bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring PD-L1 expression on circulating stromal cells in blood predicts PFS and OS in patients with metastatic NSCLC treated with PD-L1/PD-1 immunotherapy.
Authors: Moran Jillian , Adams Daniel L , Lopez Bravo Pablo , He Jianzhong , Qiao Yawei , Xu Ting , Liao Zhongxing X. , Gardner Kirby P , Tang Cha-Mei , Lin Steven H.
Published: June 2022

8535

Background: Cancer Associated Macrophage Like cells (CAMLs), a circulating stromal cell found in cancer patients (pts) blood, are phagocytic giant macrophages that appear to parallel the inflammatory PD-L1 state of the tumor microenvironment. Previously, we demonstrated in local non-small cell lung carcinoma (NSCLC), CAML PD-L1 expression is dynamic and predicts response to PD-L1/PD-1 immunotherapies (IMTs) following sequential sampling before and after chemotherapy (chemo) induction (̃30days) based on progression free (PFS) & overall survival (OS). However this has not been tested in metastatic NSCLC (mNSCLC). Here,we report the results of monitoring PD-L1 expression in CAMLs before and after chemo induction (̃30 days) to evaluate its predictive value in mNSCLC pts treated with or without IMT. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PD-L1 expression in CAMLs to PFS & OS, pre & post chemo induction, in recurrent mNSCLC with (n = 41) or without (n = 41) additional anti-PD-L1/PD-1 IMTs. This included three IMTs: atezolizumab (n = 4), nivolumab (n = 8) or pembrolizumab (n = 29). We recruited 82 pts with pathologically confirmed recurrent mNSCLC prior to treatment for newly recurrent metastatic disease. Blood samples (15 mL) were taken at Baseline (BL), prior to chemo, and ̃30 days after chemotherapy (T1). Blood was filtered by CellSieve filtration & CAMLs’ expression scored as a binary high/low, to evaluate PFS & OS hazard ratios (HRs) by censored univariate & multivariate analysis at 18 months. Results: CAMLs were found in 97% of all tested samples, 94% at BL & 100% at T1. CAML PD-L1 at BL was found not to be associated with PFS or OS in pts treated with chemo alone (PFS p = 0.620 & OS p = 0.673) or chemo+IMT (PFS p = 0.353 & OS = 0.477) at 18 months. At T1, high CAML PD-L1 in pts treated with chemo alone had no significantly different PFS (HR = 1.3, p = 0.694) or OS (HR = 1.6 p = 0.503). However, high CAML PD-L1 at T1 in pts treated with chemo+IMT had significantly better PFS (HR = 3.1, 95%CI = 1.3-7.3, p = 0.019), and OS (HR = 3.4, 95%CI = 1.4-8.3, p = 0.014). Further subtyping & analysis is ongoing to evaluate PFS and OS at 24 months. Conclusions: Our data suggests that in mNSCLC, PD-L1 expression in circulating CAMLs dynamically upregulates after induction with chemotherapy and appears to predict patients with increased benefit to PD-L1/PD-1 IMTs, though additional studies are needed to validate these findings.
A phase II study of durvalumab (MEDI4736) immediately after completion of chemoradiotherapy in unresectable stage III non–small cell lung cancer: TORG1937 (DATE study).
Authors: Nakamichi Shinji , Kubota Kaoru , Misumi Toshihiro , Murakami Shuji , Kondo Tetsuro , Okamoto Isamu , Minato Koichi , Harada Daijiro , Isobe Kazutoshi , Itani Hidetoshi , Takata Saori , Wakui Hiroshi , Misumi Yuki , Ikeda Satoshi , Asao Tetsuhiko , Inoue Takeo , Hosokawa Shinobu , Kobayashi Yumiko , Takiguchi Yuichi , Okamoto Hiroaki
Published: June 2022

8536

Background: Concurrent chemoradiotherapy followed by durvalumab maintenance for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, the best timing of starting durvalumab after completion of chemoradiation has not been identified. Progression-free survival (PFS) and overall survival (OS) were better in the subgroup of patients administered durvalumab within 14 days after last radiation to randomization according to the PACIFIC study (Antonia SJ, et al. 2017, 2018 NEJM). Methods: This study was a prospective, single-arm, multicenter, phase II clinical trial. Eligibility criteria included patients with unresectable stage III NSCLC, ECOG PS 0-1, age < 75 years old. Patients who did not have disease progression after definitive concurrent chemoradiotherapy (CCRT) (chemotherapy: 2 cycles of platinum-based doublet chemotherapy, radiotherapy: 60 Gy/30 Fr) received durvalumab (10 mg/kg, every 2 weeks for up to 12 months) from the next day (allowed up to 5 days) after last radiation. The primary endpoint was 1-year PFS rate from registration assessed by an independent review committee. The planned sample size was 47 with a threshold value of 50% based on results of the PACIFIC study, an expected value of 63%, one-sided alpha of 20% and power of 80% in 1-year PFS rate. Results: From January 2020 to August 2020, 50 patients were enrolled from 16 institutions and 47 patients were evaluable for efficacy and safety. Forty-two patients received durvalumab maintenance therapy. Patient characteristics were: male/female 41/6; median age 65 (range 42-75); ECOG PS 0/1 28/19; IIIA/IIIB/IIIC 19/21/7. The 1-year PFS rate from registration was 75.0% (60% CI: 69.0 to 80.0). The 1-year OS rate from registration was 97.7% (95%CI: 84.6 to 99.7). ORR, median PFS and median OS were 78.7%, 14.2 months (95%CI: 13.4 to not reached (NR)) and NR, respectively. Grade 3/4 adverse events were pneumonitis (4.3%), neutropenia (44.7%), febrile neutropenia (4.3%). There was no treatment-related death. Conclusions: Our study met the primary endpoint. Durvalumab can be safely administered immediately after completion of CCRT for patients with unresectable stage III NSCLC, no additional or unexpected toxicity occurred as a reference to the PACIFIC study. Clinical trial information: jRCTs031190117.
Identifying biomarkers associated with disease-free survival in stage I non–small cell lung cancer.
Authors: Seder Christopher W. , Moudgalya Hita , Donaldson Andrew E. , Layng Kayla Viets , Mauer Elizabeth , Subramanian Janakiraman , Fhied Cristina L. , Geissen Nicole , Alex Gillian , Karush Justin , Liptay Michael J. , Borgia Jeffrey Allen
Published: June 2022

8543

Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M0) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.
Multi-omic and spatial dissection of immunotherapy response groups in non–small cell lung cancer (NSCLC).
Authors: O'Byrne Kenneth John , Monkman James , Kim Honesty , Cumberbatch Marie , Bhagat Milan , Ladwa Rahul , Adams Mark N , Kulasinghe Arutha
Published: June 2022

8544

Background: Immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The composition of the tumour microenvironment (TME) is becomingly increasingly recognised as an important factor to predict response to therapy. Methods: Here, we applied digital spatial profiling of the tumour and stromal compartments from a 2nd line NSCLC ICI-treated cohort (n = 41 patient) and standard of care (SOC), platinum treated NSCLC cohort (n = 47), to identify tissue-based signatures of response to therapy. Results: We demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p = 0.012). Patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p = 0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p = 0.001) within their stroma. Immuno-inhibitory markers CTLA-4 (p = 0.021) and IDO-1 (p = 0.023) were supressed in ICI-responsive patients. Tumour CD44 (p = 0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of one of its ligands, SPP1 (osteopontin, p = 0.008). Analysis of dysregulated transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR = 1.61, p = 0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR = 1.78, p = 0.003) and MDSC/M2 macrophage marker ARG1 (HR = 2.37, p = 0.01) were associated with poorer outcome while BAD (HR = 0.5, p = 0.01) appeared protective. The SOC cohort paralleled similar roles for immune checkpoints and pro-apoptotic markers, with LAG3 (HR = 3.81, p = 0.04) indicating poorer outcome, and BIM (HR = 0.16, p = 0.014) with improved outcome. Interestingly, stromal mRNA for E-selectin (HR = 652, p = 0.001), CCL17 (HR = 70, p = 0.006) and MTOR (HR = 1065, p = 0.008) were highly associated with poorer outcome in ICI treated patients, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance. Conclusions: Through multi-modal approaches, we have dissected the characteristics of NSCLC treatment groups and provide evidence for the role of several markers including IL2, CD25, CD44 and SPP1 in the efficacy of current generations of ICI therapy.
Epidemiology and clinical impact of EGFR mutation in patients with lung cancer after radical surgical treatment.
Authors: Bryl Maciej , Sielewicz Magdalena , Budny Bartłomiej , Woźniak Aldona , Gabryel Piotr , Kasprzyk Mariusz , Barinow-Wojewodzki Aleksander , Piwkowski Cezary
Published: June 2022

8552

Background: The epidemiology of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma and its clinical impact are well-known. However, most studies have focused on advanced-stage inoperable cancer. Data on the frequency of EGFR mutation in surgically resected lung cancer are limited. Recent studies have shown a promising effect of Osimertinib in adjuvant settings. Hence, the need to estimate the target population in the real-world data. This study aimed to assess the occurrence of EGFR mutation in patients after radical surgical treatment of lung adenocarcinoma and explore its prognostic impact compared to EGFR negative group. Methods: This single-center retrospective analysis included the group of 732 consecutive Caucasian patients with histopathologically confirmed lung adenocarcinoma, evaluated for EGFR mutations expression, who underwent anatomical resection between January 2016, and December 2020. EGFR status was assessed by cobas EGFR mutation test v2. The frequency of EGFR mutations, disease-free survival (DFS) and overall survival (OS) in EGFR positive and EGFR negative groups were analyzed. Results: EGFR mutations were found in 65 surgical patients (8.9%) and did not differ from patients with advanced stages of lung adenocarcinoma (7.9%). EGFR mutations occurred more frequently in females than males, 48 out of 344 (14%) and 17 out of 388 (4.4%), respectively. Deletions within exon 19 and the L858R mutation in exon 21 constituted 49.2% and 24.6% of all mutations, respectively, while others comprised 26.2%. One case of L858R mutation coincided with T790M in exon 20 mutation. Detailed results divided by stages are presented in the Table. The occurrence of EGFR mutation had no significant influence on DFS and OS in patients after radical resection. Conclusions: The frequency of EGFR mutation in postoperative lung cancer was comparable to the occurrence in the general lung cancer population. EGFR mutation did not affect DFS and OS in patients after radical resection. [Table: see text]
Positive impact of academic center care on overall survival in malignant pleural mesothelioma (MPM): A National Cancer Database (NCDB) socioeconomic factor analysis.
Authors: Roof Logan , Wei Wei , Stevenson James
Published: June 2022

8558

Background: MPM is a rare cancer with a poor prognosis. Median survival for untreated patients is 4-13 months, and for treated patients is 6-18 months. Despite asbestos regulations in the United States, annual deaths from MPM rose from 2,479 in 1999 to 2,597 in 2015. Given recent treatment advances, including improvements in multimodality therapy and the introduction of immunotherapy as a treatment option in the frontline setting, the impact that patient demographics and treatment factors have on survival outcomes for MPM requires further evaluation. Methods: We identified all patients with MPM in the NCDB from 2004 to 2017. Differences in demographic, disease, and treatment characteristics were assessed by year of diagnosis using Chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was assessed by log-rank test. Results: There were 15,287 MPM diagnoses in the NCDB between 2004-2010 and 17,059 diagnoses between 2011-2017. OS improved between the two time periods, with median OS of 9.46 months (95% CI: 9.23-9.63) and 5-year OS rate of 8.3% (95% CI: 7.9-8.7%) in patients from 2004-2011 and median OS of 11.33 months (95% CI: 11.01-11.7) and 5-year OS rate of 12.4% (95% CI: 11.8-13.1%) in patients after 2011, despite an increase in stage IV disease in the latter group. Older patients (≥65 years-old), males, patients with stage IV disease, patients with government primary payer insurance, and patients from urban areas all had significantly worse OS. Patients without comorbidities and those treated at an academic center had significantly better OS. OS was found to significantly increase as both income and education level increase. Patients diagnosed after 2011 were significantly older, were more frequently female, had more stage IV disease, were more frequently treated at academic centers, more commonly had government primary payer insurance, and lived significantly further away from their treatment center. Patients’ time to treatment was significantly increased after 2011 (from 28 to 31 days). Conclusions: Socioeconomic factors play an important role in survival outcomes for patients with MPM. Many of these are linked with access to healthcare resources, which may increase the likelihood of evaluation at academic centers. For a rare malignancy such as mesothelioma, subspecialty care consisting of a comprehensive thoracic surgical evaluation and appropriate multimodality treatment are of great importance. Time to treatment increased during the study period yet OS improved, which our findings suggest are a result of an increase in evaluation and treatment at academic centers by providers skilled in delivering care to MPM patients.
Phase I clinical safety and preliminary efficacy of PD-1-mesoCAR-T cells in the treatment of malignant pleural/peritoneal mesothelioma.
Authors: Xu Qing , Liu Zhuqing , Xia Yong , Song Zongchang , Zhu Zhongzheng , Lin Zhicai , Wang Sitong
Published: June 2022

8559

Background: Malignant pleural/peritoneal mesothelioma (MPM) is an aggressive cancer characterized by poor therapeutic response and poor survival. Programmed cell death protein-1 (PD-1)-mediated immunosuppression is believed to be associated with T cell exhaustion and dysfunction in solid tumors. We generated chimeric antigen receptor (CAR-T) cells that can secret PD-1 nanobodies and target mesothelin (PD-1-mesoCAR-T). After identifying the anti-tumor activity and cytotoxicity of PD-1-mesoCAR-T cells by pharmacokinetics and pharmacodynamics, we conducted a proof-of-concept clinical trial in the Shanghai Tenth People's Hospital affiliated to Tongji University and the Mengchao Tumor Hospital affiliated to Shanghai University to evaluate the safety and efficacy of PD-1-mesoCAR-T cells in a dose-escalation study for malignant pleural/peritoneal mesothelioma. 6 patients received one or more infusions of the CAR-T cells with prior lymphodepletion and the longest survival is up to 18 months. Methods: This open-label, single-arm, multicenter, phase 1 study was enrolled patients with pathological diagnosis with malignant mesothelioma whose mesothelin expression in immunohistochemical samples was equal or greater than 50%. Immunohistochemical samples derived from surgical tissue, puncture tissue or pleural effusion. PD-1-mesoCAR-T cells were administered intravenously ranging 1×106−1.5×107/kg. Safety and efficacy were assessed in response-evaluable patients (ie, patients who received at least one dose of PD-1-mesoCAR-T and had at least one post-baseline response evaluation). Results: From July 20, 2020 to January 31, 2022, 9 patients were screened and enrolled and only 6 patients were evaluable. Mesothelin positive rate in the samples of these patients were from 50% to 100%. Three patients of them had PD-L1 positive staining in specimen. All patients underwent lymphodepletion before infusion. Two of patients (33.3%) had cytokine release syndrome, which were grade 1 and grade 3, respectively. Four patients (66.7%) developed fever. Two patients (25%) had grade 3 pulmonary infection. Stable disease was sustained for ≥3 months in 5 patients; 1 exhibited complete response and one partial response on PET or CT scan. The objective response rate (ORR) was 33.3%, but increased to 66.7% in the patients with PD-L1 positive. Only one patient of these patients appeared progression of disease after infusion. All enrolled patients are alive and observed continually. Conclusions: The clinical study of 6 patients with malignant mesothelioma shows that PD-1-mesoCAR-T cells are safe and feasible, indicating a promising curative effect. Effect of the CAR-T cells on the long term survival will be observed continually. Clinical trial information: 01722149.
Safety and efficacy of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): The results from a phase II single-arm trial.
Authors: Chen Dawei , Zou Bing , Meng Xiangjiao , Huang Wei , Shao Qian , Tang Xiaoyong , Guo Jun , Hu Xudong , Zhang Yan , Fu Lei , Jiajia Yuan , Yu Jinming , Wang Linlin
Published: June 2022

8563

Background: Impower133 and CASPIAN studies showed that PD-L1 antibody combined with first-line chemotherapy could prolong the overall survival. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 (PD-L1 antibody) combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Patients (pts) included in this study received 4̃6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin 75mg/m² D1-3 q3w or carboplatin AUC = 5, D1 q3w; etoposide 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved- field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included PFS, ORR and safety. Results: From October 2020 to December 2021, 31 pts with ES-SCLC received at least one dose of SHR-1316. The median age was 64 (range: 37-75) with 25(80.6%) male, 22(71%) former smokers and 31 (100%) ECOG performance status 1. 17 (54.8%) pts were with brain metastasis, 8 (25.8%) pts with liver metastasis, 8 (25.8%) pts with kidney/adrenal metastasis, 7(22.6%) pts with bone metastasis. At the data cutoff date, 15 pts remained on treatment, the average number of treatment cycles was 5.19. 24 pts had at least one 1 post-treatment tumor assessment. The median PFS was 7.56 months, the confirmed ORR and DCR in all pts were 50% (12/24) and 87.5% (21/24), respectively. The confirmed ORR and DCR in pts with brain metastasis were 38.5% (5/13) and 76.9% (10/13), and were 63.6% (7/11) and 100% (11/11) in pts without brain metastasis. In pts received chest radiotherapy, the confirmed ORR and DCR were 80% (8/10) and 100% (10/10). During the study period, 23 (74.2%) pts had adverse drug reactions, and 16 (51.6%) pts had grade 3 or 4 adverse drug reactions, including 12 (38.7%) neutropenia 8 (25.8%) leukopenia, 2 (6.5%) thrombocytopenia, 2 (6.5%) anemia, 1(3.2%) lymphocytopenia, 1(3.2%) amylase increased. No grade 5 adverse drug reaction was observed. Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337.
Impact of underrepresented populations on clinical outcomes of chemo-immunotherapy for extensive-stage small cell lung cancer: Real-world prospective cohort study.
Authors: Tamiya Motohiro , Fujimoto Daichi , Akamatsu Hiroaki , Morimoto Takeshi , Hata Akito , Matsumoto Hirotaka , Nakamura Atsushi , Oya Yuko , Amimoto Hisanori , Daga Haruko , Ikeda Hideki , Sakata Shinya , Suzuki Hidekazu , Ikeda Satoshi , Harutani Yuhei , Hiraoka Ryota , Yanai Masaaki , Hamamoto Yoichiro , Yamamoto Nobuyuki
Published: June 2022

8567

Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). Prospective data about underrepresented populations outside the clinical trial such as elderly or poor risk has not been revealed. Methods: We conducted a 32-hospitals prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. The primary outcome was 6-months progression-free survival (PFS) probability of all patients. The secondary outcomes were overall survival (OS), PFS, time to treatment failure, objective response rate, safety, and differences in efficacy and safety depending on whether or not the key eligible study criteria of previous trials are met. Results: In total, 207 patients with ES-SCLC were analyzed. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) was categorized as eligible patients. The 6-months PFS probability of all patients was 38.8 % (95%CI:32.4-45.7%). Between eligible and ineligible patients, there was significant difference of patients who attained disease control (93% versus 77%, p = 0.002). Median PFS was significantly longer in eligible patients than ineligible patients (5.1 vs. 4.7 months; P =.03, HR 0.72 (95% CI 0.53–0.97)), and median OS was longer in eligible patients than ineligible patients, without any significant difference (15.8 vs. 13.1 months; P =.10, HR 0.73 (95% CI 0.51–1.07)). Survival analysis identified a PS score of 0-1 (HR: 0.60, 95% CI: 0.39-0.97, p = 0.03) as a significant predictor of better PFS, while PS score of 0-1 (HR: 0.51, 95% CI: 0.31-0.89, p = 0.01) and younger patients ( < 75 years) (HR: 0.66, 95% CI: 0.45-0.97, p = 0.03) as significant-good predictor of OS. The rate of severe AEs was higher in ineligible patients than in eligible (39% vs. 27%, respectively; p = 0.07), although the difference was not significant. Older age was significantly associated with severe AEs (p = 0.049). Conclusions: The real-world efficacy of chemo-immunotherapy for ES-SCLC was similar to that of pivotal clinical trials. However, trial-ineligible patients with ES-SCLC had poor treatment outcome and the higher rates of severe adverse events in this prospective cohort study. Our study suggests that positive results among the trial eligible patients may not translate to ineligible patients. Clinical trial information: UMIN000038064.
Adverse events self-reported by patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with durvalumab (D) plus platinum-etoposide (EP) or EP in the CASPIAN study.
Authors: Özgüroğlu Mustafa , Goldman Jonathan W. , Chen Yuanbin , Garassino Marina Chiara , Medic Nenad , Mann Helen , Chugh Priti , Dalvi Tapashi , Paz-Ares Luis G.
Published: June 2022

8571

Background: The CASPIAN phase 3 study established D+EP as a global standard of care in ES-SCLC. Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to complement standard adverse event (AE) reporting in oncology trials. Here we describe patient-reported symptomatic AEs using PRO-CTCAE in CASPIAN, the first time the PRO-CTCAE tool has been piloted in SCLC research. Methods: In CASPIAN, treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D+EP q3w followed by maintenance D q4w until progressive disease (PD), or up to 6 cycles of EP q3w. As part of exploratory analyses, where validated local language versions were available (in English, German, Japanese or Spanish), pts were asked to complete the PRO-CTCAE by e-device at baseline, q3w during EP (in both arms), then q4w until PD, followed by day 28 post-PD, 2 months post-PD, and q8w until second progression/death. Presence/absence, frequency or severity were examined during the first 24 weeks after starting treatment across 11 AEs selected as being relevant to pts with ES-SCLC (Table). Results: In total, 164 of the 537 pts randomized to D+EP and EP in CASPIAN (31%; D+EP: 83; EP: 81) were asked to complete the PRO-CTCAE. At baseline, the PRO-CTCAE was completed by 84% of these pts in the D+EP arm and 81% in the EP arm; compliance rates > 60% were achieved up to cycle 32 for D+EP and cycle 6 for EP. Examined AEs were reported by a minority of pts before starting treatment in both arms (range D+EP vs EP: 4% vs 3% for hand-foot syndrome to 34% vs 41% for dry mouth). Baseline AE rates were generally maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which showed a numerical increase from 13% at baseline to a peak of 34% at cycle 6 in the D+EP arm and 12% at baseline to a peak of 42% at cycle 8 in the EP arm; and dizziness, which showed a numerical increase from 16% at baseline to a peak of 40% at cycle 5 in the D+EP arm, while rates were maintained vs baseline in the EP arm. Most pts reporting these AEs indicated that they occurred rarely or occasionally, or were mild or moderate in severity. Conclusions: Self-reported data from pts in CASPIAN showed that the 11 AEs examined during the 24 weeks after starting treatment were reported by a minority of pts, mostly with rare or occasional occurrence, and mild to moderate severity. Rates and patterns of AEs over time were broadly similar in the D+EP and EP arms. These results complement the CASPIAN safety profile and give insight into pts’ experience of treatment. Clinical trial information: NCT03043872. [Table: see text]
The efficacy and safety of taletrectinib in patients with TKI-naïve or crizotinib-pretreated ROS1-positive non–small cell lung cancer (NSCLC).
Authors: Li Wei , Yang Nong , Ma HuiWen , Fan Huijie , Li Kunyan , Wu Huijuan , Yu Qitao , Wang Yongsheng , Meng Xue , Wang Xicheng , Qin Xintian , Wang Ziping , Liu Yunpeng , Tao Min , Zhuang Wu , Fang Yong , Sun Ping , Lu Kaihua , Wu Jingxun , Zhou Caicun
Published: June 2022

8572

Background: Taletrectinib (AB-106 / DS-6051b) is a next-generation, potent, CNS- penetrant, selective ROS1 tyrosine kinase inhibitor. The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are TKI -naïve or crizotinib-pretreated. Here we present the updated efficacy and safety results of the study. Methods: The eligible ROS1-positive NSCLC patients were enrolled into either TKI-naïve or crizotinib-pretreated cohorts, and treated with taletrectinib 600mg once daily. The study endpoints included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), overall intracranial response rate (IC-ORR), progression-free survival (PFS), and safety profile. Results: As of the data cutoff date of September 7, 2021, 61 of the 86 stage IV patients enrolled in the study have at least three postbaseline tumor assessment of which 40 patients in the TKI-naïve cohort, and 21 patients in the crizotinib-pretreated cohort (50% patients having at least one prior chemotherapy). In the TKI -naïve cohort, the confirmed ORR by investigators per RECIST 1.1 was 90.0%: [95%CI: 76.3%; 97.2%] (36/40); and the DCR was 95% [95%CI: 83.1%; 99.4%] (38/40). In the crizotinib-pretreated cohort, the confirmed ORR by investigators was 47.6% [95%CI: 25.7%; 70.2%] (10/21); and DCR was 76.2%: [52.8%; 91.8%] (16/21). The mDOR and mPFS are not reached yet for both cohorts. Of 6 patients having brain metastasis and measurable target brain lesions at baseline, the intracranial ORR and IC-DCR were 83.3% and 100%, respectively. Of 4 patients with ROS1 G2032R mutation, 3 patients achieved partial response (PR), and 1 patient achieved stable disease (SD). The most common treatment-related adverse events (TRAEs) include diarrhea, nausea, vomiting, transaminase elevation, anemia, neutrophil count decrease, etc. were Grade 1 or 2, and the most common AEs (below 10%) were ALT/AST increased but reversible. Conclusions: Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population. Clinical trial information: NCT04395677.
Total metabolic tumor volume on 18F-fluorodeoxyglucose-positron emission tomography ([18F]-FDG-PET) scan: A potential prognostic factor in extensive-stage small cell lung cancer.
Authors: Andrini Elisa , Lamberti Giuseppe , Argalia Giulia , Fortunati Emilia , Fanti Stefano , Campana Davide , Ardizzoni Andrea
Published: June 2022

8574

Background: Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung cancer, accounting for 10-15% of all lung cancers, commonly classified in limited stage (LS-SCLC) and extensive stage (ES-SCLC). Despite the introduction of chemoimmunotherapy as new standard first-line therapy for ES-SCLC, the benefit of addition of the programmed-death ligand 1 (PD-L1) inhibitors is limited to a subset of patients, suggesting the importance to identify predictive biomarkers of response. [18F]FDG-PET/CT is commonly used for the staging and therapeutic planning of SCLC patients. Metabolic parameters derived from [18F]FDG-PET could predict patient outcomes by measuring the extension of metabolically active tumor (metabolic tumor volume [MTV]) or its metabolic heterogeneity (total lesion glycolysis [TLG]). Methods: We retrospectively collected patients with pathologically confirmed diagnosis of SCLC, who had undergone an [18F]FDG PET/CT scan within 30 days from the start of first-line treatment for ES-SCLC. Patients with LS-SCLC at diagnosis were included if presenting relapse at pre-treatment scans performed at least 90 days from the end of treatment with radical intent. We calculated metabolic parameters, MTV and TLG, by summing each single lesion’s MTV and TLD respectively. The primary endpoint of the study was overall survival (OS), defined as the time from [18F]FDG PET/CT scan acquisition to death from any cause. Results: A total of 86 SCLC patients ES-SCLC were included. Patients with hyponatremia, hypoalbuminemia and elevated LDH levels were associated with greater number of lesions, greater total MTV, and higher total TLG at [18F]FDG-PET/CT/CT scan. At a median follow-up of 20.9 months, the median OS was 11.1 months. Median survival was longer among patients with Na + ≥135 mEq/L, with normal albumin levels and in those with normal LDH levels and without bone metastases. Patients with low total MTV had longer OS compared with those with high total MTV (11.9 months vs 4.8 months, respectively). High total MTV was independently associated with the risk of death (p < 0.001) but not with the risk of progression. Conclusions: Our preliminary data showed that total MTV could provide prognostic information in patients with ES-SCLC, suggesting a potential role as stratification factor in immunotherapy-based clinical trials.
Antitumor activity of sunvozertinib in NSCLC patients with EGFR Exon20 insertion mutations after platinum and anti-PD(L)1 treatment failures.
Authors: Janne Pasi A. , Wang Mengzhao , Camidge D. Ross , Mitchell Paul , Fang Jian , Nian Weiqi , Chiu Chao-Hua , Zhou Jianying , Zhao Yanqiu , Su Wu-Chou , Yang Tsung-Ying , Zhu Viola Weijia , Millward Michael , Fan Yun , Huang Wen-Tsung , Cheng Ying , Jiang Liyan , Brungs Daniel , Zheng Li , Yang James Chih-Hsin
Published: June 2022

9015

Background: Platinum-based chemotherapy is the 1st line standard of care for NSCLC patients with EGFR exon 20 insertion mutations (Exon20ins), with anti-PD(L)1 frequently used as well. Here we present anti-tumor activity of sunvozertinib in these patients whose disease had progressed on these therapies from two ongoing phase 1/2 studies (WK-KONG1, NCT03974022 and WU-KONG2, CTR20192097). Based on these data, sunvozertinib was granted the Breakthrough Therapy Designation by both US FDA and China NMPA. Methods: The objective of this study is to characterize the safety and efficacy of sunvozertinib in platinum-pretreated advanced NSCLC patients harboring EGFR Exon20ins, with or without anti-PD(L1) treatment. In addition, the effect of prior treatment on sunvozertinib’s safety and efficacy were explored. Results: As of July 30, 2021, a total of 52 locally advanced or metastatic NSCLC patients harboring EGFR Exon20ins post platinum treatment were enrolled into WU-KONG1 and WU-KONG2 studies, and included in the efficacy analysis set (dose range: 50 mg to 400 mg, once daily). Male/Female: 21/31; Median age 59; Asian/White: 44/8; Prior therapies: median 2.5 (range 1-10); 31% received prior anti-PD(L)1 treatment (all in £ 300 mg cohorts); 40% of the subjects with baseline brain metastasis. Partial response was observed at ≥ 100 mg. At the dose level of 100 mg, 200 mg, 300 mg and 400 mg, confirmed ORR was 50% (1/2), 55.6 % (5/9), 44.8% (13/29) and 22.2% (2/9), respectively. With a median follow-up time of 10.5 months, median DoR was not reached for 200 mg cohort; with a median follow-up of 7 months, median DoR of 300 mg group was 5.6 months. Progression free survival (PFS) rate at 6 months for 100 mg, 200 mg, 300 mg and 400 mg cohorts was 50%, 53.3%, 44.6% and 44.4%, respectively. In patients with/without prior anti-PD(L)1 treatment, comparable efficacy and safety profiles were observed. Conclusions: The data suggest sunvozertinib is active in platinum-pretreated patients with EGFR Exon20ins, irrespective of prior or after anti-PD(L)1 treatment. The updated data will be presented at the meeting. Sunvozertinib is currently in phase 2 pivotal clinical development (NCT03974022 and China CTR20211009). Clinical trial information: NCT03974022.
Identifying prognostic and predictive value of mutations associated with clinical outcomes in first line (1L) patients with advanced or metastatic non–small cell lung cancer (aNSCLC).
Authors: Perez Parente Diego , Cobo-Dols Manuel , Hasan Haroon , Olson Sara , Pal Navdeep , Wilkinson Samantha , La Orden Tévar Beatriz , Pérez Fernández Mar , Provencio-Pulla Mariano
Published: June 2022

9047

Background: Whilst the impact of certain mutations on aNSCLC survival outcomes has been evaluated, real-world (rw) evidence on its predictive and prognostic value remains limited. We aimed to identify the predictive and prognostic value of non-driver mutations that are deemed to be clinically relevant in aNSCLC. Methods: This retrospective cohort study analysed de-identified electronic medical records from the Flatiron Clinico-Genomic (FCGD) and FoundationCORE™ databases of aNSCLC patients who have initiated 1L cancer immunotherapy (CIT, alone or in combination) or chemotherapy (chemo) under routine care between 2016 and 2021. Propensity-based multivariable models were used to determine associations between mutational status and progression-free survival (rwPFS), overall survival (rwOS) and overall response (rwR). Results: Of 10,795 patients identified, 2,999 met inclusion criteria (1,042 chemo, 1,957 CIT). Among these, 53% were men and 65% were ≥65 years old. Patients mostly had non-squamous histology (68%), a previous history of smoking (95%) and ECOG ≤1 (61%). 58% of patients were diagnosed as de novo. A total of 185 different mutations were identified in this population, and variants of the same mutation were grouped, identifying 58 mutation families. STK11, KEAP1 and CDKN2A/B mutations were significantly associated with all effectiveness outcomes (Table), indicating lower response (rwR OR<1) and shorter survival (rwOS and rwPFS HR>1) in patients harbouring mutated vs. wild type genes. APC and KRAS mutations were only significantly associated with lower rwR, while FGRF and HRAS mutations were related to worse rwPFS and rwOS, respectively. In contrast, a significantly higher likelihood of response or PFS was associated with ATM/R/RX and GATA3 mutations, respectively. Moreover, our results suggest that KRAS mutations potentially have predictive value for PFS in CIT-treated patients. Mutations with prognostic value on clinical outcomes (overall population). HR, hazard ratio; PFS, progression-free survival; OR, odds ratio; OS, overall survival; rw, real-world. Conclusions: STK11, KEAP1 and CDKN2A/B mutations were significantly associated with poor prognosis in all effectiveness outcomes. In addition, KRAS mutations resulted in clinically significant differences in terms of PFS. Further analyses should be conducted to confirm this clinical significance and to evaluate the relevance of these mutations in future clinical trials design.[Table: see text]
Immunophenotypic correlates and response to first-line pembrolizumab among elderly patients with PD-L1-high (≥ 50%) non–small cell lung cancer.
Authors: Barrichello Adriana Paula de Castro , Alessi Joao Victor Machado , Ricciuti Biagio , Pecci Federica , Vaz Victor R. , Lamberti Giuseppe , Turner Madison M. , Pfaff Kathleen L. , Rodig Scott J. , Awad Mark M.
Published: June 2022

9054

Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p < 0.1 were included in the multivariate model. The results were compared in patients < 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients < 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the < 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients < 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients < 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients < vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.
A phase II study of alectinib in combination with bevacizumab as first-line treatment in advanced NSCLC with confirmed ALK fusion: ALEK-B trial.
Authors: Arrieta Oscar Gerardo , Lara Mejía Luis Antonio , Cabrera Luis Antonio , Ramos Maritza , Heredia David Jose , Cruz-Rico Graciela , Salinas Miguel Angel , Cardenas Fernández Daniela , Zatarain-Barron Zyanya Lucía , Cardona Zorrilla Andres Felipe , Remon Masip Jordi , Rosell Rafael
Published: June 2022

9074

Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31st, 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no > G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.