bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of durvalumab in patients with unresectable stage 3 non–small cell lung cancer post-chemoradiotherapy.
Authors: Thurlapati Aswani , Dhaliwal Lovekirat Singh , Chennapragada Sumasri , Gutta Pranavteja , Song Diana , Ralla Deepika , Comeau Jill , Shi Runhua , Beedupalli Kavitha
Published: June 2022

8550

Background: The PACIFIC study (PS) concluded that the use of durvalumab from 1 to 42 days after concurrent chemoradiotherapy (CXRT) in stage 3 unresectable non-small cell lung cancer (NSCLC) increased the median overall survival (mOS) from 29 to 48 months. It also showed a benefit in tumors with PD-L1 <25%. However, a post-hoc analysis of the PS showed no survival benefit with durvalumab in patients with PD-L1 <1% but was not statistically powered. Currently in the US, durvalumab is approved irrespective of PDL-1 percentage, whereas in Europe it is not approved for tumors with PDL-1 <1%. Also, there was no survival benefit in starting durvalumab within and after 2 weeks of CXRT. Our objectives in this study are to analyze the impact of PDL-1 expression and the date of initiation of durvalumab post CXRT on mOS. Methods: We conducted a retrospective observational study of stage 3 unresectable NSCLC patients who received durvalumab post CXRT at LSU Health Shreveport from 2018 to 2021. A survival analysis was done including the following variables: age, race, sex, tumor histology, tumor PD-L1 percentage, and date of initiation of durvalumab post CXRT. P-value <0.05 was considered statistically significant. Results: We identified 83 patients who received durvalumab after CXRT for treatment of stage 3 unresectable NSCLC. Baseline characteristics are provided in table 1. Among all the tumors, 25% had a PDL-1 <1%. 33% of the study population received durvalumab less than 30 days after CXRT and 67% received it after 30 days. The mOS was not impacted by race, sex, or tumor hisotology. Compared to higher PDL-1 percentage, patients with PD-L1 <1% had a statistically significant lower survival probability. At 14 months, 87% of patients with a PD-L1 <1% were alive compared to 100% in those with a PD-L1 1-50% or a PD-L1 >50%. Less than 35% of patients with PD-L1 <1% survived beyond 30 months compared to 45% for PD-L1 1-50% and 100% for PD-L1 >50% (p-value 0.02). Patients who received durvalumab 30-60 days after concurrent CXRT had a lower OS at 30 months compared to those who started before 30 days (44% versus 90%). However, statistical significance was not reached (p-value 0.45). Conclusions: This study demonstrates that patients with a PD-L1 tumor expression of <1% had a statistically significant lower survival probability compared to those with a PD-L1 expression of 1-50% and > 50% in this patient population. Time from CXRT to the start of durvalumab was not shown to affect survival outcomes.[Table: see text]
Nab-PTX and nab-PTX combined with immune checkpoint inhibitors for relapsed small cell lung cancer.
Authors: Wan Rui , Wang Jie , Duan Jianchun , Wang Zhijie
Published: June 2022

8576

Background: Despite sensitivity to first-line chemotherapy, most small cell lung cancer (SCLC) patients experience disease progression after initial treatment. Nab-PTX showed comparable anti-tumor activity for relapsed SCLC. Whether immune checkpoint inhibitors (ICIs) combined with nab-PTX could improve clinical outcome for relapsed SCLC has not been fully evaluated. The aim of this study is to evaluate efficacy and safety of nab-PTX and nab-PTX combined with ICIs for relapsed SCLC. Methods: We retrospectively reviewed relapsed SCLC patients who were given nab-PTX (130mg/m2, day1,8 /Q3 weeks) or nab-PTX combined with ICIs (PD-1 or PD-L1), from Feb 2017 to Sep 2021. Clinical data were collected from electronic medical records. The clinical outcome, including progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method and standard Log-rank test. Results: A total of 56 patients with relapsed SCLC were included, 29 and 27 patients received nab-PTX (group A) and nab-PTX combined with ICIs (group B), respectively. Baseline characteristics were well balanced between the groups. Patient characteristics (group A: group B) were as follows; median age 57: 59, male 25(86.2%): 24(88.9%), heavy smoking 23(79.3%): 18(66.7%), ECOG-PS 1 19(65.5%) :19(70.4%), extensive disease 28(96.6%) :25(92.6%), liver metastasis 10(34.5%) :12(44.4%), brain metastasis 8(27.6%) :10(37%), refractory relapse 10(34.5%) :11(40.7%). ORR in group A and B were 17.2% vs 40.7%, and DCR in group A and B were 72.4% vs 66.7%, respectively. The median PFS and median OS were similar between group A and B (median PFS, 2.8months vs 3.2months; median OS, 9.3 months vs 11.0months). PFS and OS according baseline characteristics were showed in the table. Toxicity profile of group B was tolerable as well as group A. Conclusions: This retrospective study indicated nab-PTX combined with ICIs failure to improve clinical outcome for relapsed SCLC when compared with nab-PTX monotherapy.[Table: see text]
Efficacy and safety of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer: Preliminary results of a phase 1 study.
Authors: Cheng Ying , Wu Chunjiao , Chen Lulu , Xin Ying , Zhang Liang , PAN Pinghua , Wu Lin , Li Juan , Zhao Yanqiu , Li Xingya , Zhao Jun , Dong Xiaorong
Published: June 2022

8580

Background: Lurbinectedin (Zepzelca), a selective inhibitor of oncogenic transcription, was granted accelerated approval on June 15, 2020, by the FDA for adult patients (pts) with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy, based on the results from SCLC cohort in PM1183-B-005-14 trial. Here we report the preliminary results of a phase 1 study (LY01017/CT-CHN-101) which aimed to evaluate the safety, tolerability, pharmacokinetics (PK) characters and preliminary efficacy of lurbinectedin in Chinese pts with advanced solid tumors including relapsed SCLC. Methods: In the dose-escalation stage, 10 pts with advanced solid tumors received lurbinectedin (2.5-3.2 mg/m2) as 1-hour i.v. infusion q3wk in a classical 3+3 design, without primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during Cycle 1. In the dose-expansion stage, 22 pts with relapsed SCLC after first-line platinum-based chemotherapy were treated with single-agent lurbinectedin at the recommended dose (RD) defined in the dose-escalation stage, with or without G-CSF support. Endpoints included safety (CTCAE v5.0), tolerability, PK, and confirmed objective response rate (ORR; RECIST v1.1). The data cutoff was January 13, 2022. Results: No dose-limiting toxicity (DLT) was observed in the first 3 pts treated at 2.5 mg/m2, while 1/7 pts treated at 3.2 mg/m2 had DLT (grade 4 neutropenia lasting ≥3 days) in Cycle 1, thus 3.2mg/m2 without G-CSF prophylaxis was defined as the RD of the dose-expansion stage. At cutoff, 22 SCLC pts treated in the dose-expansion stage were still ongoing, with 21 and 22 pts evaluable for efficacy and safety, respectively. The investigator-assessed confirmed ORR was 42.9% (9/21, partial responses). The duration of response (DOR) is pending. The most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (16 [72.7%]), leukopenia (13 [59.1%]), thrombocytopenia (9 [40.9%]), increased ALT (4 [18.2%]), anemia (3 [13.6%]), and increased AST (2 [9.1%]). Serious treatment-related adverse events, including neutropenia (5 [22.7%]), leukopenia (4 [18.2%]), thrombocytopenia (3 [13.6%]), increased ALT (2 [9.1%]), increased AST (2 [9.1%]), vomiting (2 [9.1%]), febrile neutropenia (1 [4.5%]), and edema (1 [4.5%]), were reported in 10 pts (45.5%). No cases of infection, sepsis and Hy’s law were reported. A total of 40.9% (9/22) had dose delay and 31.8% (7/22) had dose reduction, mainly attributed to hematological toxicities. No discontinuations occurred due to AEs. No treatment-related deaths were reported. Conclusions: Lurbinectedin at the RD (3.2mg/m2) shows promising efficacy as second-line therapy in Chinese pts with SCLC, with acceptable tolerability and manageable safety profile. Clinical trial information: NCT04638491.
Trends in treatment patterns associated with small cell lung cancer in a U.S. Medicare population.
Authors: Ramirez Robert A. , Boyd Marley , Cockrum Paul
Published: June 2022

8584

Background: Characterizing changes in the incident small cell lung cancer (SCLC) patient population and SCLC treatment landscape is essential for understanding drivers of outcomes among patients diagnosed with SCLC. The objective of this study was to examine trends in patient characteristics and treatment patterns for SCLC in a Medicare population. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Patients were included if they had a record with a diagnosis of SCLC in the database from 1/1/2007 – 12/31/2017 and were ≥65 years of age at diagnosis. Patients also had continuous enrollment for ≥180 days pre-SCLC diagnosis. Characteristics and treatment patterns were stratified by year of SCLC diagnosis. Results: 13,516 patients met the study criteria. Overall, 57.7% were female, mean age was 74 years, 89.5% were white, and 45.6% had a history of tobacco use. The majority (73.1%) were diagnosed with stage IV disease. Just over half (55.4%) of patients initiated first line (1L) treatment and mean time from diagnosis to 1L treatment was 6 weeks. Only 36.7% of those initiating 1L went on to second line (2L). Platinum-based chemotherapy (carboplatin or cisplatin + etoposide) was by far the most common 1L regimen (91.3%). 44.7% of patients received monotherapy in 2L, with topotecan being the most common (28.4%) regimen. Carboplatin + etoposide was used for approximately 20% of 2L patients. Over time, the demographic characteristics of patients diagnosed with SCLC was fairly stable with the exception of patients reporting a history of tobacco use, which more than tripled, increasing from 19.3% to 67.7% between 2007 and 2017. Between 2007 and 2017 the share of SCLC patients initiating 1L treatment increased 8.2% from 53.8% to 58.2% and the share initiating 2L fluctuated between 35% and 39%. Platinum-based chemotherapy was consistently used by the vast majority (88.7%–96.6%) of patients in 1L during the study period. Other chemo monotherapy (e.g., topotecan) and platinum-based chemotherapy with or without irinotecan were the most common 2L regimens from 2007-2014. Use of checkpoint inhibitors (CPIs) in 2L began in 2015 and became the most common 2L treatment following platinum-based chemotherapy by 2017 with 41.5% of patients receiving a CPI in 2L. Conclusions: While an increasing share of SCLC patients are pursuing treatment, less than 60% of SCLC patients receive any anticancer therapy. Fewer still receive more than one line of treatment, highlighting the ongoing need for effective therapies for SCLC.
Impaired seroconversion after SARS-COV-2 mRNA vaccine in patients with thymic epithelial tumors.
Authors: Pietroluongo Erica , De Placido Pietro , Morra Rocco , Ottaviano Margaret , Tortora Marianna , Saponaro Mariarosaria , Pisapia Luca , Del Gaudio Giancarlo , Del Deo Vitantonio , Malfitano Anna Maria , Cernera Gustavo , De Angelis Carmine , Arpino Grazia , Terracciano Daniela , Castaldo Giuseppe , Formisano Pietro , Palmieri Giovannella , De Placido Sabino , Giuliano Mario
Published: June 2022

8588

Background: Thymic epithelial tumors (TET) are rare malignancies associated with dysregulation of the immune system and humoral and cell mediated immunity abnormalities. Anti-syndrome coronavirus type 2 (SARS-CoV-2) vaccine is effective at preventing COVID-19 morbidity and mortality. No published data are available regarding the immunization in TET patients (pts). The aim of this study was to evaluate the immunization in TET pts who received two doses of mRNA vaccine, by longitudinal serological detection of SARS-COV-2 spike-binding IgG antibody. Methods: Starting from April 2021 to October 2021, consecutive TET pts referred to the Rare Tumors Coordinating Center of Campania Region (CRCTR - Naples, Italy) were enrolled. All study subjects received two doses of COVID-19 mRNA vaccine (BNT162b2 by Pfizer-BioNTech). SARS-CoV-2 spike-binding IgG antibody (Ab) serological levels were analyzed by centralized chemiluminescent immunoassay (CLIA) at different time-points, including before 1st vaccine dose (T0) and 1 month after 2nd dose (T2). Cut-off for Ab titers positivity was > 25 AU/mL. Results: Forty pts were enrolled; 23 (57.5%) were female and 17 (42.5%) male. Eleven pts (27.5%) suffered from thymic carcinoma, 28 (70%) thymoma, and 1 (2.5%) thymic hyperplasia. At the time of study enrollment, 20 pts (50%) had no evidence of disease (NED) and were in follow-up; the remaining 20 pts had evidence of disease (ED) by imaging and were receiving systemic treatment (55% oral low-dose etoposide-based therapy, 40% somatostatin analogs + prednisone, 5% supportive care). Immune system disorders were diagnosed in 29 TET pts (72.5%): 19 pts (47.5%) had Good’s Syndrome (GS) and 10 (25%) other immune disorders. At T0, all enrolled pts had negative Ab titers and no prior SARS-CoV-2 infection. At T2, Ab data were available for 37 pts (92.5%): 18 pts (48.7%) had positive Ab titers, whereas 19 (51.3%) did not achieve seroconversion. Among pts with ED, seroconversion was achieved only in 2 cases (11.8%). Lack of seroconversion at T2 was significantly associated with ED (Fisher's exact test p: 0.0001) and with the presence of GS (Fisher's exact test p: 0.0489). No significant association of seroconversion with other immune disorders and disease features was found. Conclusions: Our data showed that TET pts with ED had substantially higher probability of impaired seroconversion after SARS-COV-2 vaccine as compared with NED pts. We warrant further studies to evaluate the role of disease status, anti-tumor treatments and immune disorders in post-vaccine immunization of TET pts.
Platinum-free chemotherapy in the new era of immunotherapy: A phase II study of camrelizumab combined with apatinib and albumin paclitaxel in advanced non-squamous NSCLC (CAPAP-lung).
Authors: Wu Lin , Pu Xingxiang , Lin Gen , Xiao Maoliang , Lin Jie , Wang Qianzhi , Kong Yi , Yan Xuejun , Xu Fang , Xu Yan , Li Jia , Li Kang , chen bolin , Wen Xiaoping , Tan Yali
Published: June 2022

9034

Background: Cytotoxic chemotherapy and anti-angiogenic therapy may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for non-small cell lung cancer (NSCLC), however, the optimal combination regimen remains unclear. The adverse effects of platinum-based chemotherapy are relatively serious, whether platinum chemotherapy can be eliminated in the first-line treatment of non-small cell lung cancer is a hotspot and difficulty in current research. Based on these results, we initiated CAPAP-lung study, which is a single-arm, multicenter Phase II trial to evaluate the efficacy and safety of Camrelizumab in combination with apatinib and albumin paclitaxel without platinum as the first-line therapy for non-squamous non-small cell lung cancer. Methods: Patients diagnosed with ⅢB-IV non-squamous NSCLC without EGFR and ALK sensitive mutations received Camrelizumab (200mg/3w) in combination with Albumin Paclitacxel (135mg/m2, d1, d8/3w, 4-6 cycles) and Apatinib (250mg Qd po for 5 days, resting for 2 days every week). From August 2020 to February 2022, 54 of the planned 63 patients have been enrolled. The primary endpoint is progression-free survival(PFS), and secondary endpoints were overall survival (OS), duration of Response (DOR), objective response rate (ORR), and disease control rate (DCR) assessed by RECIST v1.1. This study is registered with ClinicalTrials.gov, NCT04459078 (follow-up is ongoing). Results: The data for a total of 38 patients out of 54 enrolled patients were evaluable. Median PFS was 10.97 mo (95%CI 7.1-NR).The objective response rate (ORR) and disease control rate (DCR) were 71.1% (27/38, 95%CI 53.9-84.0) and 97.4% (37/38, 95%CI 84.6-99.9), respectively. The incidence of grade 3 and worse treatment-related adverse events was acceptable, with grade 3 events in 25(46.3%) patients and grade 4 events in 3(5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (8 [14.8%]), liver function damage (9 [16.7%]), rash (3 [5.6%]), and decreased white blood cell count (3 [5.6%]). Conclusions: Camrelizumab combined with albumin paclitaxel and apatinib showed encouraging antitumor activity with an acceptable safety profile for the first-line treatment of advanced lung adenocarcinoma. Clinical trial information: NCT04459078.
Durvalumab (D) +/- tremelimumab (T) + chemotherapy (CT) in first-line (1L) metastatic (m) NSCLC: AE management in POSEIDON.
Authors: Cho Byoung Chul , Reinmuth Niels , Luft Alexander , Alatorre-Alexander Jorge , Geater Sarayut Lucien , Trukhin Dmytro , Kim Sang-We , Ursol Grygorii , Hussein Maen A. , Lim Farah Louise , Yang Cheng-Ta , Araujo Luiz H. , Saito Haruhiro , Marotti Miriam , Barrett Karen , Shi Xiaojin , Peters Solange , Garon Edward B. , Mok Tony S. K. , Johnson Melissa Lynne
Published: June 2022

9035

Background: In the Phase 3 POSEIDON study in 1L mNSCLC, adding T to D+CT resulted in statistically significant improvements in PFS and OS vs CT. No new safety signals were identified and treatment discontinuations due to treatment-related AEs (TRAEs) were similar for the T+D+CT and D+CT arms (15.5% and 14.1%). Here we present details of AEs and their management. Methods: 1013 pts with EGFR/ ALK wild-type mNSCLC were randomized 1:1:1 to 1L T+D+CT, D+CT or CT. Safety was assessed in all treated pts. Results: 330, 334 and 333 pts received T+D+CT, D+CT and CT; 78%, 82% and 74% received at least 4 cycles of platinum-based CT. The most common grade 3/4 TRAEs were hematologic (anemia in 17%, 15% and 20% of pts in the T+D+CT, D+CT and CT arms and neutropenia in 16%, 13% and 12%) and most were managed using standard approaches per local practice; 22%, 18% and 16% of pts received colony stimulating factors and 22%, 21% and 26% received blood transfusions. All grade immune-mediated AEs (imAEs) occurred in 34%, 19% and 5% of pts in the T+D+CT, D+CT and CT arms; a higher incidence of diarrhea/colitis, dermatitis/rash and endocrinopathies was seen with the addition of T to D+CT (Table). Grade 3/4 imAEs occurred in 10%, 7% and 2% of pts in the T+D+CT, D+CT and CT arms, and serious imAEs in 10%, 6% and 1%; imAEs led to discontinuation of any study treatment in 6%, 4% and 0.6%, and led to death in 0.6%, 0.3% and 0%. Most imAEs were low grade and manageable with systemic corticosteroids (received by 26%, 13% and 4% of pts in the T+D+CT, D+CT and CT arms) or endocrine therapy (12%, 8% and 1%). Median time from first dose to onset of imAEs (TTO) was generally > 60 days and the majority of non-endocrine imAEs resolved (Table). Conclusions: In POSEIDON, the safety profile of all regimens was manageable per standard guidelines and in line with the known profiles of D, T+D and CT; the most common grade 3/4 TRAEs were those typically associated with CT. As expected, more imAEs occurred with T+D+CT than D+CT, but the incidence of grade 3 or 4 imAEs, imAE-related deaths and treatment discontinuations due to imAEs was generally similar in the IO arms. T+D did not compromise the ability to administer planned CT. Clinical trial information: NCT03164616. [Table: see text]
Association between immune-related adverse events and microbiome composition in patients with advanced non–small cell lung cancer treated with immunotherapy.
Authors: Tonneau Marion , Richard Corentin , Nolin-Lapalme Alexis , Auclin Edouard , Benlaifaoui Myriam , Ponce Mayra , Al-Saleh Afnan , Blais Normand , Florescu Marie , Tehfe Mustapha , Malo Julie , Messaoudene Meriem , Okuma Yusuke , Hakozaki Taiki , Routy Bertrand
Published: June 2022

9036

Background: Despite immune-checkpoint inhibitors (ICI) achieving high response rates in patients (pts) with advanced non-small cell lung cancer (NSCLC), immune-related adverse events (irAE) remain an important therapeutic hurdle. The gut microbiome represents a novel prognostic marker of ICI response and early clinical evidence suggests that the microbiome may also regulate the development of irAE. We aimed to assess the association between irAE and the gut microbiome composition in advanced NSCLC pts amenable to ICI. Methods: In this study, we enrolled 464 pts from two independent cohorts (Montreal and Tokyo) with advanced NSCLC treated with ICI monotherapy or combination with chemotherapy. Fecal samples were collected prior to ICI initiation. Metagenomics microbiome profiling and 16S rRNA microbiome sequencing were performed for 81 pts and 133 pts respectively. The irAE were classified as CTCEA grade 0-1 (G0-1 irAE) and grade > 2 (G2-5 irAE). Microbiome composition of both groups was represented using alpha diversity, beta diversity indexes and LEfSe relative abundances. Results: Median follow-up was 28.3 months (mos) and the incidence of G2-5 irAE was 25.1% in the Montreal cohort. For the Tokyo cohort, the median follow-up was 19.6 mos and 30.8% pts developed G2-5 irAE. First, in both cohorts, overall survival (OS) and progression-free survival (PFS) were significantly improved for pts with G2-5 irAE compared to G0-1 irAE (OS: HR: 1.71, p = 0.008 and PFS: HR: 1.65, p < 0.001) and (OS: HR: 2.34, p = 0.001, and PFS: HR = 2.34, p = 0.006) respectively. Second, metagenomics analysis of 81 pts demonstrated a numerical decrease of the alpha diversity in terms of observed species in the G2-5 irAE. Dorea sp CAG 31, Anaerosporobacter mobilis, Butyricicococcus, and Enterococcus faecium were overrepresented in pts with G2-5 irAE. Conversely, Gordonibacter was increased in G0-1 irAE. Next, 16S rRNA profiling from the Tokyo cohort revealed an enrichment of Dorea, Butyricicococcus, and Eubacterium ventriosum in G2-5 irAE . Finally, we observed an enrichment in Dorea and Butyricicococcus in the pts with PFS > 6 months, as observed in the G2-5 irAE group. Conclusions: IrAE correlated with clinical outcome and microbiome composition in two independent cohorts of pts with advanced NSCLC. These results prompt further research on the potential mechanism underling the role of the microbiome in the development of irAE.
Three-year outcomes and correlative analyses in patients with non–small cell lung cancer (NSCLC) and a very high PD-L1 tumor proportion score (TPS) ≥ 90% treated with first-line pembrolizumab.
Authors: Ricciuti Biagio , Elkrief Arielle , Alessi Joao Victor Machado , Wang Xinan , Barrichello Adriana Paula de Castro , Pecci Federica , Lamberti Giuseppe , Lindsay James , Sharma Bijaya , Felt Kristen , Nishino Mizuki , Sholl Lynette M. , Rodig Scott J. , Schoenfeld Adam Jacob , Awad Mark M.
Published: June 2022

9043

Background: Although 1st-line PD-1 monotherapy has improved survival in advanced NSCLC with a PD-L1 TPS ≥50%, responses occur in ̃45% of patients (pts). We previously showed that among pts treated with 1st-line pembrolizumab, clinical outcomes were significantly improved in those with a PD-L1 TPS of ≥90% compared to a TPS of 50-89%. Here, we report the 3-year survival analysis to 1st-line pembrolizumab in pts with a PD-L1 TPS ≥90% vs 50-89%, and characterize genomic and immunophenotypic differences between these PD-L1 expression groups. Methods: Pts with stage IV EGFR/ALK wild-type NSCLC and PD-L1 TPS ≥50% who received 1st-line pembrolizumab at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC), with a minimum follow-up of 3 years were included. Comprehensive tumor genomic profiling and multiplexed immunofluorescence (mIF) were performed to examine genomic and immunophenotypic correlates of very high PD-L1 expression on separate cohorts of NSCLC at the DFCI. Results: Among 396 pts, median age was 69, 53.3% were women, 90.1% had a history of tobacco use, 83.6% had a ECOG performance status of 0-1, and 28.8% had a KRAS mutation. At a median follow-up of 42.6 months, median progression-free (mPFS) and overall survival (mOS) in the entire cohort were 5.1 months, and 19.0 months, respectively. When compared to pts with a PD-L1 TPS of 50-89% (N = 252), those with PD-L1 TPS ≥90% (N = 144) had a significantly longer mPFS (6.0 vs 4.5 months, HR 0.67, p < 0.001), and longer mOS (30.2 vs 16.9 months, HR 0.66, p < 0.01). Kaplan-Meier estimates of the 3-year PFS and OS were 24.9% and 47.0% in the PD-L1 TPS ≥90% groups, and 9.4% and 27.7% in the PD-L1 TPS 50-89% group, respectively. A PD-L1 TPS ≥90% was confirmed to be an independent predictor of improved PFS (HR 0.68, p < 0.01) and OS (HR 0.67, p < 0.01) in multivariable analysis. Tumor genomic profiling from a separate cohort of 500 NSCLC samples revealed that mutations in STK11, KEAP1, FBXW7, and CTNNB1 were significantly more frequent in tumors with a PD-L1 TPS of 50-89% compared to those with a PD-L1 TPS ≥90% (q < 0.05). mIF on 91 NSCLCs identified significantly higher CD8+PD1+ T cells and PD-L1+ immune cells in tumors with PD-L1 TPS ≥90% vs 50-89% (p < 0.05). Conclusions: Pembrolizumab monotherapy continues to demonstrate a meaningful long-term survival benefit in pts with advanced NSCLC and a PD-L1 TPS ≥90%. NSCLCs with very high PD-L1 TPS may have a more favorable genomic and immunophenotypic profile. These findings have implications for treatment selection and clinical trial interpretation and design.
Real-world effectiveness of immune checkpoint inhibitors alone or in combination with chemotherapy in metastatic non–small cell lung cancer.
Authors: Hong Lingzhi , Rinsurongkawong Waree , Saad Maliazurina B , Chen Pingjun , Aminu Muhammad , Spelman Amy R. , Negrao Marcelo Vailati , Cascone Tina , Lin Steven H. , Lee Percy , Sepesi Boris , Lewis Jeff , Gibbons Don Lynn , Vaporciyan Ara A. , Lee J. Jack , Le Xiuning , Wu Jia , Heymach John , Zhang Jianjun , Vokes Natalie I
Published: June 2022

9055

Background: The benefit of combination immune checkpoint inhibitor (ICI) with chemotherapy over ICI monotherapy in non-small cell lung cancer (NSCLC) remains underexplored. Methods: This retrospective cohort included patients with metastatic NSCLC from a single-institution database treated with ICI monotherapy or with chemotherapy between 1/2014-2/2020. Clinical progression-free survival (PFS) and overall survival (OS) were the primary outcomes. Propensity score adjustment for clinical and sociodemographic characteristics was used for analysis of first-line treatment outcomes. Results: A total of 1,139 patients (54% male; median age, 64.9) were included. Adenocarcinoma histology, smoking history, higher PD-L1 expression, and lower metastatic stage associated with improved PFS. However, PD-L1 expression and smoking associated with PFS only in adenocarcinoma (LUAD); squamous (LUSC) patients had shorter PFS independent of PD-L1 and smoking history (PD-L1 > 50% vs 1-49%: LUAD P < 0.001; LUSC P = 0.69; Former vs never smoker: LUAD P = 0.008; LUSC P = 0.89). In first-line patients (n = 680), treatment with ICI plus chemotherapy (ICI-chemo) associated with higher progression-free rates at 3 and 6 months compared with ICI-monotherapy (ICI-chemo vs ICI-mono: 3-month PFS, 85.2% vs 68.8%, P = 0.001; 6-month PFS, 66.4% vs 52.6%, P = 0.008). However, there was no difference overall in PFS or OS in either the full or propensity-matched cohort. Treatment with ICI and chemotherapy concurrently vs sequentially was associated with similar PFS (log-rank P = 0.12). Conclusions: In this real-world cohort, the addition of chemotherapy to ICIs may protect against early progression but does not influence long-term outcomes. Treatment with sequential vs concurrent ICI and chemotherapy produced similar outcomes. These findings suggest that combination therapy may maximally benefit patients at risk of early progression.
Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations.
Authors: Mazzeo Laura , Beninato Teresa , Pircher Chiara Carlotta , Brambilla Marta , Manglaviti Sara , De Toma Alessandro , Galli Giulia , Prelaj Arsela , Ferrara Roberto , Proto Claudia , Lo Russo Giuseppe , Ganzinelli Monica , Garassino Marina Chiara , Marchetti Paolo , De Braud Filippo G. , Occhipinti Mario
Published: June 2022

9057

Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]
Association of early tumor growth rate and survival outcomes in first-line metastatic non–small cell lung cancer (mNSCLC).
Authors: Fojo Antonio Tito , Brown Kevin , Grootendorst Diederik J. , KOTAPATI SRIVIDYA , Fronheiser Matthew , Tran Phuong , Rizzo Jasmine I. , Leung David , Micsinai Balan Mariann , Kald.Abdallah@Bms.Com No Firstname , Zhao Binsheng , Schwartz Lawrence Howard
Published: June 2022

9063

Background: Tumor growth rates ( g) estimated using imaging measurements, have been associated with overall survival (OS) and progression-free survival (PFS) in patients with mNSCLC, including those treated with first-line immunotherapy (1L IO) or chemotherapy (chemo). Here, we evaluated whether early g estimates within 18 weeks of first treatment dose are associated with survival outcomes for 1L treatment in mNSCLC. Methods: This was a retrospective analysis of data from patients randomized to either nivolumab+ipilimumab (NIVO+IPI) or chemo in CheckMate 227 Part 1 (NCT02477826), or NIVO+IPI+chemo or chemo alone in CheckMate 9LA (NCT03215706). Tumor assessments were performed by blinded independent central review using RECIST v 1.1 at baseline, every 6 weeks for the first 48 weeks and then every 12 weeks until disease progression. The analysis included patients with at least 3 measurable timepoints, including baseline, week 6, week 12, and/or week 18. If a patient did not have a week 18 measurement, the first three measurements alone were used. To derive the median early g, sum of longest diameters (SLD), based on baseline, weeks 6, 12 and/or 18 assessments, and time relative to baseline were fitted to the model defined by sum of exponential growth (g) and decay (d): SLD (t) = exp (–d x t) + exp (g x t) – 1. OS and PFS were estimated using Kaplan-Meier methodology. Results: In the two studies, 865/1166 (75%) of randomized patients in CheckMate 227 Part 1 and 562/719 (78%) in CheckMate 9LA had evaluable tumor growth rate data (Table). The median early g at weeks 12 and 18 was numerically lower for the IO-containing arm vs chemo arm in both studies (Table). Patients with lower growth rate at week 12 or week 18 ( g in first quartile [Q1]) had better OS relative to those with higher rate ( g in fourth quartile [Q4]) across all treatment arms (Table). A similar trend was observed for PFS. Conclusions: Early g estimates based on 2 or 3 post-baseline tumor assessment timepoints were associated with longer-term survival outcomes for 1L treatment of mNSCLC and could discern efficacy outcomes. These findings provide the foundation for further research, which may incorporate volumetric segmentations of measurable lesions and radiomic feature changes to further explore indicators of patient outcomes that could inform future clinical trials and clinical practice.[Table: see text]
Brigatinib in Japanese patients (pts) with ALK+ NSCLC: Final results from the phase 2 J-ALTA trial.
Authors: Zhang Pingkuan , Kumagai Toru , Yoshida Tatsuya , Nishio Makoto , Toyozawa Ryo , Seto Takashi , Nakagawa Kazuhiko , Ohe Yuichiro , Yamamoto Nobuyuki , Kudou Kentarou , Asato Takayuki , Goto Koichi
Published: June 2022

9075

Background: In previous J-ALTA (NCT03410108) analyses, brigatinib demonstrated substantial efficacy and manageable safety in pts with TKI-refractory and TKI-naive ALK+ NSCLC. We report the final J-ALTA results. Methods: J-ALTA was a single arm, multicenter, open-label study that included ALK TKI-naive and -refractory NSCLC expansion parts. The main cohort within the refractory part was a group with alectinib-refractory NSCLC. Primary endpoints: IRC-assessed confirmed ORR in the alectinib-refractory cohort; IRC-assessed 12-month PFS in the TKI-naive cohort. Secondary endpoints included confirmed ORR (IRC-assessed in the total refractory cohort; investigator-assessed in all cohorts); DoR, PFS, DCR, and iPFS by IRC; and safety. Final analyses were performed following last pt last contact. Results: A total of 104 pts were enrolled; 72 had TKI-refractory (56% female; median age, 53.0 y) and 32 had TKI-naive (53% female; median age, 60.5 y) NSCLC. As of 28 July, 2021 (last pt last contact), median follow-up was 24.2 mo in the refractory cohort (alectinib-refractory subgroup [n = 47], 23.0 mo) and 22.1 mo in the TKI-naive cohort. Confirmed ORR was 34% (95% CI: 21–49) by IRC with 16 partial responses (PR) in the alectinib-refractory cohort and 32% (21–44; 22 PR) in the total refractory cohort. In the TKI-naive cohort, IRC-assessed 24-mo PFS was 73% (90% CI: 55–85); median PFS was not mature. Additional efficacy analyses are reported in Table. TEAEs were reported in all 104 pts (most common: increased CPK, 79%; hypertension, 48%; diarrhea, 47%). Grade ≥3 TEAEs were reported in 68% and 91% of pts in the TKI-refractory and -naive cohorts, respectively; most commonly (TKI-refractory/naive) elevated CPK, 24%/50%; elevated lipase, 15%/19%; hypertension, 11%/34%. Pneumonitis was mandated to be reported as an SAE regardless of severity and was the only SAE reported in > 5% of pts (refractory, n = 5 [7%; early onset, 1]; naive, n = 4 [13%; early onset, 0]). TEAEs led to dose interruption/reduction/discontinuation in 63%/31%/7% of pts in the TKI-refractory cohort and 94%/69%/0% in the TKI-naive cohort. Conclusions: Final efficacy and safety results in pts with TKI-refractory and -naive NSCLC were consistent with previous J-ALTA analyses. No new safety signals were observed in either cohort. Brigatinib demonstrated a favorable benefit-risk profile and is an important option for Japanese pts with ALK+ NSCLC regardless of TKI treatment history. Clinical trial information: NCT03410108. [Table: see text]
Efficacy of dabrafenib-trametinib combination in BRAF V600E-mutated metastatic non–small cell lung cancer: Results of the IFCT-2004 BLaDE cohort.
Authors: Swalduz Aurélie , Beau-Faller Michele , Planchard David , Mazieres Julien , Bayle Sophie , Debieuvre Didier , Fallet Vincent , Geier Margaux , Cortot Alexis B , Couraud Sebastien , Daniel Catherine , Pichon Eric , Missy Pascale , Morin Franck , Westeel Virginie , Auliac Jean-Bernard , Veillon Remi
Published: June 2022

9082

Background: BRAF V600E mutations occur up to 2% of advanced non-small cell lung (NSCLC). Dabrafenib-trametinib (D-T) combination was associated with improved OS rates in phase II study and was approved in the 1st-line setting and further. The IFCT-2004 BLaDE study reports the D-T combination efficacy in a large French real-world multicenter cohort of advanced BRAF V600E-mutated NSCLC. Methods: Patients (pts) with advanced NSCLC harboring BRAF V600E mutation diagnosed between 01.01.2016 and 31.12.2019 and treated with D-T combination (D 300 mg + T 2 mg daily) whatever the treatment line were included. Demographic, clinical, pathological data were collected as well as data of efficacy and reason of treatment discontinuation. The primary endpoint was 12 months-OS rate in pts receiving the D-T as 2nd-line or subsequent treatment (L2+). Results: 163 pts were included in 54 centers through 32 national testing labs: 50.3 % were female, 30.2% never-smokers, 95.1 % had adenocarcinoma and PDL1 was > 1% in 78.2%. Median age was 68.3 years. At D-T initiation, 80.8 % of pts were PS 0/1, 93.9 % were stage IIIB/C ineligible for surgery or local therapy and IV, 20.9% had brain metastases and 27% received D+T as 1st line treatment (L1). At the data cutoff (30.06.2021), median (m) follow-up was 27.4 months [95% CI 22.2-31.9] and 47 pts (28.8%) remained on study treatment. 12 months-OS rate in pts receiving D+T in L2+ (n = 119) was 67.4% [95% CI 57.8-75.3] with a median progression-free survival (mPFS) of 10.4 months [95% CI 7.3-13.1]. In the 44 pts receiving D+T in L1, 12 months-OS rate was also 67.4% [95% CI 51.2-79.3] with a mPFS of 18.2 months [95% CI 7.7-21.3]. Objective response rates were 73.8% [95% CI 65.5 - 82.2] and 82.9% [95% CI 71.4 - 94.4], disease progression was observed as best response in 3.7% [95% CI 0.1 - 7.3] and 0% in L2+ and L1, respectively. Other efficacy results are detailed in the table. D-T discontinuation for toxicity was reported in 10.3% of pts. 51.2% and 43.7% of pts received subsequent treatment in L2+ and L1 respectively. For L2+ pts, subsequent treatments were immunotherapy (IO)-based in 37.2 % and chemotherapy in 58.3%. For L1 pts, subsequent treatments were (IO)-based in 42.9% and chemotherapy in 42.7%. Conclusions: Our series confirms significant efficacy of D-T combination in BRAF V600E-mutated metastatic NSCLC. These results in real-world conditions are consistent with registration studies but also support its use in 1st line setting. [Table: see text]
A multicenter real-world study of tumor-derived DNA from cerebrospinal fluid in genomic profiling of NSCLC with central nervous system metastases.
Authors: Mu Yongping , Guo Wei , Zhang Xia , Wang Kai , Yuan Mingming , Chen Rongrong , Bai Jun , Hu Qun
Published: June 2022

9087

Background: Genomic profiling of cerebrospinal fluid (CSF) could be used to detect actionable mutations to guide the clinical treatment of NSCLC patients with central nervous system (CNS) metastases. Examining the performance of CSF samples in a real-world setting can further confirms the potential of CSF in genotyping for guiding therapy in clinical practice. Methods: A total of 1097 samples were collected from 773 treated NSCLC patients with CNS metastases in a real-world setting, including 117(10.67%) CSF samples, 287(26.16%) tissue samples and 693(63.17%) plasma samples. All samples were subjected to the targeted next-generation sequencing of 1021 cancer-relevant genes. Results: Of these 1097 treated samples, somatic alterations were identified in 112 (95.72%) of the CSF samples, comparing with 287 (100%) of tumor tissue samples and 592 (85.43%) of plasma. Among the tumor tissue samples, 242 were non-intracranial tissues, which could not reveal the unique genetic profiles of intracranial metastases. The median of maximal somatic allele frequency of CSF samples (72.35%) was significantly higher than those of plasma (1.30%) and tumor tissues (37.30%) (all p<0.001). In the thirty-two pairs CSF and plasma samples tested simultaneously, 442 alterations were detected, of which 377 were detected in CSFs and 92 in plasma. 27 alterations could be detected in both plasma and CSF, 65 were not detected in CSFs and 350 were not in plasma, the same alterations were 10.91% (27/442). For SNV or InDel, 220 mutations were detected, of which 155 were detected in CSFs and 89 in plasma, the same mutations were 10.91% (24/220). For CNVs, 216 CNV alterations were detected, of which 216 were detected in CSFs and only one in plasma. We compared actionable mutation of these 1097 treated samples to further analyze the detection capability of actionable mutations of CSF samples in this real-world setting (Table). Compared with plasma, the detection rates of all actionable mutation and actionable EGFR in CSF were significantly higher than those in plasma samples (93.16% vs. 53.97% for all actionable mutation, 83.76% vs. 39.54% for EGFR, all p<0.001).Conclusions: This real-world large cohort study verified that CSF had higher sensitivity than plasma for identifying actionable mutations. In the process of multiple comparison, it can be seen that CSF is better than plasma in detecting alterations, especially in detecting CNV alteration. CSF can be used as a substitute in genomic profiling for NSCLC patients with CNS metastases when there is no intracranial tumor tissue.[Table: see text]
Demographic and socioeconomic factors associated with stage at diagnosis in non–small cell lung cancer: An NCDB analysis.
Authors: Verplancke Kiana , Taylor Alexandra , Gallegos Jillian Marie , McMahon Kevin , Creech Zachary , Truong Gia Thinh , Silberstein Peter T. , Dahl Mary Elizabeth
Published: June 2022

9132

Background: There were 2.21 million new diagnoses of lung cancer worldwide in 2020, accounting for approximately 25% of all cancer related deaths. A factor that impacts the overall mortality of lung cancer is the stage at initial presentation for diagnosis. Current 5-year survival estimates of non-small cell (NSC) lung cancer range from 73% in early-stage disease to 13% in advanced disease. The stark differences in survival rate in early and late disease, highlight the importance of determining if socioeconomic and demographic factors impact the stage of cancer at diagnosis. This study sought to determine if certain socioeconomic and demographic factors are associated with receiving an early (Stage 0-I) or delayed (Stage IV) diagnosis of NSC lung cancer. Methods: Using the National Cancer Database, 1,149,539 patients were identified as having a NCDB Analytic Stage Group diagnosis of Stage 0-I (early) vs Stage IV (delayed/advanced) NSC lung cancer between 2004 and 2018. Using SPSS statistics 27, patients with early and delayed diagnoses were compared to each other based on certain characteristics including sex, race, ethnicity, and level of education. Results were analyzed using multivariate and chi square analyses, as well as one-way ANOVA. Results: We identified significant differences (p <.005) between stage at presentation and certain socioeconomic factors. Females were 70% less likely to be diagnosed with advanced disease in comparison to males (p <.001, 95% CI =.697-.708). African Americans and Native Americans were more likely to present with advanced disease in comparison to white patients (p <.001, 95% CI = 1.407-1.449 and 1.046 – 1.235, respectively). Hispanic patients were 49.3% more likely to present with advanced disease than non-Hispanic patients (p <.001, 95% CI = 1.389 – 1.605). Patients with at least one comorbidity (CCI score ≥ 1) were less likely to present with advanced disease (p <.001). Those who lived in a zip code where 21% or more of the residents lacked a high school degree were more likely to present with stage IV disease, in comparison to patients who lived in a zip code where less than 20.9% of its residents did not graduate from high school (p <.001). Conclusions: Demographic and socioeconomic factors associated with a delayed diagnosis of NSC lung cancer include male sex, non-white race, being Hispanic, having no comorbidities, and living in a zip code where 21% or more residents have no high school degree.
Meta-analysis of randomized phase II-III trials evaluating triplet combinations of immunotherapy and targeted therapy for BRAF V600-mutant unresectable or metastatic melanoma.
Authors: Ferrucci Pier Francesco , Gaeta Aurora , Cocorocchio Emilia , D'Ecclesiis Oriana , Gandini Sara
Published: June 2022

9541

Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( < 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.