bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study.
Authors: Wolf Juergen , Garon Edward B. , Groen Harry J.M. , Tan Daniel Shao-Weng , Robeva Anna , Le Mouhaer Sylvie , Carbini Mariana , Chassot-Agostinho Andrea , Heist Rebecca Suk 
Published: June 2021

9020 Background: Capmatinib, a selective MET inhibitor, is approved in the USA and Japan for the treatment of patients (pts) with MET exon 14 skipping mutation ( METex14) advanced non-small-cell lung cancer (NSCLC) based on the multi-cohort phase II GEOMETRY mono-1 study. This is the first report on expansion Cohort 7 in first line (1L) METex14 NSCLC pts, with updates to previously reported results (Wolf et al, NEJM 2020) for METex14 pts. Methods: In GEOMETRY mono-1, pts were assigned to cohorts based on previous lines of therapy and MET status ( METex14 or MET amplification). This efficacy analysis includes patients with METex14 NSCLC who were treatment-naive (Cohort 5b and 7) and those who had previously received 1L or 2L of therapy (expansion Cohort 6 and Cohort 4) for their advanced disease (data cutoff: Sep 18, 2020). Evaluated outcomes included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all by BIRC; and overall survival (OS). The safety analysis includes all patients enrolled. Results: In total, 160 pts with METex14 who received capmatinib 400 mg BID were analyzed. ORR of 65.6% (95% CI 46.8-81.4) for the treatment-naive expansion Cohort 7 was in line with that previously reported for Cohort 5b (Table). Though Cohort 7 data are still immature, median PFS was 10.8 mo (95% CI 6.87-not estimable [NE]). Mature median OS was 20.8 mo (95% CI 12.4-NE) in Cohort 5b and 13.6 mo (95% CI 8.6-22.2) in Cohort 4. Median OS for Cohorts 6 and 7 and DOR for Cohort 7 are not yet reached. The safety profile remained unchanged across all study cohorts (N = 373): 98.4% of pts reported AEs (68.6% Grade [G] 3/4) regardless of causality and 16.1% reported AEs leading to discontinuation (10.5% G3/4). The most common AEs (≥20% all G) were peripheral edema (54.2%), nausea (45.0%), vomiting (28.2%), increased blood creatinine (26.5%), dyspnea (23.3%), fatigue (22.3%), and decreased appetite (21.2%). Conclusions: Results of Cohort 7 confirm those previously reported for Cohort 5b showing higher efficacy of capmatinib when used as 1L in METex14 NSCLC pts. A clinically meaningful median OS of 20.8 mo in 1L (Cohort 5b) and of 13.6 mo in relapse (Cohort 4) was also observed and, together with the continued manageable toxicity profile, the data support capmatinib as a valuable targeted treatment option for METex14 NSCLC pts. Clinical trial information: NCT02414139. [Table: see text]
Tepotinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) with MET amplification (METamp).
Authors: Le Xiuning , Paz-Ares Luis G. , Van Meerbeeck Jan , Viteri Santiago , Cabrera Galvez Carlos , Vicente Baz David , Kim Young-Chul , Kang Jin-Hyoung , Schumacher Karl-Maria , Karachaliou Niki , Adrian Svenja , Bruns Rolf , Paik Paul K. 
Published: June 2021

9021 Background: METamp is an oncogenic driver occurring in 1–5% of NSCLCs that confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in NSCLC with MET exon 14 ( METex14) skipping in Cohort A of the Phase II VISION trial (NCT02864992). VISION Cohort B evaluated tepotinib in pts with advanced NSCLC and METamp, as detected by a convenient and minimally invasive liquid biopsy assay, in the absence of METex14 skipping. Methods: Pts with locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, 0–2 prior lines of therapy, EGFR/ ALK wild-type status, no METex14 skipping, and METamp by liquid biopsy (Guardant360®; MET gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). The primary endpoint was objective response (RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. The data cut-off was July 1, 2020. Results: Among 24 enrolled pts, median age was 63.4 years (range: 38–73), 21 pts (88%) were male, 21 (88%) had ECOG PS 1 and 21 (88%) were smokers. Tepotinib was given to 7 pts (29%) in first line (1L), 10 pts (42%) in second line (2L) and 7 pts (29%) in third line (3L). As of November 2020, treatment was ongoing for > 1 year in 5 pts (1L, n = 2; 2L, n = 2; 3L, n = 1). Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L (Table). Median DOR by IRC was not estimable (NE; 95% confidence interval [CI]: 2.8 months–NE). Investigator-assessed outcomes were similar. Five pts (20.8%) discontinued due to adverse events (AEs), which were considered unrelated to tepotinib. Treatment-related AEs were reported in 16 pts (67%; Grade 3/4, 7 pts [29%]) and included peripheral edema (9 pts [38%]; Grade 3/4, 2 pts [8%]), generalized edema (4 pts [17%]; Grade 3/4, 2 pts [8%]) and constipation (4 pts [17%]; Grade 3/4, 0 pts). Conclusions: In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in NSCLC with METamp. Clinical trial information: NCT02864992. [Table: see text]
A randomized phase II study comparing nivolumab (NIVO) with carboplatin-pemetrexed (CbPEM) for patients (pts) with EGFR mutation-positive non-small cell lung cancer (NSCLC) who acquire resistance to tyrosine kinase inhibitors (TKIs) not due to a secondary T790M mutation (WJOG8515L).
Authors: Hayashi Hidetoshi , Sugawara Shunichi , Fukuda Yasushi , Sato Yuki , Miura Satoru , Ota Keiichi , Ozawa Yuichi , Hara Satoshi , Tanizaki Junko , Azuma Koichi , Omori Shota , Tachihara Motoko , Nishino Kazumi , Hosokawa Shinobu , Chiba Yasutaka , Haratani Koji , Sakai Kazuko , Nishio Kazuto , Yamamoto Nobuyuki , Nakagawa Kazuhiko 
Published: June 2021

9037 Background: Although the efficacy of antibodies to programmed cell death–1 (PD-1) appears to be less pronounced in patients with NSCLC harboring epidermal growth factor receptor gene ( EGFR) mutations, patients who develop disease progression (PD) to TKIs due to mechanisms other than secondary T790M mutation of EGFR might be more likely to benefit from NIVO. Here, we report the results of first randomized phase II trial to compare NIVO with the CbPEM in those population. Methods: Pts with advanced EGFR mt NSCLC who experienced PD after EGFR-TKIs were randomized 1:1 to NIVO or CbPEM. Eligibility criteria included the treatment history with TKIs as follow; no evidence of T790M after PD on 1st/2nd generation (gen) TKIs (A) after PD on 3rd gen TKIs as a 2nd line for T790M positive tumor (B) or 3rd gen TKIs as a front-line (C). The primary end point is progression-free survival (PFS) and biomarker analysis were included for exploratory analysis. Results: A total of 102 patients was randomized. Median PFS and overall survival (OS) were 1.7 and 20.7 months (mo), respectively, for NIVO arm (n = 52) versus 5.6 and 19.9 months for CbPEM (n = 50) (Hazard ratio [HR] = 1.92 and 0.88, respectively). Overall response rate and duration of response were 9.6% and 5.3 months for NIVO and 36.0% and 5.5 months for CbPEM. PD-L1 expression on tumor cells and tumor mutation burden (TMB) were evaluated in 77 (TPS 0%. 1-49%, > 50%, n = 46, 20, and 11) and 50 (Median TMB 6.2mt/mb). Immune-related gene expression profiling was under evaluation and the results will be demonstrated in the meeting. The efficacy of NIVO in PD-L1 strong positive (>50%, n = 8) and no evidence of T790M after PD on 1st/2nd gen TKIs (n = 29) was tended to be better than their counterparts. There was no significant correlation between TMB and the efficacy of NIVO. Pneumonitis was observed in one patient (1.0%) for NIVO arm and no new safety signals were noted. Conclusions: NIVO was not associated with longer PFS than CbPEM in selected pts with advanced EGFR mt NSCLC. OS was similar between groups. Baseline PD-L1 status and genetic alteration features may be relevant predictive markers to select pts who would benefit from NIVO. Clinical trial information: jRCTs051180133. [Table: see text]
Differential immune-related microenvironment determines PD-1/PD-L1 blockade efficacy in advanced non-small cell lung cancer patients.
Authors: Shirasawa Masayuki , Yoshida Tatsuya , Shimoda Yukiko , Takayanagi Daisuke , Shiraishi Kouya , Kubo Takashi , Mitani Sachiyo , Matsumoto Yuji , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Ichikawa Hitoshi , Kohno Takashi , Yamamoto Noboru , Watanabe Shun-ichi , Motoi Noriko , Ohe Yuichiro 
Published: June 2021

9044 Background: Programmed death ligand-1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/anti-PD-L1 therapy in advanced non-small cell lung cancer patients (NSCLC). Immune-related tumor microenvironment (TME) is classified into four different types based on the status of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Methods: We retrospectively reviewed advanced NSCLC patients treated with anti-PD-1/anti-PD-L1 therapy between 2015 and 2019, and investigated the association between the efficacy of anti-PD-1/anti-PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, and the density of CD8-positive TILs by immunohistochemistry (/mm2), and mutational profiles assessed by next-generation sequencing. Results: Overall, 228 patients without driver mutation ( EGFR, ALK, ROS1, and RET) were included in the analysis. The patients were classified into four following groups: Type I: PD-L1High (tumor proportion score [TPS]≥50%)/TILHigh (≥85/mm2; n = 73), Type II: PD-L1Low (TPS < 50%)/TILLow ( < 85/mm2; n = 70), Type III: PD-L1High/TILLow (n = 37), and Type IV: PD-L1Low/TILHigh (n = 48). The progression-free survival (PFS) and objective response rate (ORR) of anti-PD-1/anti-PD-L1 therapy clearly differed according to the different tumor microenvironment (TME) types (ORR and median PFS; Type I: 64%, 14.5 months, Type II: 12%, 2.1 months, Type III: 24%, 3.6 months, Type IV: 41%, 10.8 months). In patients with PD-L1High tumors, Type I tumors had significantly better ORR and PFS than Type III(ORR: p < 0.001, and PFS: p < 0.001) tumors. Regarding the association between mutational profiles, histology and the TME types, the presence of TP53 mutation and KRAS mutation significantly related to TILHigh (Type I and IV) and PD-L1High tumors (Type I and III), respectively. Pleomorphic and NSCLC- not otherwise specified histology were associated with Type I tumors, while LCNEC was associated with PD-L1 low tumors (Type II and IV). Conclusions: Various factors (mutational profile and histology) are related to TME classification based on the status of TILs and PD-L1 expression. Differential types of TME, including PD-L1 expression and TILs status, can accurately predict the efficacy of anti-PD-1/anti-PD-L1 therapy.[Table: see text]
Physician concern about delaying lung cancer treatment while awaiting biomarker testing: Results of a survey of U.S. oncologists.
Authors: Mileham Kathryn Finch , Basu Roy Upal Kunal , Bruinooge Suanna Steeby , Freeman-Daily Janet , Garon Edward B. , Garrett-Mayer Liz , Jalal Shadia Ibrahim , Johnson Bruce E. , Moore Amy , Osarogiagbon Raymond U. , Rosenthal Lauren , Schenkel Caroline , Smith Robert A. , Virani Shamsuddin , Redman Mary Weber , Silvestri Gerard A. 
Published: June 2021

9067 Background: With rapid advancements in biomarker testing informing lung cancer treatment decisions, clinicians are challenged to maintain knowledge of who, what and when to test and how to treat based on test results. An ASCO taskforce including representatives from the American Cancer Society National Lung Cancer Roundtable and patient advocates conducted a study to assess biomarker testing and treatment practices for patients with advanced non-small cell lung cancer (aNSCLC) among U.S. oncologists. Methods: A survey was sent to 2374 ASCO members – lung cancer specialists and general oncologists. Eligibility required treating ≥1 lung cancer patient/month. Proportions were estimated across groups and compared using chi-square tests. Results: 170 responses were analyzed. 59% of respondents work at an academic center (i.e., have a fellowship program), while 41% work at a community (non-academic hospital/health system/private practice). Nearly all (98%) believe biomarker results should be received within 1 or 2 weeks of ordering, yet 37% wait an average of 3 or 4 weeks for results. Of respondents who usually wait 3 or 4 weeks, 37% initiate a non-targeted systemic treatment while waiting. Respondents from community practices were more likely to initiate non-targeted systemic treatment if results were not available after 2 weeks (59% compared to 40% of academic respondents; p = 0.013). ). When asked about reasons for not testing, respondents <5 years since training were more likely to report that delaying treatment while waiting for results was always/often a concern compared to those >6 years from training (41% vs 19%). Respondents reported high testing rates in both non-squamous and squamous aNSCLC. Roughly equal representation of generalists/specialists and academic/community respondents helps mitigate potential concerns about external validity. Conclusions: Respondents indicated that treatment decisions are impacted by delays in biomarker test results. Clinicians should be informed about when it is safe and appropriate to defer treatment while biomarker testing is pending. Respondents suggest that diagnostic biomarker testing companies should strive to expedite results.[Table: see text]
Phase I study of the aurora kinase A inhibitor alisertib in combination with osimertinib in EGFR-mutant lung cancer.
Authors: Blakely Collin M. , Gubens Matthew A. , Allen Gregory M. , Shah Shrusti , Jereza Matthew , Bacaltos Bianca , Bandyopadhyay Sourav 
Published: June 2021

9074 Background: The 3rd generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutant (mt) lung adenocarcinoma (LUAD). However, tumor resistance to osimertinib monotherapy invariably occurs. Activation of Aurora Kinase A (AURKA) drives resistance to osimertinib treatment in preclinical models of EGFR-mutant LUAD and is associated with TKI resistance in patients. Alisertib is a selective AURKA inhibitor with an acceptable safety profile established in early phase clinical trials. Methods: We performed a single institution phase Ia clinical trial of alisertib in combination with the 3rd generation EGFR inhibitor osimertinib in patients with metastatic EGFR-mutant LUAD who had experienced disease progression on osimertinib monotherapy (NCT04085315). The primary objective of the study was to determine the safety and tolerability of alisertib in combination with osimertinib in order to define the maximum tolerated dose (MTD) and to identify a recommended phase 2 dose (RP2D). Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Utilizing a 3+3 trial design, patients receiving osimertinib 80 mg daily were treated with alisertib using an intermittent dosing strategy of 20-50 mg twice daily (BID) oral alisertib on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle. Results: A total of 10 patients were treated with osimertinib 80 mg and received at least one dose of alisertib. 6 patients were treated at the 30 mg BID and 4 patients at the 40 mg BID intermittent dosing schedule of alisertib. The most commonly reported adverse events (AEs) were diarrhea (70%), fatigue (60%), alopecia (50%) and neutropenia (50%). All AEs, except neutropenia, were grade 1 or 2. Two patients (20%) experienced grade 3 or grade 4 neutropenia; both patients were treated at the 40 mg BID intermittent dose of alisertib. Intermittent alisertib 30 mg BID was identified as the MTD and RP2D in combination with osimertinib 80 mg daily. The ORR was 10% (1/10) and DCR 70% (7/10), with the majority of patients, 60% (6/10), achieving stable disease (SD). 30% (3/10) experienced progressive disease (PD) as their best response. The median PFS was 9.4 months (2.0 months - N.R.). Conclusions: Intermittent dosing of alisertib 30 mg BID on d1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily demonstrates an acceptable toxicity profile. Preliminary efficacy analysis suggests that alisertib + osimertinib may result in clinically meaningful disease control in EGFR-mt LUAD patients whose disease is resistant to osimertinib monotherapy. Clinical trial information: NCT04085315.
Update analysis of NEJ009: Gefitinib alone (G) versus gefitinib plus chemotherapy (GCP) for non-small cell lung cancer with mutated EGFR.
Authors: Miyauchi Eisaku , Morita Satoshi , Nakamura Atsushi , Hosomi Yukio , Watanabe Kana , Ikeda Satoshi , Seike Masahiro , Fujita Yuka , Minato Koichi , Ko Ryo , Harada Toshiyuki , Hagiwara Koichi , Kobayashi Kunihiko , Nukiwa Toshihiro , Inoue Akira ,   North East Japan Study Group (NEJSG)
Published: June 2021

9081 Background: NEJ009 study is the first randomized phase III trial that compared gefitinib plus chemotherapy with gefitinib in patients with untreated NSCLC harboring EGFR mutations. We report an updated OS and long-term tolerability analysis, including subgroup analyses focusing on a type of EGFR mutation and metastatic sites. Methods: Patients were randomly assigned to gefitinib (gefitinib 250 mg PO, QD) and GCP regimen (gefitinib 250 mg PO, QD combined with carboplatin AUC 5 and pemetrexed 500 mg/m2 in a 3-week cycle for up to six cycles, followed by concurrent gefitinib and pemetrexed maintenance). This study tested multiple primary endpoints, PFS, PFS2, and OS, which were analyzed using a preplanned hierarchical sequential testing method. Results: Three hundred forty-five patients were randomly assigned (gefitinib, n = 172; GCP, n =170). At latest data cut-off (May 22, 2020), although there was no significant difference in OS between the groups (HR, 0.82; 95% CI, 0.64 to 1.06; P=0.13), GCP still demonstrated significantly better PFS and PFS2 compared to G. The updated median PFS, PFS2, and OS was 11.2 months, 18.0 months, and 38.5 months in the gefitinib group and 20.9 months, 20.9 months, and 49.0 months in the GCP group, respectively. No severe adverse events occurred in the period since the first report. Conclusions: This updated analysis confirmed that the GCP regimen achieved significantly better PFS and PFS2 with an acceptable safety profile compared with gefitinib alone. The efficacy outcome of GCP is more favorable than gefitinib monotherapy as first-line treatment of NSCLC with EGFR mutation. Clinical trial information: UMIN000006340. Clinical trial information: UMIN000006340. [Table: see text]
Chemo-immunotherapy outcomes of KRAS-G12C mutant lung cancer compared to other molecular subtypes of KRAS-mutant lung cancer.
Authors: Arbour Kathryn Cecilia , Ricciuti Biagio , Rizvi Hira , Hellmann Matthew D. , Yu Helena Alexandra , Ladanyi Marc , Kris Mark G. , Arcila Maria E. , Rudin Charles M. , Lito Piro , Awad Mark M. , Riely Gregory J. 
Published: June 2021

9088 Background: KRAS mutations are identified in approximately 30% of NSCLC, with G12C mutations being the most common subtype and representing 12% of all non-small cell lung cancer cases. Novel direct inhibitors are in clinical development and have shown promising activity, although the efficacy of these agents compared to other standard therapies for lung cancer is not yet known. We hypothesized that patients with KRAS-G12C mutations may have distinct responses to chemo-immunotherapy regimens both with respect to STK11 and KEAP1 co-mutation status and compared to patients with non-G12C subtypes. Methods: Patients with KRAS-mutant lung cancers at Memorial Sloan Kettering Cancer Center and Dana Farber Cancer Institute treated with chemo-immunotherapy regimens as first line therapy for advanced/metastatic disease were identified. Subset with KRAS G12C mutations non-G12C subtypes were compared and response to therapy was assessed by investigator. Baseline characteristics were compared with the Chi-square and Fisher’s exact test for categorical data and Wilcoxon rank-rum test for continuous data. Response evaluations where performed by investigators and compared between groups with the Fisher’s exact test. Progression free survival and overall survival was calculated from start of therapy to date of progression or death/last follow up, respectively and compared between groups using the Cox proportional-hazards model. Results: We identified 137 patients with KRAS -mutant NSCLC treated with chemo-immunotherapy: 45% (62/137) had mutations in KRAS-G12C and 55% harbored non-G12C mutations (17% G12V, 15% G12D, 4% G12A, 4% G12S, 3% G13D). The median OS was 21 and 14 months for G12C and non-G12C patients, respectively (p = 0.24). ORR to chemo-immunotherapy for patients harboring a KRAS-G12C mutation was 40% (25/62) compared to 31% (23/75) in non-G12C subtypes (p = 0.3). Median PFS was similar for both G12C and non-G12C subtypes (7.3 vs 6.1 months, respectively, p = 0.12). Concurrent STK11 mutation was identified in 40% of patients with KRAS-G12C and KEAP1 alterations were observed in 32% of patients. In patients with KRAS-G12C, co-mutation in STK11 and/or KEAP1 was associated with shorter PFS (15.8 vs 5.1 months, p = 0.01). Conclusions: KRAS-G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development. Treatment outcomes to chemo-immunotherapy are similar in patients with G12C and non-G12C subtypes. Outcomes are poor for patients with concurrent STK11 and/or KEAP1 mutations representing a significant unmet need.