitinib in EGFR-TKIs acquired resistant NSCLC patients (pts) with T790M negative. Methods: Chinese Pts with advanced or metastatic NSCLC, acquired resistant to at least one EGFR-TKI, T790M negative were enrolled. Pts received Ningetinib 30, 40, 60 mg + Gefitinib 250mg orally once daily in dose-escalation (n = 12) by a Fibonacci 3+3 design. Expansion phase (n = 74, enrollment is ongoing) started at tolerated dosage. Safety, RP2D were primary endpoints; PK, antitumor activity were secondary endpoints. Non-mandatory tumor samples at baseline were collected for exploratory objectives. Results: Totally, 86 eligible pts were enrolled between Nov 2016 and Dec 2019, and received treatment (Ningetinib 30 mg, n = 36; 40 mg, n = 46; 60 mg, n = 4), with median age 56.7 years, 36% with baseline brain metastasis, 66%/33%/1% prior 1/2/3 lines EGFR-TKI treatment, respectively. Treatment-related adverse events (TRAEs) occurred in 82 (95%) pts, grade 3/4 in 32 pts (37%). Most common TRAEs (≥30%) were myocardial enzyme elevation (all grade 74.4%; grade 3-4 0%), transaminase elevation (73.3%; 2.3%), skin rash (60.5%; 3.5%), albuminuria (44.2%; 0%), coagulation abnormalities (mostly asymptomatic Fbp decrease; 37.2%; 15.1%), diarrhea (33.7%; 2.3%) and hypertension (32.6%; 11.6%). Two Dose limited toxicities were observed at 60 mg dosage (both were grade 3 Fbg decrease), RP2D was decided at 40 mg. Of 84 efficacy evaluable pts, ORR was 19.1% (16 PR), DCR was 91.7% (61 SD, 7 PD). Totally, 65 (75.6%) progression events occurred at data cut-off (9 Jan 2020), the median PFS for all pts was 4.4 months (95%CI 3.7-4.6). No PFS differences were found between pts grouped by 3rd TKIs history or brain metastasis. C-Met gene amplification by FISH was conducted in 72 pts (83.7%). Pts with higher gene copy number (GCN) responded better in treatment, ORR in the GCN ≥6 (n = 11), GCN ≥5 (n = 16) and GCN ≥3 (n = 37) subgroups was 36.4%, 25.0% and 21.6% respectively. Conclusions: Ningetinib was well tolerated at 30 mg and 40 mg dosage with Gefitinib 250 mg, the RP2D for Ningetinb was 40 mg. This combination therapy showed promising anti-tumor activity in prior EGFR-TKIs acquired resistant NSCLC pts with T790M negative. C-Met GCN was the potential efficacy biomarker. Clinical trial information: NCT03758287 .
Genomic characterization of metastatic lung cancers.
Authors: Yu Hui , Bao Hua , Wei Yulin , Wu Min , Wu Shuyu , Wu Xue , Shao Yang , Zhao Xinmin 
Published: May 2020

9584 Background: Lung carcinomas are most often diagnosed at stage IV, with metastases, which contribute to 90% of deaths of patients. Enormous efforts have been made in previous studies in seek of underlying mechanisms and treatments that prevent or cure metastases. However, few comprehensive conclusions have been drawn on organ-specific genomic landscapes and molecular dependencies of lung cancer metastases, largely due to limited sample sizes. Methods: We employed massive targeted next generation sequencing (NGS) with a panel covering 425 cancer-related genes on 10409 samples from 8619 patients with lung cancer, including 8479 from primary tumors and 1930 from metastases to the brain, liver, pleura, bones, and lymph nodes. We investigated single nucleotide variants (SNVs), copy number variants (CNVs), structural variations (SVs), mutational signatures, and other genomic characteristics at all primary and metastatic sites. With data of primary-metastatic tumor pairs, we also examined genomic evolutionary patterns. Results: Our data revealed that metastases harbored more instable and complicated genomes. Most SNVs (5/6), CNVs (41/47), and SVs (2/3) that showed significant differences of prevalence between primary tumors (PTs) and metastases (MTs) were MT-enriched. Among them, we identified a novel MT-enriched event, PTK2 amplification (2.33 folds), as well as known ones including mutations of TP53, ARID1A, and BRCA1 (1.23, 1.74, and 2.29 folds) , and amplifications of MYC, RICTOR, and EGFR (2.04, 2.15, and 1.59 folds). In addition, almost all actionable CNV alterations (6/7) showed higher frequencies in MTs. ALK fusions and EGFR mutations, which indicate distinct target therapies, exhibited opposite preference in MTs and PTs, respectively. We also identified MT site-specificity of alterations, such as NF2, TSC2, and LRP1B mutations enriched in the brain, BRAF and GNAS mutations absent in the liver, and APOBEC-associated mutational signatures enriched in lymph nodes. Moreover, we unraveled organ-specific patterns of genomic evolutionary trajectories in metastatic diseases. Conclusions: The genomic profile and evolutionary pattern of metastatic lung cancer differed from that of primary tumors. The identification of site-specific characteristics that may have empowered directional metastasis, such as NF2, TSC2, and LRP1B mutations in the brain and APOBEC-associated mutational signatures in lymph nodes, may guide personalized disease management, design of clinical trials, and/or discovery of therapeutic targets for metastatic lung cancer at different body regions.