bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization of treatment options for EGFR-mutant, stage III, unresectable NSCLC: A systematic review and meta-analysis.
Authors: Liu Lian , Dai Xin , Li Song , Sheng Lei , Huang Kai , Chu Jiahui , Wang Jian , LI Jisheng , Liu Yanguo
Published: June 2022

8548

Background: The PACIFIC study established a new treatment standard for Stage III unresectable NSCLC, but CRT followed by durvalumab failed to bring survival benefit to patients with EGFR mutations. EGFR-TKIs have been successful in the setting of first-line treatment of advanced NSCLC and postoperative adjuvant treatment of NSCLC. We explored whether locally advanced inoperable patients with EGFR mutations can benefit from EGFR-TKIs and the possibly best treatment regimen through meta-analysis. Methods: Studies involving unresectable stage III NSCLC with EGFR mutations published in PubMed, Embase, Cochrane, ClinicalTrials.gov, and abstracts of important international conferences (ASCO, ESMO, WCLC) from January 1, 2000 to September 30, 2021 were screened. An integrative analysis was performed using STATA (version 16.0), and a network meta-analysis based on a Bayesian framework was performed using R (version 3.6.1) for the studies with a control group. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 3291 patients were identified in 17 studies, including 5 treatment measures including concurrent chemoradiotherapy (CRT), CRT followed by durvalumab (CRT+Durva), TKI monotherapy, radiotherapy combined with TKI (RT+TKI), and CRT combined with TKI (CRT+TKI). PFS with TKI-free treatments (CRT, CRT+Durva) was significantly shorter than TKI-containing ones (TKI, RT+TKI, CRT+TKI) (HR 2.17, 95%CI 1.47-3.19), but its advantage only translated into borderline OS benefit (1.27, 0.99-1.63). In detail, the PFS with TKI-containing measures, including TKI monotherapy (0.66, 0.50-0.87), RT+TKI (0.37, 0.28-0.50), or CRT+TKI (0.14, 0.03-0.75) were all significantly longer than CRT. Furthermore, the PFS with both RT+TKI (0.40, 0.21-0.76) and CRT+TKI (0.15, 0.03-0.74) were significantly longer than CRT+Durva, while no statistical difference existed in PFS between RT+TKI and CRT+TKI. However, TKI alone had significantly shorter PFS than RT+TKI (1.78, 1.17-2.67). There was no statistical difference in OS among all the treatments, with RT+TKI ranking first in the Bayesian ranking. The integrated analysis found that RT+TKI had the longest OS (65.7 months, 55.5-76.0 months) and PFS (21.8 months, 18.0-25.7 months) and the highest response rate (77.7%, 68.8%-86.6%). Severe neutropenia was the most common with CRT+TKI, while RT+TKI brought the highest incidences of radiation pneumonitis and esophagitis. Conclusions: For EGFR mutant Stage III unresectable NSCLC, RT and TKI are both essential. RT+TKI and CRT+TKI have significantly longer PFS than CRT±immunotherapy, and RT+TKI has OS benefit trends. Due to the lack of sufficient studies on CRT+TKI, it is urgent to conduct large randomized clinical trials to explore the optimal treatment for these patients.
Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).
Authors: Ponce Santiago , Cedres Perez Susana , Ricordel Charles , Isambert Nicolas , Levitsky Victor , Hansen Thomas Birkballe , Jaderberg Magnus Erik , Paz-Ares Luis G.
Published: June 2022

8561

Background: MPM is an aggressive malignancy without curative treatment. ONCOS-102 is an oncolytic adenovirus expressing GM-CSF (Ad5/3-D24-GMCSF) with a clinically documented ability to stimulate local and systemic immune responses and re-modulate the tumor microenvironment, both as a monotherapy and in combination with anti-PD1 blockade. The study objectives included determining safety and tolerability, efficacy and immunological activation in repeat tumor biopsies, and correlations with clinical outcomes. Methods: Following a safety run-in of n = 6 pts, 25 patients were randomized to receive ONCOS-102 intratumorally under CT or US guidance at a dose of 3 x 1011 Virus Particles on Day 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22, or control comprising six cycles of P/C only. Both treatment-naïve (1L) and previously treated patients (2L) were enrolled. Imaging was done at baseline, Day 43-64 and 127-148 and tumor biopsy were collected at baseline and at Day 36. Final survival analysis (n = 25) was performed after 30 mo follow up. Multiplex immunofluorescence for immune cell subsets, RNASeq and qPCR was performed on repeat tumor samples. Results: The most frequent adverse events were anaemia, neutropenia and asthenia reported by > 50% in both groups with more frequent reports of pyrexia and nausea in the experimental (exp) group. No difference in the rate of severe events (Gr 3/4 acc to NCI CTCAE vs 4.0) were observed. 30-month survival rate (n = 25) was 34.3 % vs 18.2 % (NS) with mOS of 19.3 mo (95% CI: 4.6, NA) vs 18.3 mo (95% CI: 3.1, 28.9) in the exp group vs control. For patients treated in the 1L setting, 30 mo survival was 33.3 % in the exp group (n = 8) and 0% in the control group (n = 6) with mOS of 25.0 months and 13.5 months, respectively (NS). mPFS was unchanged from prior cut-offs; 9.8 months in the exp group and 7.6 in the control (NS). ONCOS-102 + P/C induced a pronounced increase in tumor infiltration by CD4+, CD8+ and granzyme B expressing CD8+ T-cells as well as M1:M2 macrophage polarization in patients with disease control (n = 13) vs progressing patients (n = 3). The data from RNAseq and qPCR analysis will be presented. Conclusions: The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted Clinical trial information: NCT02879669.
Preliminary safety and efficacy of camrelizumab plus nab-paclitaxel and carboplatin as frontline setting in extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.
Authors: Ren Shengxiang , Yu Jia , Xiong Anwen , Wang Qi , Wang Lei , Chen Bin , Yang Menghang , Li Wei , Yuan Jiajia , Zhao Changhong , Zhou Caicun
Published: June 2022

8564

Background: Impower133 and CASPIAN studies showed that PD-L1 antibody combined with first-line chemotherapy could prolong the overall survival. Our previous study showed that nab-paclitaxel had a promising efficacy as later line setting in ES-SCLC. This phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus nab-paclitaxel and carboplatin as front-line setting in ES-SCLC. Methods: Key inclusion factors were18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Patients (pts) received 4 ̃ 6 cycles of camrelizumab (200mg, D1, q3w) combined with nab-paclitaxel (230mg/kg, D1, q3w) plus carboplatin (AUC = 5, D1, q3w), then camrelizumab maintenance until disease progression or intolerable side effects. The primary endpoint was 6 months progression free survival rate. Secondary endpoints included PFS, ORR and safety. Results: From April 2021 to December 2021, 36 pts who received at least one dose of camrelizumab were included into this report. The median age was 60.5 (range: 32-73) with 30 (83.3%) males, 19 (52.8%) former smokers, and 36 (100%) ECOG performance status 1. The median drug exposure was 5 cycles, and 18 (50%) pts entered the maintenance stage. 33 pts had at least one 1 post-treatment tumor assessment. Among them, 32 partial responses (5 unconfirmed), 1 progressive disease (new lesion). The confirmed ORR was 81.8% (27/33), the unconfirmed ORR was 97% (32/33), DCR was 97% (32/33). The median PFS was 7.27 months (95% CI: 4.7 – 9.8 months). 24 (66.7%) pts had at least one adverse event, and 10 (27.8%) pts experienced grade 3 or 4 adverse events, including 10 (27.8%) neutropenia, 4 (11.1%) leukopenia, 2 (5.6%) thrombocytopenia, 2 (5.6%) anemia, 2 (5.6%) hepatic function abnormal,1(2.8%) alanine aminotransferase increased, 1(2.8%) hyperglycaemia, 1(2.8%) diabetes mellitus, and no grade 5 adverse event happened. Conclusions: Camrelizumab plus nab-paclitaxel and carboplatin had promising efficacy and safety profile as first-line setting in ES-SCLC, further validation is warranted. Clinical trial information: NCT04790539.
Efficacy and safety of camrelizumab combined with chemotherapy (irinotecan combined with platinum) followed by camrelizumab combined with apatinib in the first-line treatment of advanced small cell lung cancer: A phase II study.
Authors: Ni Jun , Zhang Xiaotong , Pan Ruili , Wang Hanping , Si Xiaoyan , Cui Xiaoxia , Zhang Li
Published: June 2022

8573

Background: The treatment mode of small cell lung cancer (SCLC) is mainly based on the comprehensive treatment of chemotherapy and radiotherapy. IMpower133 study, suggesting that immune checkpoint inhibitors combined with chemotherapy first-line treatment for advanced SCLC may bring new research directions of clinical benefit. Previous study suggested that the combination of anti-PD-1 antibody camrelizumab and VEGFR-2 inhibitor apatinib significantly improved antitumor effects. The aim of this study was to evaluate the efficacy and safety of camrelizumab combined with chemotherapy (irinotecan combined with platinum) followed by camrelizumab combined with apatinib in the first-line treatment of SCLC. Methods: Extensive-stage small cell lung cancer patients were enrolled in this single-center, single-arm study. During the induction treatment phase, Patients received camrelizumab (200mg q3w), irinotecan (65 mg/m2, q3w) and platinum (cisplatin: 30 mg/m2, carboplatin: AUC=4̃5), after 4-6 cycles, the patient entered the maintenance phase, and then patients received camrelizumab combined with apatinib until disease progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary endpoint is progression-free survival (PFS). Secondary endpoints are objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and overall survival (OS), which are based on RECIST 1.1. Results: At data cut-off (Jan 10, 2022), 20 extensive-stage SCLC patients were enrolled in the study, of which 18 patients were evaluable. Median age was 64 years, male accounts for 85.0% (17/20). Median follow-up was 5.0 months (range 0.4̃17.6 months). Of 18 evaluable patients, no one achieved complete response Partial response was achieved by 17 (94.4%) patients and stable disease exhibited by 1 (5.6%) patient. The ORR and DCR were 94.4% and 100%, respectively. mPFS and mDoR have not been reached. In terms of adverse events (AEs), reactive cutaneous capillary hyperplasia (RCCEP) was observed in 10 (47.6%) patients 10 patients. Grade III-IV AEs were observed in 7 (35.0%) patients with neutropenia, thrombocytopenia, hemoglobin reduction, leukopenia, rash. The rest were grade I-II AEs. Conclusions: The treatment in this study showed impressive ORR and DCR, and acceptable toxicity, and may be a promising method as a first line treatment. Clinical trial information: NCT04453930.
Immunological signature of patients with thymic epithelial tumors.
Authors: Morra Rocco , De Placido Pietro , Pietroluongo Erica , Ottaviano Margaret , Tortora Marianna , Mucci Brigitta , Montella Liliana , Del Deo Vitantonio , Malfitano Anna Maria , Pirolo Miriam , Mirra Federico , Vaia Angelo , D'Esposito Vittoria , Terracciano Daniela , De Placido Sabino , Formisano Pietro , Palmieri Giovannella , Giuliano Mario
Published: June 2022

8589

Background: Thymic epithelial tumors (TETs) are complex diseases frequently associated with immune disorders, including Good Syndrome (GS). Etiopathogenesis of immune dysregulations in TETs patients is still not totally explained. The aim of this study was to evaluate differences in immune cell phenotype, as well as in the serum expression levels of a panel of cytokines, chemokines, and growth factors in patients with TETs and GS with or without autoimmune disorders (AD). Methods: From May 2019 to June 2020, consecutive patients with TETs and GS were recruited at Rare Tumors Coordinating Center of Campania Region (CRCTR – Naples, Italy). We analyzed the immunophenotype from peripheral blood focusing on selected immune cell subsets (monocytes, neutrophils, eosinophils, CD4+T cells, CD8+T cells, B-cells, NK cells and NKT- cells, T regulatory cells) processed for blood cell count and immunophenotyping, according to the 8-color immunophenotyping kit and Treg detection kit (CD4/CD25/CD127), and a panel of cytokines, chemokines, and growth factors from peripheral blood serum screened with pre-formed kits by Bioplex multiplex. D’Agostino-Pearson normality test was used to evaluate whether the continuous data were normally distributed, and a two-tailed t-test for independent samples was used. p-values < 0.05 were considered statistically significant. Results: Overall, 29 patients were enrolled [17 (58.6%) with and 12 (41.4%) without AD]. Sixteen patients (55.2%) were female and 13 patients (44.8%) were male. Tumor histology included thymoma in all the patients with AD, whereas there were 10 cases of thymoma and 2 of thymic carcinoma in the group of patients without AD. The analysis of leucocytes by blood cell count showed a statistically significant higher number of leucocytes, ascribable to T lymphocytes (p = 0.023), B lymphopenia (p = 0.003) and decrease of T regulatory cells (p = 0.009) in TET patients with AD, as compared with TET patients without AD. Moreover, TET patients with AD showed significantly higher circulating levels of IL-15 (p = 0.032), VEGF (p = 0.007), IP-10 (p = 0.013), GM-CSF (p = 0.042), IL-6 (p = 0.031), and MIP-1α (p = 0.017) with respect to TET patients without AD. Conclusions: To our knowledge, this is the first report describing a profound alteration in B and T lymphocytes in TET patients associated with AD. The observed differences may be potentially important in the clinical management of this complex disease. Additional studies are needed to better understand the immunophenotypic alterations in TETs patients.
A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.
Authors: Felip Enriqueta , Majem Margarita , Doger Bernard , Clay Timothy Dudley , Carcereny Enric , Bondarenko Igor , Peguero Julio Antonio , Cobo-Dols Manuel , Forster Martin , Ursol Grygorii , García Ledo Gema , Vilà Laia , Krebs Matthew , Iams Wade Thomas , Mueller Christian , Triebel Frederic
Published: June 2022

9003

Background: Eftilagimod alpha (E) is a soluble LAG-3 protein binding to a subset of MHC class II molecules to mediate antigen presenting cell (APC)/CD8 T-cell activation. Stimulation of the APCs and subsequent T cell recruitment with E may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We hereby report results of the extended first-line non-small cell lung carcinoma (NSCLC) cohort of the TACTI-002 (“Two ACTive Immunotherapies”) phase II trial. Methods: Pts with untreated metastatic NSCLC, unselected for PD-L1 expression were recruited. Objective response rate (ORR) by iRECIST was the primary endpoint (EP) and secondary EPs include ORR by RECIST 1.1, tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS) and exploratory biomarker. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) and then q3w for up to 1 year with P (200 mg IV q3w for up to 2 years). Imaging was done every 8 weeks. PD-L1 was assessed centrally. This has been approved by relevant CAs, ECs, and IRBs. Results: From Mar 2019 to Nov 2021 114 pts were enrolled. Median age was 67 years (44-85) and 74% were male. ECOG PS was 0 and 1 in 37% and 63% of pts, respectively. Pts presented squamous (35%) or non-squamous (62%) NSCLC with 88% of pts at stage IV at the time of study entry. All PD-L1 subgroups were represented (Table). Pts received median 6.0 (range 1–35) P and 7.0 (1-22) E administrations. 19 (17%) pts discontinued treatment due to adverse events (AEs). The most common (≥15%) AEs were dyspnea (33%), asthenia (30%), decreased appetite (22%), cough (20%), anemia (20%), fatigue (19%), pruritus (18%), constipation (17%) and diarrhea (15%). At data cut-off (Jan 2022), 75 pts with a minimum follow-up of 6 months were evaluated for efficacy. ORR (iRECIST) was 37.3% in the ITT and 41.8%% in the evaluable pts assessed by local read. DCR 73.3% was reported. Response rate for squamous and non-squamous pathology were 33.3 % and 40.3 %, respectively. Results according to RECIST 1.1 were comparable. Responses were observed in all PD-L1 subgroups (Table). 24/28 (86%) responses were already confirmed while median duration of response was not yet reached (5 events). Conclusions: E + P is safe and shows encouraging antitumor activity in first-line metastatic NSCLC patients unselected for PD-L1, warranting further investigation. Clinical trial information: NCT03625323. [Table: see text]
Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study.
Authors: Riess Jonathan W. , Krailo Mark D. , Padda Sukhmani Kaur , Groshen Susan G. , Wakelee Heather A. , Reckamp Karen L. , Koczywas Marianna , Piotrowska Zofia , Steuer Conor Ernst , Kim Chul , Paweletz Cloud P. , Sholl Lynette M. , Heavey Grace , Kolesar Jill , Moscow Jeffrey , Janne Pasi A. , Lara Primo "Lucky" N. , Newman Edward M. , Gandara David R.
Published: June 2022

9014

Background: Osimertinib (Osi) is standard of care in 1st line (1L) EGFR mut NSCLC and TKI resistant T790Mpos NSCLC but acquired resistance emerges; outcomes are less robust in T790Mneg, C797Xpos and EGFR exon 20 insertion (ex20ins) disease. We examined Osi with the EGFR monoclonal antibody Necitumumab (Neci) in select settings of EGFR TKI resistance. Methods: Pts were accrued to 5 expansion cohorts (ExC) at recommended phase 2 dose (RP2D) of Osi 80 mg daily and Neci 800 mg D1 + D8 of q21d cycle. ExC (18 pts/cohort): A) T790Mneg progressive disease (PD) on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 1st/2nd gen TKI and PD on 3rd gen TKI, C) T790Mpos PD on 1st/2nd gen TKI and PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy, E) PD on 1L osi. In ExC A-C, T790M was confirmed centrally (tissue) by ddPCR. Additional correlative studies include: tissue NGS (> 400 gene panel), EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR. Adverse events were graded (Gr) by CTCAEv5; ORR, PFS by RECIST 1.1. Primary pre-specified efficacy endpoint ≥3/18 pts responding per cohort. Results: 101 patients accrued (100 evaluable). Efficacy is summarized in the Table. Drug related Gr 3 AEs were seen in 38% of pts, mainly rash (21%). ORR among all pts was 19% (95% CI 12-28%) that varied across cohorts (Table). In ExC A-C, 69% pts had detectable EGFR activating mutations in ctDNA, with decline in mutant allele frequency (AF) on treatment in 80% and ctDNA clearance in 33%. Conclusions: Osi/Neci is feasible and tolerable at the RP2D. EGFR ctDNA was detectable at baseline in the majority of pts with decrease in AF on treatment. Osi/Neci was active in select settings of EGFR-TKI resistance, meeting its prespecified efficacy endpoint in T790Mneg PD on 1st/2nd gen TKI as last therapy (ExC A), EGFR ex20ins post-chemo (ExC D) and PD on 1L osimertinib (ExC E). mPFS in the EGFR ex20ins cohort was within the range of current EGFR Exon 20 ins agents in development. EGFR monoclonal antibodies with osimertinib warrant further study in settings of de novo and acquired EGFR dependent resistance to EGFR-TKI. Clinical trial information: NCT02496663. [Table: see text]
A randomized phase II/ III trial of nivolumab versus nivolumab plus docetaxel for previously treated advanced or recurrent non–small cell lung cancer: TORG1630.
Authors: Kawashima Yosuke , Taniguchi Yuri , Shimokawa Tsuneo , Takiguchi Yuichi , Misumi Toshihiro , Nakamura Atsushi , Furuya Naoki , Tanaka Kentaro , Harada Toshiyuki , Tanaka Hisashi , Miura Satoru , Sata Masafumi , Kato Terufumi , Tokito Takaaki , Naoki Katsuhiko , Bessho Akihiro , Goto Yasuhiro , Nakamichi Shinji , Okamoto Hiroaki
Published: June 2022

9030

Background: Immuno-checkpoint inhibitor (ICI) monotherapy is a standard second-line treatment for non-small-cell lung cancer (NSCLC). Addition of a cytotoxic agent to ICI may enhance the benefits. Methods: This multi-institutional open-label randomized phase II/III study compared the arm A consisting of nivolumab (NIV) monotherapy and arm B consisting of NIV + docetaxel (DTX) for patients with previously treated ICI-naïve NSCLC, prestratified by PS/histological types/sex/driver-mutations. The primary endpoint was superiority of arm B in OS in the phase III part. Assuming a HR of 0.75 for OS with the estimated mOS of arm A/B as 10.5/14.0 mo, a total 350 patients would be required to provide 80% power at a one-sided α of significance being 0.05. It was started at Nov. 2017, however, the patients’ accrual was discontinued due to the approval of ICI in the first-line setting in late 2018. Eventually, a total of 131 patients were enrolled for analysis. Results: 128 patients (64 in each arm) were eligible and included in full analysis set (FAS), and the patients’ demographics were well-balanced in each arm. The mOS was 14.7 mo (95%CI, 11.4-18.7) in arm A, and 23.1 mo (95%CI, 16.7-NR) in arm B. The HR of OS was 0.63 (90%CI, 0.42-0.95; p = 0.0310). The mPFS was 3.1 mo (95%CI, 2.0-3.9) and 6.7 mo (95%CI, 3.8-9.4) in arm A and B, respectively. The HR for PFS was 0.58 (95%CI, 0.39-0.88; p = 0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B, with a statistical significance (p = 0.0014). Subgroup analyses for OS disclosed that the HRs favored arm B over arm A across all prespecified subgroups. The mOS of EGFR-mutant subgroup also showed better tendency in arm B than A (11.0 mo in arm A; 95%CI, 3.5-14.0; vs 20.6 mo in B; 95%CI, 5.8-NR; HR 0.45; 95%CI, 0.17-1.17). The hematological toxicity and gastrointestinal adverse events were more common in arm B than in A. Six (9.4%) in arm A and 25 patients (39.1%) in arm B discontinued protocol treatment due to adverse events. Overall, two treatment-related deaths were observed; one from pneumonitis in arm A, and one from myocarditis in arm B. Conclusions: Although the resulting statistical power was limited because of reduced sample size, the addition of DTX to NIV in the second-line NSCLC therapy significantly improved OS, PFS, and ORR, despite slightly elevated risk of toxicity. This is the first randomized clinical trial that confirmed significant survival benefit of ICI + chemotherapy over ICI alone in any cancer type. Clinical trial information: UMIN000021813.
Association of depth of target lesion response to brigatinib with outcomes in patients with ALK inhibitor-naive ALK+ NSCLC in ALTA-1L.
Authors: Camidge D. Ross , Kim Hye Ryun , Ahn Myung-Ju , Yang James Chih-Hsin , Han Ji-Youn , Hochmair Maximilian , Lee Ki Hyeong , Delmonte Angelo , Campelo Rosario Garcia , Kim Dong-Wan , Griesinger Frank , Felip Enriqueta , Califano Raffaele , Spira Alexander I. , Thomas Michael , Gettinger Scott N. , Tiseo Marcello , Liu Yuyin , Zhang Pingkuan , Popat Sanjay
Published: June 2022

9072

Background: In patients (pts) with crizotinib (CRZ)-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial (NCT02094573), the depth of target lesion response to brigatinib (BRG) correlated with PFS and OS. Here, we examine the association of maximum decrease in target lesions with PFS and OS in ALTA-1L (NCT02737501), a randomized phase 3 trial of BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC. Methods: Pts were randomized 1:1 to receive BRG 180 mg qd (7-day lead-in at 90 mg; n=137) or CRZ 250 mg bid (n=138). Pts with target lesion assessment by blinded independent review committee (BIRC) were grouped based on greatest decrease from baseline per RECIST v1.1: none–50%, 51%–75%, and 76%–100% shrinkage. Outcomes in the ≤50% target lesion shrinkage group served as the comparator for outcomes in the 51%–75% and 76%–100% groups. Results: At study end (last pt contact: Jan 29, 2021), 124/137 pts in the BRG arm and 125/138 pts in the CRZ arm had ≥1 evaluable target lesion assessment; female (BRG/CRZ), 51%/59%; median age, 57.5/60.0 years. Median follow-up was 40.8/15.7 months. In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively. BRG was associated with significantly more pts with target lesion shrinkage >75% vs CRZ ( P=0.0005), and a Cochran-Armitage trend analysis demonstrated significantly deeper response across all shrinkage groups for BRG compared with CRZ ( P<0.0001). A majority of pts in the BRG arm experienced 76%–100% target lesion shrinkage in all subgroups analyzed. Pts treated with BRG or CRZ with target lesion shrinkage >50% had lower risk of a PFS event (BRG HR [95% CI]: 51%–75% shrinkage, 0.58 [0.29–1.18]; 76%–100%, 0.23 [0.12–0.46]; CRZ: 51%–75% shrinkage, 0.68 [0.41–1.12]; 76%–100%, 0.26 [0.15–0.45]) or an OS event (BRG: 51%–75% shrinkage, 0.39 [0.17–0.89]; 76%–100%, 0.15 [0.07–0.35]; CRZ: 51%–75% shrinkage, 0.43 [0.21–0.85]; 76%–100%, 0.23 [0.10–0.50]) than pts with ≤50% shrinkage. Longer median time to PFS and OS and higher 4-year estimated OS rates were associated with depth of response in both arms (Table). Conclusions: In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ. Pts with >75% shrinkage had significantly reduced risk of a PFS or OS event vs pts with ≤50% target lesion shrinkage. Clinical trial information: NCT02737501. [Table: see text]
Use of RET inhibitors among patients with advanced NSCLC: A real-world evidence analysis.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen
Published: June 2022

9079

Background: RET rearrangements are found in approximately 1% to 2% of patients with NSCLC. Two selective RET inhibitors have been FDA approved based on phase 1/2 data showing significant activity among patients with advanced NSCLC that have RETrearrangements. The objective of this retrospective analysis was to look at the prognostic outcome associated with the use of selective RET inhibitors (sRETi) and multikinase inhibitors (MKIs) that have been used to target RET fusions among pts with NSCLC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 84 million pt lives available through the TriNetX Research Network. We identified 1,215 pts with metastatic NSCLC treated with selpercatinib, praseltinib, cabozantanib or vandetanib. Overall survival (OS) was evaluated with Kaplan Meier statistics and compared between patients treated with either sRETi (selpercatinib or pralsetinib) vs either MKI (cabozantanib or vandetanib). Results: Mean age among all anti-RET treated patients was 67.6 years. 518 pts (43%) were female and 697 (57%) were male. 531 (39.6%), 205 (15.3%) and 605 (45.1%) pts had received selpercatinib, pralsetinib, and either cabozantinib or vandetinib, respectively. 56.6% of pts receiving pralsetinib received prior selpercatinib. Among pts receiving sRETi, 39.7%, 6.4%, 11.2%, and 32.4% received sRETi in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, respectively. Among pts receiving MKIs, 17.0%, 8.4%, 13.3%, and 44.9% received MKIs in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis. Median OS after treatment with MKIs and sRETi during any time frame was 16.3m and 25.0m, respectively (p < 0.01). Among pts treated with MKIs vs sRETi during the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, 1-year survival probability after treatment was 59.7% vs 55.9% (p = 0.39), 45.0% vs 83.1% (p < 0.01), 53.9% vs 82.2% (p < 0.01), and 57.7% vs 87.1% (p < 0.01), respectively. 30% of pts of all anti-RET treated patients had brain metastases, and median OS from index metastasis among pts with and without brain metastases was 31.4m and 63.1m respectively (p < 0.01). Conclusions: To our knowledge this is the first real world data set to show a > 8m improvement in OS with the use of sRETi compared to MKIs among pts with metastatic NSCLC. OS improvements may be more significant in pts treated in later lines of therapy with sRETi.
Evaluation of weight gain and overall survival of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy.
Authors: Roeland Eric , Fintelmann Florian J. , Hilton Fiona , Tarasenko Lisa , Calle Roberto A , Bonomi Philip D.
Published: June 2022

9088

Background: Cachexia is a multifactorial syndrome frequently associated with cancer characterized by anorexia and unintentional weight loss, including skeletal muscle loss, fatigue, functional impairment, poor quality of life, and worse survival. The objective of this post-hoc analysis was to examine the relationship between weight gain and overall survival (OS) in patients with NSCLC treated with first-line platinum-based regimens. Methods: Data were pooled from three phase 3 clinical trials (NCT00254891, NCT00254904, and NCT00596830) conducted between Nov 2005 and Mar 2011 in patients with advanced NSCLC (stage IIIB or stage IV) treated with first-line standard-of-care (SOC) chemotherapy (control arm). Weight was recorded at baseline, prior to dosing on day 1 of each 3-week treatment cycle (up to 6 cycles), and post-treatment according to each study’s schedule. Weight gain was categorized as > 0%, > 2.5%, and > 5% increase from baseline up to 4.5 months. Cox Proportional Hazards modeling of OS including time to weight gain and time to confirmed objective response (RECIST v1.0) and baseline covariates were used to estimate hazard ratios (HR) for each category. Results: The total 1,030 patients from the SOC control arms were predominantly male (70.5%) with Stage IV NSCLC (88.5%) and a mean age (SD) of 60.9 (9.4) years and BMI 24.6 (4.4) kg/m2. Overall, 486 (47.2%), 299 (29.0%), and 164 (15.9%) patients experienced weight gain from baseline of > 0%, > 2.5%, and > 5%, respectively. Median time to > 0%, > 2.5%, and > 5% weight gain was 24, 43, and 64 days, respectively. After adjusting for statistically significant time-dependent confirmed objective response, the risk of death was significantly less for patients with weight gain. For patients with > 0% vs. ≤0% weight gain, HR was 0.70 (95%CI 0.61, 0.82) with median OS of 13.6 vs. 8.3 months. For patients with > 2.5% vs. ≤2.5% weight gain, HR was 0.70 (95%CI 0.59, 0.83) with median OS of 15.3 vs. 9.1 months. For patients with > 5% vs. ≤5% weight gain, HR was 0.76 (95%CI 0.61, 0.94) with a median OS of 14.4 vs. 9.8 months. Conclusions: In this pooled analysis, weight gain during treatment with first-line platinum-based chemotherapy was associated with a significantly reduced risk of death in patients with advanced NSCLC, independent of tumor response defined by RECIST criteria. The survival benefit was comparable for > 2.5% vs. > 5% weight gain. Weight gain of 2.5% may be an earlier predictor of survival outcomes and may have implications for the design of cancer cachexia trials. Clinical trial information: NCT00254891, NCT00254904, and NCT00596830.
Molecular analysis of circulating tumor DNA (ctDNA) in patients (pts) with EGFR exon 20 insertion-positive (ex20ins+) advanced NSCLC treated with mobocertinib.
Authors: Vincent Sylvie , Su Zhenqiang , Bunn Veronica , Joshi Adarsh , Yu Ziji , Chatterjee Sampurna , Guha Minakshi , Zhang Pingkuan
Published: June 2022

9108

Background: ctDNA is an important tool to diagnose and monitor mutations in pts with non–small cell lung cancer (NSCLC). We evaluated epidermal growth factor receptor gene ( EGFR) ex20ins mutations in tumor vs plasma samples, assessed changes in EGFR ex20ins variant allele frequency (VAF) with mobocertinib treatment and correlation with response, and identified potential emerging variants of acquired resistance. Methods: Tumor tissue samples were collected at baseline (BL) from pts with EGFR ex20ins+ advanced NSCLC receiving mobocertinib 160 mg QD in a phase 1/2 study (NCT02716116); plasma samples were collected at BL, after 2 treatment cycles (Cycle 3, Day 1 [C3D1]) and at disease progression/end of treatment (DP/EOT). ctDNA samples were analyzed by next-generation sequencing for EGFR ex20ins to determine concordance rate detection between tissue and plasma ctDNA at BL. Changes in VAF for EGFR ex20ins from BL were analyzed at C3D1 and DP/EOT by confirmed response (RECIST v1.1) to mobocertinib per independent review committee. Emerging variants at DP/EOT were evaluated by elimination of germline variants seen in healthy populations (gnomAD databases and 1000 Genomes) and nonharmful variants predicted by PolyPhen and SIFT tools or annotated as benign in ClinVar database. Results: BL EGFR ex20ins mutations were detected by ctDNA sequencing in 29 of 38 pts (76%) with tissue-confirmed EGFR ex20ins+ NSCLC. VAFs for EGFR ex20ins significantly decreased at C3D1 in mobocertinib-treated pts with confirmed partial response (PR; P=0.0057) or stable disease (SD; P=0.0016), but not in pts with progressive disease (PD; P=0.14) (Table). ctDNA at EOT/DP analysis identified numerous genetic variants; EGFR, TP53, and DNMT3A were the most common genes with emerging variants. Twelve emerging missense mutations were identified in EGFR in 9 pts, including mutations located in the exon 20 loop following the C-helix (6), T790M (5), and D379E (1). Conclusions: Concordance between tissue and plasma ctDNA for EGFR ex20ins mutations at BL was 76%. EGFR ex20ins VAF decreased significantly after 2 treatment cycles in mobocertinib-treated patients with PR and SD. Plasma ctDNA longitudinal monitoring may be useful to assess mutation status and disease progression in pts with NSCLC treated with mobocertinib. Clinical trial information: NCT02716116. [Table: see text]
Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms.
Authors: Bar Jair , Peled Nir , Schokrpur Shiruyeh , Dudnik Elizabeth , Wollner Mira , Girard Nicolas , Aboubakar Nana Frank , Derijcke Sofie , Kian Waleed , Patel Sandip P. , Gantz Sorotsky Hadas Yocheved , Zer Alona , Moskovitz Mor , Metro Giulio , Rottenberg Yakir , Calles Antonio , Hochmair Maximilian , Cuppens Kristof , Decoster Lynn , Addeo Alfredo ,   UNICORN Study Investigators
Published: June 2022

9109

Background: About 10% of EGFR mutations (EGFRm) are ‘uncommon mutations’ (ucEGFRm). osimertinib is a 3rd generation EGFRi, active against common EGFRm. We aimed to collect real-world data about systemic and brain response and resistance mechanisms to osimertinib for ucEGFRm patients. Methods: This is a multi-center, retrospective study of ucEGFRm mNSCLC treated with osimertinib as first EGFRi. RECIST and RANO-BM response was evaluated by investigators. Progression free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated from initiation of osimertinib. Mutations found at resistance were collected. Results: 62 patients (pts) were identified in 22 centers from 9 countries. Median age was 64 (35-91) years, 74% females, 84% Caucasian, never/former/current smokers were 48%/39%/11% respectively, ECOG PS was 0-1/2/3-4 in 84%/10%/5%. Histology was adenocarcinoma in 97%. The largest subgroups were G719X, de novo T790M and L861Q (Table). Compound EGFR mutations were found in 27 pts (44%), TP53 mutations in 21 pts (34%). In 17 cases (27%), compound mutations included the common L858R/deletion19 and/or de novo T790M. Most frequent metastatic sites were lung/bone/brain in 45%/44%/39%. Most frequent toxicities were gastrointestinal (32 pts, 52%) and skin (24 pts, 39%); 8 pts had grade 3-4 AEs. No grade 5 AE occurred. 3 pts had AEs leading to discontinuation. RECIST response (RR) was available for 53 pts, CR - 4 (8%), PR - 27 (51%), SD - 17 (32%), and PD - 5 (9%). Median DOR (mDOR) was 17.4 months (95% CI 9.1-NA). mPFS was 9.5 months (95% CI 8.5–17.4). mOS was 24.5 months (95% CI 17.4-35.1). See Table for efficacy in the major subgroups. 24 pts (39%) had brain metastasis at presentation, for 12 pts a brain response by RANO-BM was available with 25%/25%/33%/17% CR/PR/SD/PD. For 14 pts, rebiopsy mutation analysis at progression on osimertinib was available: 3 pts with an additional EGFR mutation (C797S,D585Y, E709K), 3 pts with a new TP53 mutation, 1 with c-Met amplification and 1 pt with transformation to neuroendocrine carcinoma. Conclusions: Osimertinib demonstrated activity in ucEGFRm with 91% disease control rate and encouraging PFS and DOR. Brain response was seen in 50% of cases. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRm presented so far. [Table: see text]
NEJ043: A phase 2 study of atezolizumab (atezo) plus bevacizumab (bev) plus carboplatin (carbo) plus paclitaxel (pac; ABCP) for previously treated patients with NSCLC harboring EGFR mutations (EGFRm).
Authors: Furuya Naoki , Watanabe Satoshi , Nakamura Atsushi , Shiihara Jun , Nakachi Ichiro , Tanaka Hisashi , Nakao Mika , Minato Koichi , Seike Masahiro , Sasaki Shinichi , Kisohara Akira , Takeuchi Susumu , Honda Ryoichi , Takamura Kei , Kagamu Hiroshi , Yoshimura Kenichi , Kikuchi Toshiaki , Kobayashi Kunihiko ,   North East Japan Study Group (NEJSG)
Published: June 2022

9110

Background: Previous studies have demonstrated poor clinical outcomes of patients (pts) with EGFRm NSCLC treated with PD-1/PD-L1 inhibitors. However, a recent subgroup analysis of the IMpower150 trial suggested the effectiveness of ABCP in NSCLC with EGFRm. The aim of this study is to further evaluate efficacy and safety of ABCP in patients with EGFRm NSCLC. Methods: This single-arm multicenter phase 2 study included pts with nonsquamous NSCLC harboring sensitizing EGFRm with prior EGFR-TKI therapy. Pts received the combination dose of atezo 1200 mg, bev 15 mg/kg, carbo AUC 6 mg/mL/min and pac 175 mg/m2 every 3 weeks up to 4 cycles followed by atezo plus bev until loss of clinical benefit. The primary endpoint was PFS by extramural review (ER). The key secondary endpoints included OS, ORR, DoR, relative dose intensity of pac, and safety. Results: 60 pts were enrolled (median age 68 y [40–74 y], 67% were female, 55% were Ex19del and 40% were L858R). At data cutoff (November 30, 2021), median follow-up was 12.8 months in the ITT population. Median cycles of induction and maintenance therapy were 4 and 9, respectively. Median PFS was 7.4 month (95% CI, 5.7-8.2) and median OS was 18.9 month (95% CI, 13-not reached). Confirmed ORR by ER was 56% (95% CI, 43-69) and median DoR was 7.1 months (95% CI, 4.9-9.8). T790M was associated with a favorable PFS and response to the combination therapy (PFS 8.1 vs 6.8, ORR 71% vs 50%). Relative dose intensity of pac was 84%. Grade ≥3 adverse events (AEs) were reported in 92% of pts and the most common grade ≥3 AE was neutropenia (63%). Interstitial lung disease occurred in one patient (2%). AEs leading to treatment discontinuation occurred in 12% of pts. Conclusions: NEJ043 study showed that the median PFS of ABCP was 7.4 months with good tolerability. We will continue to investigate the tail plateau phenomenon of PFS and OS to conclude the clinical efficacy. Clinical trial information: 031190066.
Efficacy and safety of capmatinib plus pembrolizumab in treatment (tx)-naïve patients with advanced non–small cell lung cancer (NSCLC) with high tumor PD-L1 expression: Results of a randomized, open-label, multicenter, phase 2 study.
Authors: Mok Tony S. K. , Cortinovis Diego Luigi , Majem Margarita , Johnson Melissa Lynne , Mardjuadi Feby Ingriani , Zhao Xuan , Siripurapu Sagar Vidya , Jiang Zhiqiang , Wolf Juergen
Published: June 2022

9118

Background: Capmatinib is a selective MET inhibitor approved for patients (pts) with metastatic NSCLC harboring MET exon 14 skipping mutation. Pembrolizumab (pembro) is a programmed death protein-1 (PD-1) inhibitor approved as monotherapy for pts with advanced NSCLC expressing PD-ligand 1 (PD-L1). Preclinical studies have shown that capmatinib enhances T cell mediated antitumor response in mice treated with PD-1 inhibitors. Combining capmatinib with pembro may be beneficial in pts with advanced NSCLC expressing high tumor PD-L1. Methods: Herein we evaluated the efficacy and safety of capmatinib plus pembro (combo) versus pembro alone in tx-naïve pts with advanced MET-unselected NSCLC expressing PD-L1 with tumor proportion score (TPS) ≥50%, and no ALK or EGFR tumor aberrations. Pts received pembro 200 mg IV q3w in the pembro alone arm or with capmatinib 400 mg orally BID in the combo arm. The primary endpoint was investigator-assessed progression-free survival (PFS) using RECIST v1.1. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), pharmacokinetics and safety. Results: As of the data cut off (DCO) of 28 Feb 2021, 76 pts were randomized 2:1 to the combo arm (n = 51) or pembro alone arm (n = 25). Baseline demographics and disease status were mostly comparable across study arms. At this interim analysis, PFS data were not mature. Median PFS (95% CI) was 6.3 (3.2, not evaluable [NE]) months in the combo arm and 4.3 (2.3, NE) months in the pembro alone arm. The ORR (95% CI) was 15.7% (7.0%, 28.6%) and 28.0% (12.1%, 49.4%) in the combo and pembro alone arms, respectively. The DCR (95% CI) was comparable across study arms; combo: 56.9% (42.2%, 70.7%) and pembro alone: 56.0% (34.9%, 75.6%). In the combo arm, capmatinib exposure (Cmax: 3580 ng/mL [n = 7] and AUCtau: 19700 hr*ng/mL [n = 2]) was consistent with data from previous studies. Tx-related grade (GR) ≥3 adverse events (AEs) were more common in the combo (37.3%) vs pembro alone arm (16%). Tx-related AEs occurring in ≥10% of pts are shown in the Table. Tx discontinuation and dose adjustment/interruptions were more common in the combo (27.5% and 52.9%) vs pembro alone arm (16% and 16%). Capmatinib was stopped prematurely in the combo arm, and at DCO, 32 (62.7%) pts in the combo arm and 18 (72%) pts in the pembro alone arm were receiving pembro monotherapy. Conclusions: Combination tx with capmatinib and pembro was not well tolerated and did not improve antitumor activity in tx-naïve pts with advanced NSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT04139317. [Table: see text]
Activating MET kinase domain mutations define a novel molecular subtype of non–small cell lung cancer that is clinically targetable with the MET inhibitor elzovantinib (TPX-0022).
Authors: Pecci Federica , Ricciuti Biagio , Alessi Joao Victor Machado , Barrichello Adriana Paula de Castro , Vaz Victor R. , Lamberti Giuseppe , Lee Jessica Kim , Schrock Alexa Betzig , Goel Vikas K , Zimmerman Zach , Bahcall Magda , Janne Pasi A. , Awad Mark M.
Published: June 2022

9124

Background: In non-small cell lung cancer (NSCLC), MET exon 14 skipping (METex14) mutations and MET amplification can be targeted with MET inhibitors. Here, we describe a novel, actionable molecular subtype of NSCLC characterized by activating MET-tyrosine kinase domain (MET-TKD) mutations in the absence of METex14 mutations. Methods: Clinicopathologic and genomic data were abstracted from NSCLC cases included in a multi-institutional cohort of tumors that underwent genomic profiling in the GENIE v10, China PanCancer, and the International Cancer Genome Consortium/ The Cancer Genome Atlas (ICGC/TCGA) datasets. External validation of the prevalence of MET-TKD mutations was performed on an independent cohort of NSCLC tissue and liquid samples from the Foundation Medicine genomic database. Results: Among 14,099 NSCLC samples in the multi-institutional cohort, 71 (0.5%) harbored MET-TKD mutations without concurrent METex14 mutations: 55 of these had uncertain pathogenic significance and 16 had known oncogenic potential, including MET H1094Y/R, D1228H/N/V, N1100S, H1106D, V1188I, and M1250T, in order of decreasing prevalence. In a separate cohort of 91,515 NSCLC samples from the Foundation Medicine database, MET-TKD mutations lacking concurrent METex14 mutations were identified in 799 (0.9%) samples, including H1094Y, L1195V, D1228H/N, M1250T and others. Among 60 NSCLC samples harboring MET-TKD mutations without concurrent METex14 mutations with complete genomic data in the multi-institutional cohort, 36 (60%) had concurrent driver alterations in KRAS, EGFR, ROS1, BRAF, HER2, or RET, while 24 (40%) had no concurrent oncogenic drivers. Among patients with available demographic data in the multi-institutional cohort, those with MET-TKD-mutant NSCLC (N = 70) were significantly younger than patients with METex14-mutant NSCLC (N = 353) (median age 63 [range 30-86] vs 73 [range 44-88], p < 0.0001), and there was no significant difference in sex or self-reported race. Confirmed partial responses to the MET tyrosine kinase inhibitor elzovantinib (TPX-0022) were observed in two patients with MET-TKD-mutant NSCLC and no other detectable driver mutations: a 64-year-old man with MET H1094Y-mutant NSCLC, and an 80-year-old man with MET F1200I-mutant NSCLC. Conclusions: Potentially actionable MET-TKD mutations lacking concurrent METex14 mutations represent a novel genomic subtype in 0.5-0.9% of NSCLC, and occur in the absence of other known drivers in a subset of cases.