TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC

Antibody–drug conjugate; Immuno-oncology; Non-small-cell lung cancerConjugado anticuerpo-fármaco; Inmuno-oncología; Cáncer de pulmón de células no pequeñasConjugat anticòs-fàrmac; Immuno-oncologia; Càncer de pulmó de cèl·lules no petitesPembrolizumab monotherapy is a standard first-line treatment for PD-L1–high advanced non-small-cell lung cancer (NSCLC) without actionable genomic alterations (AGA). However, few patients experience long-term disease control, highlighting the need for more effective therapies. Datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2-directed antibody–drug conjugate, showed encouraging safety and antitumor activity with pembrolizumab in advanced NSCLC. We describe the rationale and design of TROPION-Lung08, a phase III study evaluating safety and efficacy of first-line Dato-DXd plus pembrolizumab versus pembrolizumab monotherapy in patients with advanced/metastatic NSCLC without AGAs and with PD-L1 tumor proportion score ≥50%. Primary end points are progression-free survival and overall survival; secondary end points include objective response rate, duration of response, safety and presence of antidrug antibodies.This study is sponsored by Daiichi Sankyo, Inc. In July 2020, Daiichi Sankyo entered into a global development and commercialization collaboration agreement with AstraZeneca for datopotamab deruxtecan (Dato-DXd). Pembrolizumab is being provided under agreement by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD). BP Levy received consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Janssen, Mirati, Novartis, Pfizer, and Roche/Genentech. E Felip received consulting fees and/or honoraria from Amgen, AstraZeneca, Bayer, BerGenBio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Roche, GSK, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Novartis, PeerVoice, Peptomyc, Pfizer, Sanofi, Takeda, and touchONCOLOGY and grant funding to her institution from Merck KGaA and Fundación Merck Salud. E Felip is an independent member of the Grífols Board of Directors. M Reck received consulting fees, honoraria, and support for attending meetings from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, GSK, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, Roche, and Regeneron and served on data safety monitoring boards for Daiichi Sankyo and Sanofi. JCH Yang received consulting or advisory fees from Ono Pharmaceuticals and Pfizer, grant funding to his institution from AstraZeneca and advisory or consulting fees to his institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Johnson & Johnson, Merck KGaA, MSD, Novartis, Puma Technology, Roche/Genentech, Takeda and Yuhan Pharmaceuticals. F Cappuzzo received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, MSD, Novartis, Pfizer, PharmaMar, Roche, and Takeda. C Zhou received consulting fees and/or honoraria from Amoy Diagnostics, AnHeart Therapeutics, Boehringer Ingelheim, CStone Pharmaceuticals, Luye Pharma Group, Eli Lilly China, Jiangsu Hengrui Pharmaceuticals, Innovent Biologics, MSD, Qilu Pharmaceutical, Roche, Sanofi, and TopAlliance Biosciences. S Rawat is an employee of and owns stock and/or stock options in Daiichi Sankyo. P Basak and J Xie are employees of Daiichi Sankyo. L Xu was an employee at MSD at the time this study was designed and is a current employee of AstraZeneca. J Sands received consulting fees from AstraZeneca, Curadev, Daiichi Sankyo, Guardant Health, Jazz Pharmaceuticals, Medtronic, PharmaMar, Sanofi, and Takeda and is the treasurer of the Rescue Lung Society. Y Yoneshima declares no potential conflicts. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Regulation of PD-L1 expression in non–small cell lung cancer by interleukin-1β

IntroductionProgrammed cell death–ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non–small cell lung cancer (NSCLC).MethodsWe performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.ResultsThe IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ.DiscussionOur study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β–MAPK axis being a promising therapeutic target for attenuation of PD-L1–mediated suppression of antitumor immunity

Pleuroparenchymal fibroelastosis secondary to autologous peripheral blood stem cell transplantation: A case report

Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonitis. Although most cases of PPFE are idiopathic, some cases of PPFE occur secondary to stem cell transplantation. We report a 41-year-old woman developed pneumonia after autologous peripheral blood system cell transplantation (PBSCT). Eleven years after PBSCT, she presented with dyspnea. A computed tomographic scan showed pleuroparenchymal thickening and predominantly in the upper lobes. She was diagnosed with PPFE secondary to PBSCT. She was started nintedanib and administered oxygen therapy. Most cases of PPFE secondary to stem cell transplantation have been reported. However, we experienced the case of PPFE post-autologous PBSCT

Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell–specific Itpa–conditional KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure

Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells.

Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity

Paired analysis of tumor mutation burden for lung adenocarcinoma and associated idiopathic pulmonary fibrosis

Abstract Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF