PD-1/PD-L1 Inhibitors as Monotherapy in the First-Line Treatment of Advanced Non-Small Cell Lung Cancer Patients with High PD-L1 Expression : An Expert Position Statement

There are currently three first-line immunotherapy options used as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand 1 (PD-L1) expression (≥50%). This manuscript aims to evaluate the available data on atezolizumab (AT), cemiplimab (CEMI), and pembrolizumab (PEMBRO) and to study the results obtained during pivotal trials, especially regarding patient subgroups. Nominal group and Delphi techniques were used. Eight Spanish experts in lung cancer (the scientific committee of the project) analyzed the use of immunotherapy monotherapy as first-line treatment in patients with NSCLC and high PD-L1 expression. The expert scientific committee formulated several statements based on a scientific review and their own clinical experience. Subsequently, 17 additional Spanish lung cancer experts were selected to appraise the committee's statements through two Delphi rounds. They completed a Delphi round via an online platform and voted according to a scale from 1 (strongly disagree) to 10 (strongly agree). The statements were approved if ≥70% of experts voted 7 or more. A total of 20 statements were proposed covering the following areas: (1) general characteristics of pivotal clinical trials; (2) overall main outcomes of pivotal clinical trials; and (3) subgroup analysis. All statements reached consensus in the first round. AT, CEMI, and PEMBRO as monotherapy can be considered the standard of care in patients with advanced NSCLC and high PD-L1 expression (≥50%). Moreover, some differences noted among the drugs analyzed in this document might facilitate treatment decision-making, especially in clinically relevant patient subgroups, when using PD-1/PD-L1 inhibitors. The high level of agreement reached among experts supports the proposed statements

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

Abstract Introduction Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively. Conclusions Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy

Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small- cell lung cancer

Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC

Cost estimate of immune-related adverse reactions associated with innovative treatments of metastatic melanoma

Background and Objective Immuno-oncology therapies represent a new treatment opportunity for patients affected by metastatic melanoma. The purpose of this study was to estimate the costs of immune-related adverse events (irAEs) associated with the new anti-PD1 immuno-oncology therapies, with the anti-CTLA-4 immuno-oncology therapy and with the combined therapy (CTLA4 + anti-PD1) in patients affected by metastatic melanoma.Materials and Methods A probabilistic cost-of-illness (COI) model was developed to estimate the management costs of grade >= 3 adverse events associated with the new anti-PD1 therapies (pembrolizumab and nivolumab), the anti-CTLA-4 therapy (ipilimumab) and the combined therapy CTLA4 + anti-PD1 (nivolumab + ipilimumab) for the treatment of patients with metastatic melanoma from the National Health Service (NHS) perspective in Italy. Identification of the epidemiological and cost parameters was carried out through a systematic literature review (SLR). Univariate and probabilistic sensitivity analyses were performed to account for uncertainty and variation in the model results.Results The model estimated a cost associated with the management of grade >= 3 immune-related adverse events in patients with metastatic melanoma equal to (sic)176.2 (95% CI 63.5-335.0) for anti-CTLA-4 therapy, (sic)48.6 (95% CI 40.1-58.5) for the new anti-PDI therapies and (sic)276.8 (95% CI 240.4-316.2) for the combined therapy. Among the innovative therapies for the considered metastatic melanoma, the combined therapy was the most expensive innovative treatment in terms of event management of immune-related grade >= 3 adverse events.Conclusion This study may represent a useful tool to understand the economic burden associated with the management of irAEs associated with patients affected by metastatic melanoma

Competing ultrafast intersystem crossing and internal conversion in the "channel 3" region of benzene

We report new, detailed, femtosecond time-resolved photoelectron spectroscopy experiments and calculations investigating the competition between ultrafast internal conversion and ultrafast intersystem crossing in electronically and vibrationally excited benzene at the onset of “channel 3”. Using different probe energies to record the total photoelectron yield as a function of pump–probe delay we are able to confirm that S1, T1 and T2 electronic states are involved in the excited state dynamics. Time-resolved photoelectron spectroscopy measurements then allow us to unravel the evolution of the S1, T1 and T2 components of the excited state population and, together with complementary quantum chemistry and quantum dynamics calculations, support our earlier proposal that ultrafast intersystem crossing competes with internal conversion (Chem. Phys. Lett., 2009, 469, 43).<br/

Quantitative assessment of cd200 and cd200r expression in lung cancer

CD200/CD200R is an immune checkpoint with broad expression patterns and a potential target for immune therapy. In this study, we assess both CD200 and CD200R expression in solid tumors, with a focus on lung cancer, and evaluate their association with clinicopathologic characteristics, mutation status, outcome, and programmed death-ligand 1 (PD-L1) expression. We used multiplexed quantitative immunofluorescence (QIF) to measure the expression of CD200 and CD200R in a total of 455 patients from three lung cancer cohorts. Using carefully validated anti-bodies, we performed target measurement with tyramide-based QIF panels and analyzed the data using the PM2000 microscope and AQUA software. CD200 tumor positivity was found in 29.7% of non-small cell lung cancer (NSCLC) patients and 33.3% of lung large cell neuroendocrine carcinoma (LCNEC) patients. CD200 demonstrated notable intratumoral heterogeneity. CD200R was expressed in immune cells in 25% of NSCLC and 41.3% of LCNEC patients. While CD200R is predominantly expressed in immune cells, rare tumor cell staining was seen in a highly heterogeneous pattern. CD200R expression in the stromal compartment was significantly higher in patients with squamous differentiation (p &lt; 0.0001). Neither CD200 nor CD200R were associated with other clinicopathologic characteristics or mutation status. Both biomarkers were not prognostic for disease-free or overall survival in NSCLC. CD200 showed moderate correlation with PD-L1. CD200/CD200R pathway is frequently expressed in lung cancer patients. Differential expression patterns of CD200 and CD200R with PD-L1 suggest a potential role for targeting this pathway alone in patients with NSCLC. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Clinical Utility of Combined Plasma and Tissue NGS in Patients With Newly Diagnosed Advanced Non-Small Cell Lung Cancer

Introduction: The incremental clinical value of performing both tissue and plasma next-generation sequencing (NGS) to detect actionable alterations (AA) at diagnosis in patients with advanced non-small cell lung cancer (aNSCLC) has not been comprehensively assessed. Methods: We conducted a study with two aNSCLC cohorts, prospectively assessed with tissue and plasma NGS at diagnosis. Guardant360 CDx and FoundationOne Liquid CDx were used in cohort 1 (N=127) and cohort 2 (N=149), respectively. We considered AA according to ESCAT I-III levels. Undetectable ctDNA and unavailable tissue were considered non-informative results. Results: AA were found in 50/127 (39%) and 65/149 (44%) patients in cohorts 1 and 2, respectively (Figure 1). In cohort 1, AA were detected only in plasma in 14/50 (28%) and only in tissue in 9/50 (18%). In the 14 cases with AA only detected in plasma, 3 had informative tissue results (1 EGFR and 1 KRAS G12C mutations detected in plasma but not in tissue). In the 9 cases with AA only detected in tissue, 6 had informative plasma results (1 ALK fusion, 1 ERBB2 amplification, 1 EGFR and 2 KRAS G12C mutations detected in tissue but not in plasma). In cohort 2, AA were detected only in plasma in 22/65 (34%) and only in tissue in 15/65 (23%). In the 22 cases with AA only detected in plasma, 11 had informative tissue results (1 RET and 1 ALK fusions, 3 ERBB2 alterations, 2 KRAS G12C mutations detected in plasma but not in tissue). In the 15 cases with AA only detected in tissue, 6 had informative plasma results (3 EGFR mutations, 1 ROS1 fusion and 2 ERBB2 amplifications detected in tissue but not in plasma). Conclusion: Due to data observed, plasma NGS should be considered when AA are not detected by tissue, and vice versa, in patients with newly diagnosed aNSCLC