bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: Interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332).
Authors: Wang Xiaoshan , Zeng Ming 
Published: May 2020

9508 Background: The effectiveness of aggressive local therapy for oligometastatic non-small-cell lung cancer (NSCLC) is unknown. This multi-institutional, randomized, open label, phase III clinical trial was performed to assess upfront stereotactic radiotherapy to all sites at diagnoses in previously untreated EGFRm oligometastatic non-small-cell lung cancer on progression-free survival and overall survival. Methods: The study was conducted at five centers located in different provinces of China.Eligible participants had pathologically confirmed adenocarcinoma, gene sequencing confirmed EGFRm, stage IV, five or fewer metastatic disease lesions, an ECOG performance status score of ≤ 2, systemic therapy naive, and no brain disease before randomization.Participants were randomized to receive either first-line tyrosine kinase inhibitor (TKI) treatment alone or up front stereotactic radiotherapy to all sites of disease along with TKI treatment.The primary endpoint was progression-free survival and the secondary endpoint was overall survival. Results: From January 2016 to January 2019, 133 participants were enrolled, including 65 (48.8%) in the TKI arm who received standard of care TKI alone and 68 (51.1%) in the stereotactic radiotherapy sites at diagnosis arm who received stereotactic radiotherapy and TKI.At a median follow-up of 19.6 months (IQR 9.4 - 41.0), the median progression-free survival for tyrosine kinase inhibitor alone was 12.5 months, and for tyrosine kinase inhibitor and stereotactic radiotherapy was 20.20months, respectively (HR 0.6188 [95% CI 0.3949-0.9697], log rank P< .001). The median overall survival in the TKI alone arm was 17.40 months, and for TKI and stereotactic radiotherapy arm was 25.50 months, respectively (HR 0.6824 [95% CI 0. 4654-1.001], log rank P< .001). Adverse events were similar between groups, with no grade 5 or deaths due to treatment. Grade 3/4 adverse events with or without radiotherapy included pneumonitis (7.3% vs. 2.9%; P> .05) and esophagitis (4.4%vs. 3.0% P> .05). Conclusions: Upfront stereotactic radiotherapy to sites at diagnosis along with first line TKI improved both progression-free survival and overall survival significantly compared with TKI alone. This finding suggests aggressive local therapy to sites at diagnosis should be explored further in large cohort phase III trials as a standard treatment option in this clinical scenario. Clinical trial information: NCT02893332 .
Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).
Authors: Camidge D. Ross , Janku Filip , Martinez-Bueno Alejandro , Catenacci Daniel V.T. , Lee Jeeyun , Lee Se-Hoon , Dowlati Afshin , Rohrberg Kristoffer Staal , Navarro Alejandro , Moon Yong Wha , Awad Mark M. , Heist Rebecca Suk , Poulsen Thomas Tuxen , Yablonovitch Arielle , Fosler Lindsay , Rudbaek Helle , Nygaard Frank , Wood Debra L. , Dalal Rita P. , Felip Enriqueta 
Published: May 2020

9510 Background: Sym015, a mixture of 2 humanized antibodies, triggers MET degradation by a unique mechanism with superior specificity compared to tyrosine kinase inhibitors (TKIs). The Sym015-01 phase (P)1a trial met, the primary objective of identifying the recommended P2 dose (RP2D) as 18 mg/kg on cycle 1 day 1 followed by 12 mg/kg Q2W. The P2a was expanded to enroll METAmp/Ex14∆ NSCLC patients (pts) based on preliminary efficacy findings. Here we present interim safety (n = 45) and efficacy (NSCLC cohort, n = 20) results from P2a. Methods: The expansion NSCLC Cohort enrolled pts with METEx14Δ (n = 12) or METAmp (n = 8 defined as > 5 MET copies by NGS or MET/CEP7 ratio > 2.2 updated to ≥3.0 by in situ hybridization; including 1 with METAmp+Ex14Δ). Tumor MET status was confirmed centrally and longitudinal ctDNA was analyzed by Guardant360. Results: By January 2020, 45 pts (median age 61.7 years) have been treated in P2a. Median duration of exposure (DoE) was 3.8 months (m) (n = 45; range 0.4+ to 22 m). Treatment emergent adverse events occurred in 93%, treatment related AEs (TRAE) in 42.2% and TRAE ≥G3 in 13.3% pts. No pts discontinued or died due to TRAE. The most common TRAE in ≥10% pts were fatigue (13.3%) and peripheral edema (11.1%). Of 20 NSCLC pts, 5 had confirmed PR (ORR 25%; 2/8 METAmp and 3/12 METEx14Δ); 11 had SD (DCR 80%; 6/8 METAmp and 5/12 METEx14Δ); 2 had PD (2/12 METEx14Δ); and 2 were not evaluable. 10 NSCLC pts were MET TKI naive (7 METAmp and 3 METEx14Δ) and had 50% ORR and 100% DCR (5 PR and 5 SD; DoR range 1 to 18.3 m; DoE 1.5 to 22 m); 10 NSCLC pts were prior MET TKI treated (9 METEx14Δ and 1 METAmp+Ex14Δ) with DCR 60%, (6 SD; DoE 0.4-9.6 m). Median PFS was 5.5 m overall (95% CI 3.5-9.7 m). Median PFS for MET TKI naive and MET TKI pre-treated NSCLC pts was 6.5 m (95% CI 3.4-21.9 m) and 5.4 m (95% CI 1.2-9.7 m) respectively. Median OS was not reached for overall or for prior MET TKI subgroups. 89% METEx14∆ tumor tissue to blood concordance (8/9 NSCLC pts) was observed. Conclusions: Sym015 was well-tolerated at the RP2D with a response rate similar to MET TKI in MET-treatment naïve METAmp/Ex14Δ NSCLC and seems to delay disease progression in MET TKI pretreated NSCLC pts. Combination with MET TKI to delay or prevent resistance should be further explored. Clinical trial information: NCT02648724 .
Evaluation of blood TMB (bTMB) in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) with pemetrexed and platinum versus placebo plus chemo as first-line therapy for metastatic nonsquamous NSCLC.
Authors: Garassino Marina Chiara , Gadgeel Shirish M. , Rodriguez-Abreu Delvys , Felip Enriqueta , Esteban Emilio , Speranza Giovanna , Hochmair Maximilian , Powell Steven Francis , Garon Edward B. , Hui Rina , Nogami Naoyuki , Cristescu Razvan , Morrissey Michael , Loboda Andrey , Kobie Julie , Ayers Mark , Piperdi Bilal , Pietanza Maria Catherine , Snyder Alexandra , Reck Martin 
Published: May 2020

9521 Background: In a previous analysis of KEYNOTE-189 (NCT02578680), we showed that tissue TMB (tTMB) assessed by whole-exome sequencing was not significantly associated with efficacy in either arm and that pembro + chemo improved outcomes vs placebo + chemo in both the tTMB ≥175 and tTMB < 175 mut/exome subgroups. Here, we explored the association of bTMB with efficacy in KEYNOTE-189. Methods: 616 patients (pts) were randomized 2:1 to pembro + chemo or placebo + chemo. bTMB was assessed in cfDNA using the Guardant Health Omni assay. Association of bTMB (continuous square root transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR) adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of bTMB on outcomes was assessed using the cutoff that most closely approximated the 175 mut/exome tTMB cutoff as determined by AUROC analysis. Data cutoff was 21 Sep 2018. Results: 235 (38%) treated pts had evaluable tTMB and bTMB: 160 in the pembro + chemo arm and 75 in the placebo + chemo arm. bTMB as a continuous variable was not significantly associated with OS or ORR for pembro + chemo (one-sided P = .229 and .051) or placebo + chemo (two-sided P = .641 and .069); bTMB was significantly associated with PFS in the pembro + chemo arm (one-sided P = .015) but not the placebo + chemo arm (two-sided P = .058). bTMB and tTMB scores were moderately correlated (r = .61). The bTMB cutoff that most closely approximated tTMB 175 mut/exome was 15 mut/Mb (AUROC 0.81, 95% CI 0.75-0.86). 178 (76%) pts had concordant bTMB and tTMB results—101 low and 77 high by both—whereas 57 (24%) had discordant results—21 high bTMB but low tTMB, 36 low bTMB but high tTMB. Pembro + chemo improved OS, PFS, and ORR vs placebo + chemo for bTMB ≥15 and < 15 mut/exome (Table). Conclusions: Similar to previous findings based on tTMB, bTMB has limited clinical utility in the setting of pembro with pemetrexed and platinum given as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680 . [Table: see text]
Brigatinib in Japanese ALK positive NSCLC patients previously treated with ALK tyrosine kinase inhibitors: J-ALTA.
Authors: Yoshida Tatsuya , Nishio Makoto , Kumagai Toru , Hida Toyoaki , Toyozawa Ryo , Shimokawaji Tadasuke , Goto Koichi , Nakagawa Kazuhiko , Ohe Yuichiro , Yamamoto Nobuyuki , Kudou Kentarou , Asato Takayuki , Zhang Pingkuan , Seto Takashi 
Published: May 2020

9537 Background: Brigatinib is an ALK inhibitor with demonstrated activity against ALK resistance mutations. To evaluate efficacy and safety in Japanese patients with ALK-positive non-small cell lung cancer (NSCLC), a prospective, single-arm, phase 2 study was conducted. We report the efficacy and safety of brigatinib in patients who have progressed on alectinib with or without prior crizotinib and of those who previously received up to two ALK tyrosine kinase inhibitors (TKIs) with or without prior chemotherapy. Methods: A safety evaluation lead-in was followed by an expansion stage of an ALK TKI-naïve and two ALK TKI-refractory cohorts. The refractory cohorts included patients with stage IIIB, IIIC, or IV NSCLC with ALK rearrangements. This report describes efficacy results from the post-alectinib patients in the expansion cohort and safety results from all refractory patients. The primary endpoint was confirmed objective response rate (ORR) assessed by IRC, secondary endpoints included duration of response (DoR), progression-free survival (PFS), disease control rate (DCR), and intracranial ORR (iORR). Brigatinib was administered at 180 mg QD with 90 mg QD lead-in for the first 7 days, and efficacy was evaluated every 8 weeks. Results: A total of 72 patients were enrolled in 28 sites, including a cohort of 47 patients with prior alectinib, with/without crizotinib between January 2018 and September 2019. The primary analysis of brigatinib in this cohort (data cut-off date 26 September 2019) demonstrated an IRC-assessed, confirmed ORR of 30% and a median DoR of 6.1 months. The median PFS was 7.3 months. Clinically meaningful intracranial efficacy was also observed (see table). Grade ≥3 TEAEs included blood creatine phosphokinase increase (18.1%), lipase increase (13.9%), hypertension (11.1%), amylase increase (4.2%), and pneumonitis (1.4%). Brigatinib also showed anti-tumor activity in patients with refractory secondary mutations in the ALK kinase domain, including G1202R, I1171N, V1180L, and L1196M. Conclusions: Brigatinib showed clinically meaningful efficacy in Japanese patients refractory to prior alectinib (first line or post crizotinib), regardless of prior chemotherapy. The safety profile of brigatinib was consistent with prior studies and no new safety findings were identified. Clinical trial information: NCT03410108 . [Table: see text]
An FDA analysis of the association of tumor growth rate and overall and progression-free survival in metastatic non-small cell lung cancer (NSCLC) patients.
Authors: Gong Yutao , Mason Jeremy , Shen Yuan-Li , Chang Elaine , Kazandjian Dickran , Blumenthal Gideon Michael , Singh Harpreet , Theoret Marc Robert , Tang Shenghui , Pazdur Richard , Beaver Julia A. 
Published: May 2020

9541 Background: Previous studies have suggested that tumor growth rate (g), estimated using prostate-specific antigen values, is associated with overall survival (OS) in prostate cancer (Wilkerson, 2016). We performed a retrospective pooled analysis in non-small cell lung cancer (NSCLC) to investigate the extent to which g values estimated using radiological tumor measurements in clinical trials are associated with survival. Methods: We identified 24 randomized clinical trials submitted to FDA between 2013 and 2019 investigating either immune checkpoint inhibitor (ICI) or targeted therapy (TT) in pts with metastatic NSCLC. Of 9934 patients (pts) enrolled, 5532 pts (2401, 1189, and 1942 pts treated with ICI, TT, and chemotherapy respectively) had sufficient data to derive a valid g. The g was evaluated by both type and line of therapy. Pts were then grouped according to quartiles of g, with Q1 being the lowest. We calculated OS and progression-free survival (PFS) for each group via the Kaplan-Meier method, and used the Cox model for group comparison. Results: Median g was 9.7E-4, 1.4E-3, and 2.2E-3/day, and median OS was 34.2, 21.3, and 15.3 months (mo), in pts treated with TT, ICI, and chemotherapy, respectively, regardless of lines of therapy. When treated with the same type of therapy, pts receiving 2nd line therapy had a higher median g than those receiving 1st line. The median survival and log-rank hazard ratios for pts treated with 1st line ICI monotherapy are shown in the Table. Conclusions: TT is associated with the lowest median g, followed by ICI, and then chemotherapy, perhaps due to patient selection, better inherent biology/natural history, or favorable results of TT on selected tumors. Regardless, we found that g is inversely associated with survival, across treatment types. This relationship is also observed in pts treated with the same type and line of therapy (for example, 1st line ICI), where Q1 has the longest survival, followed by Q2, Q3, and then Q4. In summary, our exploratory analysis suggests that g derived from radiological tumor measurements in NSCLC may relate to survival. Prospective studies are needed to evaluate if g might be an earlier endpoint compared to classical response criteria. [Table: see text]
Comparative efficacy of chemoimmunotherapy versus immunotherapy alone in the front-line treatment of advanced non-small cell lung cancer: A systematic review and network meta-analysis.
Authors: Pathak Ranjan , Lopes Gilberto , Yu Han , Ji Wenyan , Aryal Madan , Frumento Katherine Stemmer , Wallis Christopher J.D. , Klaassen Zachary William Abraham , Park Henry Soo-Min , Goldberg Sarah B. 
Published: May 2020

9552 Background: Immune checkpoint inhibitors (ICI) and combination chemotherapy (chemo) plus ICI (Chemo-ICI) have been shown in RCTs to have improved OS compared to chemo in the 1L treatment of advanced NSCLC. However, the benefit of chemo-ICI compared with ICI alone is unknown. Methods: Systematic review using MEDLINE, Embase and Cochrane CENTRAL was done to identify relevant studies up to December 2019. Phase 3 RCTs that evaluated the efficacy of 1L ICI or chemo-ICI and reported outcomes stratified by PD-L1 status (<1%, 1-49%, ≥50%) were included. ICI was defined as single-agent PD-1 axis inhibitor or dual checkpoint blockade with PD-1 axis inhibitor plus CTLA-4 inhibitor. Comparison for PD-L1<1% included chemo-ICI vs ipi/nivo and for PD-L1 1-49% and PD-L1>50% included chemo-ICI vs ipi/nivo or single-agent ICI. OS, PFS, and ORR were extracted. Network meta-analysis (NMA) was done in Bayesian random-effects regression models. Results: Ten phase 3 RCTs (7971 screened) involving 7,218 patients assigned to ICI (pembro or atezo or ipi/nivo) or chemo-ICI (platinum-doublet + atezo, pembro, or nivo) were included. In PD-L1 <1% patients, NMA comparing chemo-ICI with ipi/nivo failed to show a statistically significant difference in OS, PFS or ORR. In PD-L1 1-49% patients, there was no significant difference between chemo-ICI vs ICI in OS or ORR; PFS could not be analyzed due to lack of available data. In PD-L1 >50% patients, chemo-ICI was associated with improved PFS and ORR compared to ICI alone, but without any OS difference (Table). Conclusions: Although the addition of chemo to ICI appears to improve ORR and PFS in PD-L1 ≥50% patients when compared to ICI alone, chemo-ICI does not confer an OS benefit in the 1L treatment of NSCLC patients regardless of PD-L1 status. Prospective trials comparing chemo-ICI, ICI monotherapy, and combination ICI are needed to confirm these findings. OS, PFS and ORR with chemo-ICI vs ICI. [Table: see text]
Two-year follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, for second-line (2L) treatment of non-small cell lung cancer (NSCLC).
Authors: Cho Byoung Chul , Kim Tae Min , Vicente David , Felip Enriqueta , Lee Dae Ho , Lee Ki Hyeong , Lin Chia-Chi , Flor Maria José , Di Nicola Massimo A. , Alvarez Rosa Maria , Dussault Isabelle , Helwig Christoph , Ojalvo Laureen S. , Gulley James L. , Paz-Ares Luis G. 
Published: May 2020

9558 Background: Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. Interim analysis of a global phase 1 study (NCT02517398) found an objective response rate (ORR) of 27.5% and a manageable safety profile in patients with NSCLC who received bintrafusp alfa 1200 mg in the 2L setting; median overall survival (OS) was not reached. Here we present the longest efficacy and safety follow-up in a cohort receiving bintrafusp alfa. Methods: Patients with advanced NSCLC unselected for PD-L1 expression level who progressed after first-line standard treatment (no prior immunotherapy) were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each) Q2W until disease progression, unacceptable toxicity or trial withdrawal. The primary objective was best overall response (BOR) per RECIST 1.1; secondary and exploratory objectives include safety and OS, respectively. Results: As of October 15, 2019, a total of 40 patients received bintrafusp alfa at the recommended phase 2 dose of 1200 mg Q2W for a median of 17 (range, 2-136) weeks, with a median follow-up of 128 weeks; 18 patients were still alive, 3 patients had an ongoing response, and 1 patient remained on treatment. Results for the 1200 mg dose cohort showed an ORR of 27.5%, and a median duration of response of 18 months. The 18- and 24-month progression-free survival and OS rates were 18.4% and 11.0%, and 49.7% and 39.7%, respectively. Duration of response rates at 18 and 24 months were 42.4% and 21.2%, respectively. Median OS in patients with positive (≥1%) PD-L1 expression was 21.7 months; 6 of 7 patients with high (≥80% with Ab clone 73-10, which is equivalent to ≥50% with 22C3) PD-L1 expression were still alive. The overall safety profile has remained consistent since the interim analysis, with no new safety signals or deaths and 1 additional treatment-related discontinuation (blood alkaline phosphatase increased). Conclusions: After two years of follow-up, bintrafusp alfa continues to show manageable safety with durable responses and encouraging long-term survival, especially in patients with high PD-L1 expression. A study evaluating bintrafusp alfa vs pembrolizumab as first-line treatment for NSCLC is ongoing in patients with high PD-L1 expression (NCT03631706). Clinical trial information: NCT02517398 .
Nivolumab (NIVO) plus ipilimumab (IPI) with two cycles of chemotherapy (chemo) in first-line metastatic non-small cell lung cancer (NSCLC): CheckMate 568 Part 2.
Authors: Gainor Justin F. , Schneider Jeffrey Gary , Gutierrez Martin , Orcutt James Michael , Finley Gene Grant , Otterson Gregory Alan , Rybkin Igor I. , Reddy Pavan S. , Horn Leora , Brahmer Julie R. , Bastos Bruno R. , Awad Mark M. , Hellmann Matthew David , Ramalingam Suresh S. , Ready Neal E. , Spigel David R. , Kasinathan Ravi S. , Dorange Cécile , Borghaei Hossein 
Published: May 2020

9560 Background: In Part 1 of the phase II CheckMate 568 study (NCT02659059), NIVO + IPI was active and tolerable in patients (pts) with advanced NSCLC. The addition of chemo to dual immune checkpoint inhibitor therapy may further improve initial disease control. We report results from Part 2 of CheckMate 568, which evaluates NIVO + IPI combined with 2 cycles of chemo in pts with advanced treatment-naive NSCLC. Methods: Adult pts with untreated stage IV NSCLC received NIVO 360 mg Q3W + IPI 1 mg/kg Q6W combined with 2 cycles of histology-based platinum-doublet chemo, followed by NIVO + IPI without chemo until disease progression/unacceptable toxicity for ≤ 2 years. The primary endpoints were dose-limiting toxicity (DLT) within the first 9 weeks and safety/tolerability. Treatment was considered safe if ≤ 25% of at least 22 evaluable pts had a DLT. DLTs included but were not limited to: uncontrolled grade 3 non-skin treatment-related adverse events (TRAEs), grade 4 TRAEs, grade 2 treatment-related pneumonitis not resolved within 14 days, and treatment-related hepatic function abnormalities. Results: In total, 36 pts received treatment; 97% of pts completed 2 cycles of chemo combined with NIVO + IPI. Three pts discontinued IPI while continuing NIVO. Minimum follow-up was 14.9 months. Only 1 (3%) pt experienced a DLT (transient, asymptomatic grade 3 AST and ALT elevation) within the first 9 weeks. The elevation occurred on cycle 1, day 21 and resolved 2 weeks later with discontinuation of IPI, delay of NIVO, and treatment with prednisone; chemo was continued throughout and NIVO was restarted thereafter without recurrent toxicity. Grade 3–4 TRAEs occurred in 21 (58%) pts. Eight (22%) pts experienced a TRAE leading to discontinuation, most commonly colitis, encephalopathy, pneumonitis, and arthralgia (each in 2 [6%] pts); these events occurred outside of the 9-week window for DLT assessment. The most common select TRAEs (defined as AEs of potential immunologic causes) were skin related (18 [50%] pts); the most common grade 3–4 select TRAEs were endocrine (3 [8%] pts), skin related, gastrointestinal, and pulmonary (each in 2 [6%] pts). No treatment-related deaths occurred. Updated safety in addition to efficacy data will be presented. Conclusions: In pts with untreated advanced NSCLC, the addition of 2 cycles of platinum-doublet chemo to NIVO + tumor-optimized IPI was tolerable. No unexpected safety signals were observed. Clinical trial information: NCT02659059 .