bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC.
Authors: Peters Solange , Mok Tony S. K. , Gadgeel Shirish M. , Rosell Rafael , Dziadziuszko Rafal , Kim Dong-Wan , Perol Maurice , Ou Sai-Hong Ignatius , Shaw Alice Tsang , Bordogna Walter , Smoljanovic Vlatka , Hilton Magalie , Ruf Thorsten , Archer Venice Rosale , Camidge D. Ross
Published: May 2020

9518

Background: Final, mature PFS from the global phase III ALEX study (NCT02075840) of ALC vs CRZ in untreated, advanced/metastatic ALK+ NSCLC have been previously published: ALC 34.8 months (m) (95% CI 17.7–NR) vs CRZ 10.9 m (95% CI 9.1–12.9), (HR 0.43, 95% CI 0.32–0.58). We report 5-year OS and updated safety data from ALEX with a further 12 m follow-up (FU) (cutoff date: Nov 29, 2019). Methods: Patients (pts) with stage IIIB/IV ALK+ NSCLC (by central IHC), ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC were randomized 1:1 to ALC 600 mg BID (n = 152) or CRZ 250 mg BID (n = 151). Asymptomatic CNS metastases (mets) at baseline (BL) were allowed. OS was a secondary endpoint, and no formal statistical testing was planned. Results: Median duration of FU: 48.2 m with ALC vs 23.3 m with CRZ. OS data remain immature (events: 37%; stratified HR 0.67 [95% CI 0.46–0.98]); median OS with CRZ was 57.4 m (95% CI 34.6–not estimable [NE]) vs NE with ALC. The 5-year survival rate was 62.5% (95% CI 54.3–70.8) with ALC vs 45.5% (95% CI 33.6–57.4) with CRZ (Table). In pts with CNS mets at BL the OS HR was 0.58 (95% CI 0.34–1.00) and 0.76 (95% CI 0.45–1.26) in pts without CNS mets at BL. The OS benefit of ALC vs CRZ was generally consistent across all subgroups. Considering the longer treatment duration for ALC (28.1 m) vs the previous analysis (27.7 m), the safety profile of ALC remains consistent; no new safety signals were observed. With ALC, 35% of pts remain on study treatment vs 9% of pts remaining on CRZ. In pts with ≥1 known post-progression treatment (ALC: 32.2%; CRZ: 45.7%), lorlatinib was the most common ALK TKI received after first-line ALC (7.2%), compared with ceritinib after first-line CRZ (15.2%). Conclusions: This is the first global randomized study of a 2nd generation ALK TKI to demonstrate a clinically meaningful improvement in OS vs CRZ in ALK+ NSCLC (5-year survival rate: 62.5%, ALC vs 45.5%, CRZ); longer FU is required as OS data remain immature. Clinical trial information: NCT02075840 . [Table: see text]
Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).
Authors: Lu Shun , Fang Jian , Li Xingya , Cao Lejie , Zhou Jianying , Guo Qisen , Liang Zongan , Cheng Ying , Jiang Liyan , Yang Nong , Han Zhigang , Shi Jianhua , Chen Yuan , Xu Hua , Zhang Helong , Zhang Di , Li Jing , Wang Linfang , Ren Yongxin , Su Weiguo
Published: May 2020

9519

Background: There are unmet medical needs for pts with METex14+ NSCLC. PSC is a rare type of NSCLC with high incidence of MET exon 14 mutations and poor prognosis. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective oral MET tyrosine kinase inhibitor, and its anti-tumor activity has been shown in combination with osimertinib in pts with EGFR-mutant, MET-amplified NSCLC (Yu H, et al. 2019 AACR, Abstract CT032). Methods: This was a multicenter, multi-cohort, single-arm phase II study (NCT02897479) to evaluate the efficacy, safety, and pharmacokinetics of savolitinib in pts with unresectable or metastatic METex14+ PSC and other NSCLC. MET mutation was tested or retrospectively confirmed by central laboratory. Savolitinib was taken orally, once daily (QD) (600mg for weight ≥50kg or 400mg weight < 50kg) until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks during the 1st year and every 12 weeks thereafter. The primary endpoint was independent review committee (IRC) assessed objective response rate (ORR) (RECIST version 1.1). Here we report the results of one cohort of prior MET-treatment naïve patients. Results: As of October 31, 2019, 593 pts were pre-screened/screened, 87 identified with METex14+ and 70 treated. Among treated pts, median age was 68.7 years (range 51.7-85.0), 58.6% pts were male, 92.9% stage IV, 60.0% previously treated, 57.1% with adenocarcinoma, 35.7% with PSC and the rest with other pathological types. Sixty-one pts were efficacy evaluable by IRC assessment (N = 61) (including pts who had at least one measurable lesion at baseline and had ≥1 scheduled post-baseline tumor assessment or evidence of any post-baseline radiological disease progression): ORR was 47.5% (95% CI: 34.6%, 60.7%), disease control rate 93.4% (95% CI: 84.1%, 98.2%) and median duration of response not reached yet. The median progression-free survival was 6.8 months (95% CI 4.2, 13.8) among all treated pts. Efficacy results were consistent with investigators’assessments. The most common (≥20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of ≥ grade 3 TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% pts, among which liver injury and hypersensitivity were most common (each 2.9%). Conclusions: Savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in METex14+ NSCLC pts. Clinical trial information: NCT02897479 .
Comprehensive modeling of longitudinal circulating tumor DNA dynamics to predict clinical response to first-line immunotherapy and chemoimmunotherapy in advanced non-small cell lung cancer.
Authors: Murray Joseph Christopher , Rhymee Lamia , Marrone Kristen , Naidoo Jarushka , Levy Benjamin Philip , Ferreira Leonardo , Rosner Samuel , Lanis Mara , Hann Christine L. , Feliciano Josephine Louella , Lam Vincent K. , Ettinger David S. , Illei Peter Bela , Wang Chenguang , Brahmer Julie R. , Forde Patrick M. , Velculescu Victor E. , Scharpf Robert B. , Anagnostou Valsamo
Published: May 2020

9525

Background: First-line immunotherapy (IO) and chemo-immunotherapy (chemo-IO) are approved for PD-L1-expressing advanced non-small cell lung cancer (NSCLC), but PD-L1 expression does not reliably predict therapeutic response. Therefore, accurate on-therapy response assessment is needed to guide clinical decision-making. Conventional radiographic imaging is the gold-standard, but may not capture the nature and timing of an immune-mediated response. We investigated whether comprehensive longitudinal circulating tumor DNA (ctDNA) dynamics could enhance prediction of clinical response. Methods: We conducted targeted error correction sequencing (TEC-Seq) of longitudinal plasma specimens and matched white blood cells (WBCs) in patients with NSCLC treated with first-line IO or chemo-IO. Plasma ctDNA variants were identified by filtering out clonal hematopoiesis (CH) and germline (GL) variants found in matched WBCs. Clinical and pathological data, including PD-L1 tumor proportion score (TPS), and imaging response by RECIST1.1 were assessed. ctDNA dynamics were modeled to predict durable clinical benefit (at 6 months), progression-free survival (PFS), and overall survival (OS). Results: A total of 143 longitudinal plasma and 24 white blood cell samples underwent TEC-Seq for 31 patients with NSCLC treated with IO (n = 17) or chemo-IO (n = 14). ctDNA variants were found in 77% (n = 24) of patients after filtering out CH and GL variants, which comprised 53% (n = 196 of 373) of all variants. Molecular response, signified by elimination of ctDNA variants, was detected in 32% (n = 10) of patients and associated with improved PFS (p = 0.0004, log rank) and OS (p = 0.017, log rank). Time to molecular response was shorter than time to best RECIST response (median 3 vs. 7.71 weeks, p = 0.048, Mann-Whitney U test). A logistic regression model incorporating molecular response, recrudescence, or emergence of new variants predicted durable clinical benefit (sensitivity 84%, specificity 76%, AUC 0.88) better than PD-L1 TPS (AUC 0.67, p = 0.046, bootstrap method). Conclusions: Comprehensive modeling of ctDNA variant dynamics predicts clinical outcome independent of PD-L1 status in patients with advanced NSCLC treated with first-line IO or chemo-IO. Verification of bona fide ctDNA variants by matched WBC sequencing is essential. Molecular response can be identified earlier than imaging response and could enable on-therapy decision-making to alter clinical outcomes.
Targeted DNA sequencing analysis to reveal genetic diversity and androgen-receptor alteration in advanced EGFR mutant lung adenocarcinoma.
Authors: Wu Wei , Okimoto Ross A. , Blakely Collin Michael , Fraser James , Bivona Trever G.
Published: May 2020

9526

Background: Lung cancer remains the leading cause of death from cancer around the world. Several oncogenic drivers have been identified from large cancer genome projects focused mainly on profiling early-stage lung cancers. Targeted therapies have been developed for specific activated driver gene mutations and are used in advanced-stage patients. For instance, advanced EGFR mutant lung cancer is primarily treated with EGFR tyrosine receptor inhibitors (TKIs). However, resistance remains an obstacle to durable anti-tumor control. We hypothesize that concurrent genetic alterations co-exiting with EGFR driver mutations contribute to the failure of EGFR TKI therapy. Methods: To understand the complexity and diversity of genetic alterations present in EGFR mutant advanced lung cancers, we utilized 660 EGFR mutant advanced lung adenocarcinomas samples with targeted DNA sequencing from Foundation Medicine, 394 cases from MSK-IMPACT dataset, along with TCGA lung cancer data. We performed systematic co-mutation analysis, molecular simulation, functional annotation and pathway enrichment analysis. Results: We updated mutational profiling on EGFR gene with hotspots at exon 18, 19, 20 and 21. Among them, EGFR L858R, exon19 deletion, T790M and G719A are top ranking alleles among EGFR mutations. Interestingly, a subset (n = 26 cases) of EGFR T790M mutations parallel with other EGFR mutations, which could affect the TKI binding pocket as inferred by molecular simulations. Furthermore, in advanced lung cancer EGFR mutations co-occurred with known oncogenic mutations in KRAS, MET, NF-1, MAP2K1, ERBB2, and ALK/ROS-1/RET fusions. Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR mutant lung cancer were enriched in signatures of epigenetic modifiers, genome instability, WNT signaling, and RNA splicing. Compared to early stage TCGA-lung adenocarcinomas, Cell cycle, DNA repair, WNT signaling and androgen receptor-mediated signaling pathways are predominantly altered in advanced EGFR mutant lung cancers. Conclusions: We characterized the genetic landscape of advanced EGFR-mutant lung adenocarcinomas and further dissected concurrent mutated genes with EGFR driver mutations. Our findings provide a rational for polytherapy roadmap for testing in advanced EGFR-mutant lung cancer.
Residual circulating tumor DNA (ctDNA) after two months of therapy to predict progression-free and overall survival in patients treated on S1403 with afatinib +/- cetuximab.
Authors: Mack Philip C. , Redman Mary Weber , Moon James , Goldberg Sarah B. , Herbst Roy S. , Melnick Mary Ann C. , Walther Zenta , Hirsch Fred R. , Politi Katerina A. , Kelly Karen , Gandara David R.
Published: May 2020

9532

Background: ctDNA from patient plasma has demonstrated diagnostic utility in non-small cell lung cancer (NSCLC). Longitudinal changes in mutant allele frequency (MAF) have great potential to refine clinical management on targeted therapies. Methods: S1403 was a first-line phase II study of afatinib w or w/o cetuximab in pts with EGFR-mutant NSCLC. Between March, 2015 and April, 2018, 174 pts were randomized with 168 determined to be eligible. The study closed early due to futility. Plasma specimens were prospectively collected at baseline, Cycle 3 Day 1 (C3D1; 8 weeks) and at progression, and processed for batch analysis of ctDNA by next-generation sequencing (Guardant 360). A complete case analysis approach was used. The Kaplan-Meier method was used to estimate survival distributions, a Cox model to estimate hazard ratios and confidence bounds, and the log-rank test to compare distributions. A landmark analysis was used to assess predictive value of ctDNA clearance at C3D1. Results: 104 patients (62%) had analyzable baseline plasma specimens available, with EGFR mutations detected in 83 (80%). PFS was significantly shorter for pts with EGFR ctDNA positivity at baseline (p = 0.03) (Table) compared to those with no detectable ctDNA, likely a prognostic effect. Kinetic changes in ctDNA MAFs were analyzed in 79 pts with matching baseline and C3D1 specimens. Of 62 cases with detectable ctDNA at baseline, 68% (42/62) became undetectable at C3D1 (“ctDNA clearance”); ctDNA clearance relative to residual ctDNA was associated with significantly longer PFS (p = 0.00001) and OS (0.003) (Table). To date, 29 pts had matching at-progression samples. T790M mutations were observed at progression in 6/29 (24%) cases. Other putative emergent resistance factors include: a TACC3-FGFR3 and an EML4-ALK fusion, MET exon 14 skipping, multiple MET amplifications and NF1 frameshift mutations. Conclusions: Clearance of EGFR ctDNA after 60 days of therapy was associated with a substantial and statistically significant improvement in subsequent PFS and OS. Incorporation of ctDNA kinetics into routine clinical care represents a promising platform to identify patients with inferior outcomes on TKIs and detect targetable emergent resistance mechanisms. [Table: see text]
Prediction of the molecular status in non-small cell lung cancer based on metastatic pattern: A free webtool powered by artificial intelligence.
Authors: Besse Benjamin , Dormieux Alison , Mezquita Laura , Monnet Renaud , Tazdait Melodie , Lacroix Ludovic , Rouleau Etienne , Adam Julien , Remon Masip Jordi , Bluthgen María , Facchinetti Francesco , Tzelikas Lambros , Lavaud Pernelle , Naltet Charles , Le Pechoux Cecile , Balleyguier Corinne , Planchard David , Lassau Nathalie , Cournede Paul-Henri , Caramella Caroline
Published: May 2020

9535

Background: Molecular characterization of metastatic lung adenocarcinomas is mandatory but might be hampered by the quantity of tissue, restricted access to molecular platforms or limited economical resources. Our aim was to develop a tool supported by the hypothesis that radiological patterns of pts could help predict the rate of positivity of the most common oncogenic drivers. Methods: We defined an algorithm based on a molecularly defined cohort of 656 pts with stage IV lung adenocarcinoma. Two radiologists centrally reviewed the baseline imaging. Clinical data were retrospectively collected. There were 135 EGFR mutations, 81 ALK fusions, 47 BRAF mutations, 141 KRAS mutations, and 146 pan-negative tumors for these 4 oncogenic drivers. Univariate correlation analyses were performed to define an algorithm predicting the molecular testing positivity based on the metastatic pattern. Subsequently, an online tool was developed. This study was approved by our institutional review board. Results: Metastatic patterns correlated with the genomic drivers when compared to the pan-negative group. In the EGFR group, pleural metastases were more frequent (32% vs. 20%; p = 0.021), whereas adrenal and node metastases less frequent (6% vs.23%; p < 0.001 and 11% vs. 23% respectively; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% vs. 29%; p = 0.043 and 37% vs. 24% respectively; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (47% vs. 20%; p < 0.001 and 11% vs. 3% respectively; p = 0.04) and bone metastases less common (21% vs. 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK and BRAF groups (6%, 7% and 15% vs. 1%; p = 0,016, p = 0,009 and p < 0,001 respectively). A free online access to the algorithm is now available after registration at http//tactic-ct.fr. Physicians enter age, sex, smoking status and the sites of metastases at diagnosis (present/absent/unknown). A mutation score is calculated, reflecting the % of chance to find an oncogenic driver. On the website, contributors can also enter new cases and an artificial intelligence will refine the algorithm and expand the number of oncogenic drivers. Conclusions: Our free access tool allows establishing a hierarchy in the molecular testing based on simple clinical and radiological information. Continual learning from new cases entered in the database will increase the sensitivity of the tool. This tool might save time, tumor tissue, economical resources and accelerate access to personalized treatment.
Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC).
Authors: Liu Stephen V. , Vanderwalde Ari M. , Mamdani Hirva , Raez Luis E. , Baca Yasmine , Xiu Joanne , Korn Wolfgang Michael , Nagasaka Misako , Pai Sachin Gopalkrishna , Socinski Mark A. , Nieva Jorge J. , Kim Chul , Wozniak Antoinette J. , Ikpeazu Chukwuemeka , Lopes Gilberto , Spira Alexander I. , Judd Julia , Kim Edward S. , Borghaei Hossein
Published: May 2020

9544

Background: KRAS is the most commonly mutated oncogene in NSCLC and the development of direct KRAS inhibitors has renewed interest in this molecular subtype. However, there are several different KRAS mts, representing unique biology and different prognostic and therapeutic impact. A more comprehensive understanding of the genomic landscape relative to each KRAS mt subset will help guide therapeutic development. Methods: Molecular profiles of 17,113 NSCLC specimens were obtained using next-generation sequencing of 592 genes (Caris Life Sciences) and classified based on presence and types of KRAS mt. Incidence of KRAS mts was noted across the cohort and by histology. Co-occurring genomic alterations, tumor mutational burden (TMB) and PD-L1 IHC (22C3, TPS score) were analyzed by KRAS mt type. Results: Across the entire cohort, 4706 (27%) of samples harbored a KRAS mt (Table). The most common was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mt was 37.2% among adenocarcinoma and only 4.4% in squamous. High TMB, defined by > 10 mts/Mb, varied across the different KRAS mt types, most common in G13X (68.3%) and least common in G12D (43.2%). PD-L1 expression also varied. G12C was the most likely to be PD-L1 positive, with 65.5% TPS > 1%, and the most likely to be PD-L1 high, with 41.3% TPS > 50%. STK11 was mutated in 8.6% of KRAS wild type NSCLC but more frequently noted in every KRAS subtype, with the highest rate in G13X (36.2%) and the lowest in G12D(14.2%). TP53 mts were more frequent in KRAS wild type NSCLC (73.6%), with the highest rate among KRAS mutants at 55.4% (G12other) and the lowest at 36.8% (Q61X). NF1 was noted to be mutated in 21.4% of KRAS G13X cases, while all other KRAS mts had a lower frequency of NF1 mts than KRAS wild type (11.5%). Conclusions: KRAS mts are relatively common in lung adenocarcinoma and KRAS G12C is the most common variant. The different KRAS mts have different co-occurring mutations and a different genomic landscape. KRAS G12C was associated with the highest rate of PD-L1 expression. The clinical relevance of these differences in the context of therapeutic intervention warrants investigation. [Table: see text]
Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Luo Jia , Bandlamudi Chaitanya , Ricciuti Biagio , Vokes Natalie , Schoenfeld Adam Jacob , Egger Jacklynn V. , Sauter Jennifer L. , Plodkowski Andrew J. , Preeshagul Isabel Ruth , Kris Mark G. , Van Allen Eliezer Mendel , Taylor Barry S. , Rizvi Hira , Donoghue Mark , Awad Mark M. , Hellmann Matthew David
Published: May 2020

9549

Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting < 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p < 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p < 0.001). Patients with LTR were younger ( < 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p < 0.001, p < 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p < 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p < 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response.
Final analysis of KEYNOTE-189: Pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).
Authors: Rodriguez-Abreu Delvys , Powell Steven Francis , Hochmair Maximilian , Gadgeel Shirish M. , Esteban Emilio , Felip Enriqueta , Speranza Giovanna , Dómine Gomez Manuel , Cheng Susanna Y. , Bischoff Helge , Peled Nir , Reck Martin , Hui Rina , Garon Edward B. , Boyer Michael J. , Kurata Takayasu , Yang Jing , Bas Tuba , Souza Fabricio G. , Garassino Marina Chiara
Published: May 2020

9582

Background: The phase III KEYNOTE-189 study (NCT02578680), showed significant improvements in OS and PFS with pembro + chemo vs placebo + chemo in pts with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK mutations. We report the protocol-specified final analysis of KEYNOTE-189. Methods: Pts were randomized 2:1 to receive 35 cycles of pembro 200 mg Q3W (n = 410) or placebo Q3W (n = 206) plus 4 cycles of pemetrexed (pem) and carboplatin/cisplatin followed by maintenance pem. Pts in the placebo + chemo arm could crossover to pembro upon PD. PFS and OS were primary endpoints; ORR was a secondary endpoint. PFS2 (time from randomization to objective tumor progression on next-line treatment/death), was an exploratory endpoint. Results: At data cutoff (May 20, 2019), median (range) time from randomization to data cutoff was 31.0 (26.5–38.8) mo. 17 pts in the pembro + chemo arm and 1 pt in the placebo + chemo arm were receiving initially assigned treatment; 84 pts crossed over to pembro. Median (95% CI) OS (22.0 [19.5–24.5] vs 10.6 [8.7–13.6] mo; HR 0.56 [95% CI, 0.46–0.69]) and PFS (9.0 [8.1–10.4] vs 4.9 [4.7–5.5] mo; HR 0.49 [95% CI, 0.41–0.59]) were longer with pembro + chemo vs placebo + chemo (Table). The 2-y OS rate was 45.7% vs 27.3% and the 2-y PFS rate was 22.0% vs 3.4%. ORR was 48.3% with pembro + chemo vs 19.9% with placebo + chemo. 56 pts in the pembro + chemo arm completed 35 cycles of pembro among whom ORR was 85.7% (4 CR, 44 PR, 8 SD) and median OS was not reached. 292 (72.1%) pts in the pembro + chemo arm and 135 (66.8%) pts in the placebo + chemo arm had grade 3–5 AEs. Conclusions: Pembro + chemo continued to show improved outcomes in OS, PFS, ORR and PFS2 compared with placebo + chemo, with manageable toxicity. These findings support first-line pembro + chemo in pts with previously untreated metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680 . [Table: see text]
High-dose osimertinib for CNS progression in EGFR+ non-small cell lung cancer (NSCLC): A multi-institutional experience.
Authors: Piper-Vallillo Andrew , Rotow Julia K , Aredo Jacqueline V , Shaverdashvili Khvaramza , Luo Jia , Carlisle Jennifer W , Husain Hatim , Muzikansky Alona , Heist Rebecca Suk , Rangachari Deepa , Ramalingam Suresh S. , Wakelee Heather A. , Yu Helena Alexandra , Sequist Lecia V. , Bauml Joshua , Neal Joel W. , Piotrowska Zofia
Published: May 2020

9586

Background: High-dose osimertinib 160 mg QD (osi160) has activity in osi-naïve, EGFR+ NSCLC pts with CNS or leptomeningeal disease (LMD) per the BLOOM trial, but the role of dose-escalation for CNS progression (PD) and/or LMD that develops while on 80 mg QD (osi80) is unclear. We describe here our multi-institutional experience with osi160. Methods: 105 pts from 8 institutions with advanced EGFR+ NSCLC treated with osi160 were retrospectively reviewed. To assess the CNS efficacy of dose escalation for CNS PD, we focused on pts who escalated from osi80 to osi160 for CNS PD without the addition of chemo and/or RT during dose escalation (cohort A, 24 pts). We also examined osi escalation for CNS PD while receiving chemo and/or RT (cohort B, 34 pts) and those who started on osi160 for CNS PD as the initial osi dose without overlapping therapies (cohort C, 11 pts). Radiographic responses were clinically assessed via chart review of scan reports. Kaplan-Meier analysis was used for time-to-event endpoints. We defined median duration of CNS disease control (MedDurCNSCon) on osi160 as time from the start of osi160 to CNS PD or discontinuation of osi160. Results: Among the 105 pts, 69 (26M, 43F; median age 57) EGFR+ NSCLC pts (29 del19, 31 L858R, 9 other) received osi160 for CNS PD between 10/2013 and 1/2020. Median lines of therapy pre-osi was 1 (range 0-8). While all 69 pts had CNS PD at the start of osi160, 61 (90%) had isolated CNS/LMD PD, without systemic PD. In cohort A, osi160 monotherapy had a MedDurCNSCon of 3.8 mos (95% CI, 1.7 – 5.8). Cohort A pts with isolated LMD (11) had MedDurCNSCon 5.8 mos (95% CI, 1.7 – 9) while those with parenchymal mets only (11) had MedDurCNSCon of 2 mos (95% CI, 1 - 4.9). In cohort B, osi160 in combination with RT (22) and/or chemo (14), had a MedDurCNSCon of 5.1 mos (95% CI, 3.1 – 6.5). In cohort C, osi160 monotherapy had a MedDurCNSCon of 4.2 mos (95% CI, 1.6 – NA). Pts on osi160 had no severe or life-threatening side effects. Conclusions: In this real-world cohort of EGFR+ NSCLC pts with CNS and/or LMD PD on osi80, dose escalation to 160 provided modest benefit with median 3.8 mos added CNS disease control. Dose escalation appeared more effective in pts with LMD versus parenchymal disease (MedDurCNSCon of 5.8 vs 2 mos). Treatment intensification with osi escalation plus RT and/or chemo appeared to confer about 1 month additional CNS disease control (power for comparison limited). Osi naïve pts started at 160 for CNS PD derived similar benefit. While limited by small numbers and retrospective design, this study suggests we need improved strategies to optimally manage CNS PD arising on osi80.
Longitudinal monitoring by next generation sequencing of plasma cell-free DNA in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with ALK tyrosine kinase inhibitors.
Authors: Kwon Minsuk , Ku Bo Mi , Park Sehhoon , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju
Published: May 2020

9603

Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) NSCLC inevitably acquire resistance to ALK inhibitors. We hypothesized that longitudinal monitoring of cell-free plasma DNA (cfDNA) next generation sequencing (NGS) could predict the response and resistance of TKI therapy in ALK+NSCLC Methods: Patients with ALK+ advanced NSCLC determined by standard tissue testing and planned for TKI therapy were prospectively recruited. Plasma was collected before therapy (n = 92), two months post-therapy (n = 58), and at progression (n = 35). Plasma DNA NGS analysis was done retrospectively by Guardant360. Results: From April 2015 to July 2019, 92 patients enrolled; 81 (88.0%) received ALK TKI as first-line (crizotinib, n = 59; alectinib, n = 22), 10 (10.9%) received TKI as second-line (alectinib, n = 6; crizotinib, n = 2; ceritinib, n = 1; brigatinib, n = 1), and 1 (1.1%) was treated in third-line (lorlatinib). At the cut-off date of January 28, 2020, 56 of 92 patients had disease progression. Circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%); among these were 43 ALK fusions (62.3%) and 1 ALK G1202R without fusion (1.4%). Fusions included EML4-ALK v1 (n = 19), EML4-ALK v3 (n = 14), CLTC-ALK (n = 1), TPM3-ALK (n = 1), GCC2-ALK/CLIP4-ALK (n = 1), and other EML4-ALK fusions (n = 7). Eight patients developed ALK resistance mutations after crizotinib therapy: L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Two patients developed ALK resistance mutations after ceritinib: G1202R (n = 1), and co-occurring G1202R and T1151R (n = 1). The absence of detectable ctDNA at baseline was associated with longer progression-free survival (PFS; median 36.1 vs 11.6 months, HR 0.432, p = 0.004) and overall survival (OS; median not reached vs 27.9 months, HR 0.418, p = 0.034). Patients with clearance of ctDNA at two months (n = 29) had significantly longer PFS (median 25.4 vs 13.9 months, HR 0.343, p = 0.030) and OS (median not reached vs 25.7 months, HR 0.173, p = 0.035) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 9) showed shorter PFS (median 7.0 vs 12.5 months, HR 3.596, p = 0.0154) than those without TP53 alterations (n = 35). Conclusions: NGS of cell-free plasma DNA is useful not only for the detection of ALK fusions and resistance mutations but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK TKI.
Establishment of the first international large-scale, genomic screening platform to identify patients with rare oncogene drivers in non-small cell lung cancer (NSCLC) in East Asia.
Authors: Matsumoto Shingo , Zhou Caicun , Kuo Chih-Hsi , Yoh Kiyotaka , Kato Terufumi , Nishino Kazumi , Furuya Naoki , Zhang Shucai , Lin Dongmei , Han Yuchen , Wang Chin-Chou , Ikeda Takaya , Zenke Yoshitaka , Goto Koichi
Published: May 2020

9605

Background: A rapidly increasing number of oncogenic drivers have been identified in non-small cell lung cancer (NSCLC), and most of them occur in less than 5% of patients. Large-scale genomic screening to identify patients with rare driver alterations is thus necessary to enable precision medicine and to support the development of novel targeted therapies and companion diagnostics (CDx). Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 with 206 institutions in Japan and 5 in Taiwan currently participating. A separate genomic screening project with similar structure was established in China (LC-IRICA-China) in collaboration with LC-SCRUM-Asia in 2019 (3 institutions enrolling, 17 about to open, 63 undergoing review). Samples are analyzed by a multi-gene PCR panel and targeted next-generation sequencing. The target is to enroll 70000 NSCLC patients (20000 from LC-SCRUM-Asia and 50000 from LC-IRICA-China) by 2022. Results: From March 2013, a total of 9383 lung cancer patients were enrolled in LC-SCRUM-Asia, and from October 2019, 1649 pts were included in LC-IRICA-China (January 2020). The rates of genomic alterations in LC-SCRUM-Asia: EGFR (17%) of which ex20ins (2%), KRAS (13%) of which G12C (4%), ALK fusions (2%), ROS1 fusions (2%), RET fusions (2%), HER 2 ex20ins (3%), MET ex14skip (2%), BRAF V600E (1%), NRG1 fusions (0.2%) and NTRK3 fusions (0.03%). Corresponding rates in the initial 243 pts in LC-IRICA China: EGFR (45%) of which ex20ins (2%), KRAS (8%), ALK (5%), ROS1 (2%), RET (1%), HER2 (2%), MET ex14skip (1%), BRAFV600E (1%). Through the screening, 266 patients from Japan and Taiwan were enrolled into genotype-matched clinical trials of unapproved targeted drugs. In Japan, ROS1-, BRAF- and TRK-targeted therapies were successfully approved based on these clinical trials, and a NGS-based multi-gene CDx for EGFR/ALK/ROS1/BRAF targeted-therapies was approved based a concordance study using archival samples from the project. Conclusions: An East Asian international genomic screening platform has been established to enable precision medicine for patients, accelerate drug and diagnostic development in patients with very rare alterations and to help provide a deeper understanding of the underlying biology of NSCLC in East Asian patients. The screening network will be further expanded to other countries in East Asia in the near future.
Resistance to lorlatinib in ROS1 fusion-positive non-small cell lung cancer.
Authors: Lin Jessica Jiyeong , Johnson Ted , Lennerz Jochen K , Lee Charlotte , Hubbeling Harper Grace , Yeap Beow Y. , Dagogo-Jack Ibiayi , Gainor Justin F. , Shaw Alice Tsang
Published: May 2020

9611

Background: Lorlatinib is a potent, brain-penetrant ROS1/ALK tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in advanced ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC), including in patients (pts) previously treated with crizotinib. Despite initial benefit, however, most pts experience disease progression on lorlatinib. Mechanisms of resistance to lorlatinib in ROS1+ NSCLC are poorly understood. Methods: We analyzed repeat tumor biopsies derived from advanced ROS1+ lung cancer pts progressing on lorlatinib. Next-generation sequencing (NGS, n = 17) or whole exome sequencing (n = 1) was performed to detect mutations, indels, and copy number alterations. Results: Sixteen pts underwent a total of 18 repeat tumor biopsies after progression on lorlatinib. Fourteen had received prior crizotinib; two received prior crizotinib and entrectinib. Median duration of therapy on lorlatinib was 13.5 months (95% CI, 8.3-18.4). Among the 18 cases analyzed by sequencing, 7 (38.9%) harbored a ROS1 resistance mutation, including G2032R (4/18, 22.2%), S1986F/L2000V (1/18, 5.6%), L2086F (1/18, 5.6%), and G2032R/S1986F/L2086F (1/18, 5.6%). Of note, ROS1 L2086F was a novel resistance mutation not previously reported in the literature, but analogous to ALK L1256F (a lorlatinib-resistant ALK mutation). Structural modeling studies showed that ROS1 L2086F causes steric interference with binding of lorlatinib, as well as crizotinib and entrectinib. In addition to ROS1 kinase domain mutations, NGS analyses also identified MET copy number gain in a lorlatinib-resistant case, validated by fluorescence in situ hybridization as high-level focal MET amplification (MET/CEP7 copy number ratio 6.3) without a concomitant ROS1 resistance mutation. Duration of therapy on lorlatinib was significantly shorter in pts with a post-lorlatinib ROS1 resistance mutation compared to those without (8.3 vs 18.1 months; p = 0.005). Conclusions: ROS1 resistance mutations are observed in over one-third of cases progressing on lorlatinib, including the solvent front mutation G2032R and a novel L2086F mutation. These findings underscore the importance of developing next-generation ROS1 TKIs with activity against ROS1 mutations, and the need to elucidate ROS1-independent resistance mechanisms.
Genomic characterization and outcome evaluation of kinome fusions in a large non-small cell lung cancer population.
Authors: Wu Fengying , Liu Sisi , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Zhou Caicun
Published: May 2020

9620

Background: Lung cancer is the leading cause of cancer death worldwide. Kinase fusion represents an important type of somatic alterations which promote oncogenesis and serve as a diagnostic marker in lung cancer. This study aims to identify the landscape of kinase fusions in lung cancer and expand our understanding of druggable fusions, together providing valuable information for therapeutics decision making. Methods: We performed genomic profiling of tumor/plasma biopsies of a total of 18,839 Chinese lung cancer patients using next generation sequencing (NGS) by targeting 425 cancer-relevant genes. Patients’ clinical characteristics and treatment history were retrospectively studied. Results: A total of 1,048 patients (5.56%, 1,048/18,839) were identified with kinase fusions, including 815 adenocarcinomas (ADCs) and 34 squamous cell carcinomas (SCCs). Briefly, a total of 198 unique gene fusion events have been observed, including 37 recurrent fusions and 114 novel fusions which have previously not been documented. ADC patients with kinase fusions were relatively younger than SCC patients (median: 53 vs 61 years old, p< 0.01). The most frequently observed fusion was EML4-ALK for both ADCs (50.0%) and SCCs (32.4%), followed by FGFR3-TACC3 (29.4%) in SCCs and KIF5B-RET (11.8%), CD74-ROS1 (9.2%), CCDC6-RET (3.9%) and SLC34A2-ROS1 (2.3%) in ADCs, retrospectively. A total of 14 recurrent fusions including FN1-ALK, MEMO1-ALK, CUX1-ALK, KIF13A-RET and PHF20-NTRK1 were also identified at low frequencies. Of note, EML4- or STRN- ALK fusion events mainly rearranged in the intron 19 of ALK, but the breakpoints of VCL-ALK were mostly located upstream of ALK exon 18. Meanwhile, CD74-, SLC34A2- and TPM3- ROS1 rearrangement mainly occurred in the ROS1 introns 31, 33 and 34. In addition, among patients with novel fusions, RORB- ALK and AFF2-RET may potentially function as oncogenic drivers in lung cancer and have demonstrated clinical benefit from crizotinib treatment. Conclusions: Our data have depicted a comprehensive overview of the landscape of kinase fusions in lung cancer, which helps recognize potentially druggable fusions and translate into therapeutic applications.
Difference in clinicopathological characteristics between pure and mixed invasive micropapillary breast carcinomas from eastern China.
Authors: Wang Rong , Li Nani , Jia Wang Xiao , Cao Wen-Ming
Published: May 2020

e12500

Background: Invasive micropapillary carcinoma of the breast (IMPC) is a rare pathologic subtype of breast cancer with frequent lymph node metastases. Since the differences in pathological features between pure and mixed IMPCs are not fully understood, we aimed to investigate the difference in clinicopathological characteristics between pure and mixed IMPC. Methods: Overall 121 IMPC cases were included from Zhejiang Cancer Hospital, China during May 2010-August 2018. The clinicopathological features and survival estimates between the pure IMPC and mixed IMPC groups were compared. Targeted sequencing was performed to investigate the genomic profile of paired primary breast cancer and metastatic tissue samples from two pure IMPC and four mixed IMPC. The copy number variations (CNVs) and the tumor mutation burden (TMB) from metastatic tissues were analyzed. Results: Overall 48 cases were pure IMPC and 73 were mixed IMPC. The pure group had significantly higher proportion of luminal B compared to the mixed group (37.5% vs.15.1%), but lower proportion of luminal A (33.3% vs. 45.2%). The pure group had similar HER2 overexpression rate (31.2% vs. 32.9%) and mean age at diagnosis (51.0 vs. 50.2 years), compared to the mixed group. The pure group had significant higher proportion of stage ⅢC cases compared to the mixed group (38.3% vs.17.8%). We found no significant difference in 3-year disease-free survival (DFS) between the two groups (83.7% vs. 80.0%), but the mixed group had a better overall survival (OS), compared to the pure group (HR = 0.28 (0.091-0.868), P = 0.047). Conclusions: We found that pure IMPC had more aggressive behavior with locally advanced disease and higher proportion of luminal B than mixed IMPC. Mixed IMPC had a longer OS compared to pure IMPC, but no significant difference in 3-year DFS between two groups.
Paclitaxel-induced peripheral neuropathy in early-stage breast cancer patients.
Authors: Liu Jacqueline , Sorooshian Hormozan
Published: May 2020

e12503

Background: Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and can persist for up to two years after completing treatment, greatly affecting both the course of chemotherapy and quality of patients. Few studies have characterized the side effect profiles of two commonly used paclitaxel-based adjuvant regimens, dose-dense biweekly paclitaxel with growth factor support (ddP, 175 mg/m2 biweekly for four cycles) and weekly paclitaxel (wP, 80 mg/m2 weekly for 12 cycles). Conflicting results exist regarding the incidence of paclitaxel-induced neuropathy related to either administration scheme. Methods: This is a data-only retrospective cohort study that consisted of adult patients with early-stage breast cancer who received either ddP or wP at Kaiser Permanente Diablo Service Area (Walnut Creek and Antioch Medical Centers) between January 1, 2010 and January 1, 2019. The primary endpoint was the proportion of patients with dose-limiting chemotherapy-induced peripheral neuropathy (DL CIPN). Results: 244 patients were included in the final analysis with 159 and 85 patients receiving wP and ddP, respectively. Baseline demographics were well matched between the two groups. There was no significant difference in the proportion of patients who experienced DL CIPN with wP (17.6%) compared to ddP (19.1%) (p = 0.647). Grade 3 or 4 adverse events occurred in 8.9% of patients who received wP and 10.6% of patients who received ddP. No significant difference was observed (p = 0.650). Conclusions: The results of this study support the current National Comprehensive Cancer Network (NCCN) guidelines, which recommend dose-dense doxorubicin and cyclophosphamide (ddAC) followed by either sequential wP or sequential ddP with growth factor support as preoperative and/or adjuvant therapy for the treatment of early-stage breast cancer. The selection of an appropriate paclitaxel schedule is provider preference and largely based on the consideration of patient tolerability. These findings suggest that the concern for paclitaxel-induced peripheral neuropathy, including DL CIPN, may potentially play a smaller role in helping guide clinicians who are choosing between the two paclitaxel-based adjuvant regimens.
Differential expression of micro-RNAs in breast cancer with relapsed disease: A clinical data base study.
Authors: Pandey Yadav , Chen Zhongning , Makhoul Issam
Published: May 2020

e12514

Background: Micro-RNAs (miRNAs) are small, noncoding RNA molecules that play important role in RNA silencing and post-transcriptional regulation of gene expression that are dysregulated in cancer. miRNAs are divided into oncogenic and tumor suppressor miRNAs. Both of these subtypes are known to regulate breast cancer development and progression. We studied the expression of these miRNAs before and after treatment in patients with breast cancer with relapsed disease. Methods: Data was obtained from the TCGA database. 11 patients with biopsy proven diagnosis of invasive ductal adenocarcinoma of the breast receiving adjuvant chemotherapy with relapsed disease who had tissue biopsy post-treatment were included in the study. miRNA expression was assessed in the pre- and post-treatment tissue samples. A total of 178 miRNA were analyzed after filtering out miRNA expression counts < 10. A pair-wise comparison of the differential expression of miRNA before and after treatment with adjuvant chemotherapy was analyzed using a quasi-likelihood F test implemented by bioconductor package, edgeR. This package is well documented for analyzing RNA-seq data due to adjustment for biological variations and measuring error using a negative binomial distribution. The expression of miRNA |Log2FC| > 1 and P value < 0.05 were obtained. Results: Out of 11 female patients, 10 were Caucasian. 9 out of 11 patients’ tumors were Estrogen Receptor positive; 8 patients had progesterone Receptor positive and 1 patient had Human epidermal growth factor receptor2 positive cancer. Of the 178 miRNAs of interest, we found 14 miRNA that are differentially expressed. The miRNA that are up-regulated post-treatment were hsa-miR-148a, hsa-miR-126, hsa-miR-142, hsa-miR-210, hsa-miR-374a, hsa-miR-192. The miRNA that were down-regulated were hsa-miR-197, hsa-miR-155, hsa-miR-149, hsa-miR-365a, hsa-miR-365b, hsa-miR-484, hsa-miR-339 and hsa-miR-3653. Among the miRNA up-regulated post-treatment, miR-148 and miR-126 are known major tumor suppresser miRNA whereas miR-210 and miR-374a are major oncogenic miRNA in breast cancer. Among the miRNA down-regulated post treatment, miR-155 is major oncogenic miRNA whereas miR-365 is major tumor suppressor miRNA in breast cancer. Conclusions: There is mixed expression profile of tumor suppressor miRNA and oncogenic miRNA molecules between before and after treatment in patients with breast cancer with relapsed disease. Further studying these miRNA molecules can help us better understand about the tumor progression and disease relapse.