First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02142738","term_id":"NCT02142738"}}NCT02142738.     

Real‐world data on NGS using the Oncomine DxTT for detecting genetic alterations in non‐small‐cell lung cancer: WJOG13019L

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.     

Current status of first‐line treatment with pembrolizumab for non–small‐cell lung cancer with high PD‐L1 expression

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) should be selected for patients with advanced non–small‐cell lung cancer (NSCLC) exhibiting high PD‐L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0–1) in the COMB group (p < 0.01). With a median follow‐up time of 10.6 (range: 0.1–20.6) months, the median progression‐free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first‐line treatment for NSCLC with high PD‐L1 expression and good performance status.     

Cost‐effectiveness of carbon‐ion radiotherapy versus stereotactic body radiotherapy for non‐small‐cell lung cancer

Carbon‐ion radiotherapy (CIRT) for clinical stage I non‐small‐cell lung cancer (NSCLC) is used as an advanced medical treatment regimen in Japan. Carbon‐ion radiotherapy reportedly aids in achieving excellent treatment outcomes, despite its high medical cost. We aimed to compare CIRT with stereotactic body radiotherapy (SBRT) in terms of cost‐effectiveness for treating clinical stage I NSCLC. Data of patients with clinical stage I NSCLC treated with CIRT or SBRT at Gunma University between 2010 and 2015 were analyzed. The CIRT and SBRT groups included 62 and 27 patients, respectively. After propensity‐score matching, both groups comprised 15 patients. Life year (LY) was used as an indicator of outcome. The CIRT technical fee was 3 140 000 JPY. There was no technical fee for the second CIRT carried out on the same organ within 2 years. The incremental cost‐effectiveness ratio (ICER) was calculated by dividing the incremental cost by the incremental LY for 5 years after treatment. Sensitivity analysis was applied to evaluate the impact of LY or costs of each group on ICER. The ICERs were 7 491 017 JPY/LY and 3 708 330 JPY/LY for all patients and matched patients, respectively. Hospitalization and examination costs were significantly higher in the CIRT group, and the impact of the CIRT technical costs was smaller than other costs and LY. Carbon‐ion radiotherapy is a cost‐effective treatment approach. However, our findings suggest that reducing excessive costs by considering the validity and necessity of examinations and hospitalizations would make CIRT a more cost‐effective approach.     

Pembrolizumab plus pemetrexed‐platinum for metastatic nonsquamous non–small‐cell lung cancer: KEYNOTE‐189 Japan Study

Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Ramucirumab or placebo plus erlotinib in EGFR‐mutated,metastatic non‐small‐cell lung cancer: East Asian subset of RELAY

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression‐free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation‐positive metastatic non‐small‐cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46‐0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator‐assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485‐0.833]; P = .0009). The 1‐y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut‐off (censoring rates, 81.2%‐84.3% and 64.1%‐70.5%, respectively). Grade ≥ 3 treatment‐emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post‐progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR‐mutated metastatic NSCLC in East Asia.     

Multiplex immune protein profiling of fine‐needle aspirates from patients with non‐small‐cell lung cancer reveals signatures associated with PD‐L1 expression and tumor stage

Biomarker signatures identified through minimally invasive procedures already at diagnosis of non‐small‐cell lung cancer (NSCLC) could help to guide treatment with immune checkpoint inhibitors (ICI). Here, we performed multiplex profiling of immune‐related proteins in fine‐needle aspirate (FNA) samples of thoracic lesions from patients with NSCLC to assess PD‐L1 expression and identify related protein signatures. Transthoracic FNA samples from 14 patients were subjected to multiplex antibody‐based profiling by proximity extension assay (PEA). PEA profiling employed protein panels relevant to immune and tumor signaling and was followed by Qlucore^® Omics Explorer analysis. All lesions analyzed were NSCLC adenocarcinomas, and PEA profiles could be used to monitor 163 proteins in all but one sample. Multiple key immune signaling components (including CD73, granzyme A, and chemokines CCL3 and CCL23) were identified and expression of several of these proteins (e.g., CCL3 and CCL23) correlated to PD‐L1 expression. We also found EphA2, a marker previously linked to inferior NSCLC prognosis, to correlate to PD‐L1 expression. Our identified protein signatures related to stage included, among others, CXCL10 and IL12RB1. We conclude that transthoracic FNA allows for extensive immune and tumor protein profiling with assessment of putative biomarkers of important for ICI treatment selection in NSCLC.     

Predictive value of EGFR mutation in non–small‐cell lung cancer patients treated with platinum doublet postoperative chemotherapy

The mutation status of tumor tissue DNA (n = 389) of resected stage II‐III non‐squamous non–small‐cell lung cancer (Ns‐NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG‐TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22‐2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30‐2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15‐2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II‐III Ns‐NSCLC patients. This result supports a role for mandatory molecular diagnosis of early‐stage Ns‐NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum‐based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).     

Cost‐effectiveness of precision diagnostic testing for precision medicine approaches against non‐small‐cell lung cancer: A systematic review

Precision diagnostic testing (PDT) employs appropriate biomarkers to identify cancer patients that may optimally respond to precision medicine (PM) approaches, such as treatments with targeted agents and immuno‐oncology drugs. To date, there are no published systematic appraisals evaluating the cost‐effectiveness of PDT in non‐small‐cell lung cancer (NSCLC). To address this gap, we conducted Preferred Reporting Items for Systematic Reviews and Meta‐Analyses searches for the years 2009–2019. Consolidated Health Economic Evaluation Reporting Standards were employed to screen, assess and extract data. Employing base costs, life years gained or quality‐adjusted life years, as well as willingness‐to‐pay (WTP) threshold for each country, net monetary benefit was calculated to determine cost‐effectiveness of each intervention. Thirty‐seven studies (50%) were included for analysis; a further 37 (50%) were excluded, having failed population‐, intervention‐, comparator‐, outcomes‐ and study‐design criteria. Within the 37 studies included, we defined 64 scenarios. Eleven scenarios compared PDT‐guided PM with non‐guided therapy [epidermal growth factor receptor (EGFR), n = 5; programmed death‐ligand 1 (PD‐L1), n = 6]. Twenty‐eight scenarios compared PDT‐guided PM with chemotherapy alone (anaplastic lymphoma kinase, n = 3; EGFR, n = 17; PD‐L1, n = 8). Twenty‐five scenarios compared PDT‐guided PM with chemotherapy alone, while varying the PDT approach. Thirty‐four scenarios (53%) were cost‐effective, 28 (44%) were not cost‐effective, and two were marginal, dependent on their country’s WTP threshold. When PDT‐guided therapy was compared with a therapy‐for‐all patients approach, all scenarios (100%) proved cost‐effective. Seven of 37 studies had been structured appropriately to assess PDT‐PM cost‐effectiveness. Within these seven studies, all evaluated scenarios were cost‐effective. However, 81% of studies had been poorly designed. Our systematic analysis implies that more robust health economic evaluation could help identify additional approaches towards PDT cost‐effectiveness, underpinning value‐based care and enhanced outcomes for patients with NSCLC.     

Proposing synchronous oligometastatic non–small‐cell lung cancer based on progression after first‐line systemic therapy

Despite the importance of accurate disease definitions for effective management and treatment decisions, there is currently no consensus on what constitutes oligometastatic non–small‐cell lung cancer (NSCLC). Predominant patterns of initial progressive disease (PD) after first‐line systemic therapy have been shown to be a substantial basis for local ablative therapy (LAT) for all disease sites in patients with oligometastatic NSCLC, suggesting that these patterns could be helpful in defining synchronous oligometastatic NSCLC. Therefore, this retrospective study aimed to propose a threshold number of metastases for synchronous oligometastatic NSCLC, based on the pattern of initial PD after first‐line systemic therapy. The cut‐off threshold number of metastases compatible with synchronous oligometastatic NSCLC was determined using receiver operating characteristic (ROC) curve analyses of PD at the initially involved sites alone. ROC analysis of 175 patients revealed that the presence of 1‐3 metastases before first‐line treatment (sensitivity, 85.9%; specificity, 97.3%; area under the curve, 0.91) was compatible with oligometastatic NSCLC, therefore we divided patients into oligometastatic NSCLC and non‐oligometastatic NSCLC groups. Multivariate logistic regression analyses revealed oligometastatic NSCLC to be the only independent predictor of PD at initially involved sites alone (odds ratio 165.7; P < .001). The median survival times in patients with oligometastatic or non‐oligometastatic NSCLC were 23.0 and 10.9 mo (hazard ratio, 0.51; P = .002), respectively. Based on these findings, we propose synchronous oligometastatic NSCLC as 1‐3 metastases in accordance with patterns of initial progression. The result of our study might be contributory to provide a common definition of synchronous oligometastatic NSCLC.     

PD‐1‐induced T cell exhaustion is controlled by a Drp1‐dependent mechanism

Programmed cell death‐1 (PD‐1) signaling downregulates the T‐cell response, promoting an exhausted state in tumor‐infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin‐related protein‐1 (Drp1)‐dependent mitochondrial fission plays a crucial role in sustaining T‐cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD‐1 in tumor‐infiltrating T cells. Here, we show that PD‐1^pos CD8⁺ T cells infiltrating an MC38 (murine adenocarcinoma)‐derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD‐1^neg counterparts. Also, PD‐1^pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD‐1 signaling directly prevents mitochondrial fragmentation following T‐cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor‐infiltrating PD‐1^pos CD8⁺ T cells seems to be a mechanism exploited by PD‐1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor‐infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.     

CD24, not CD47, negatively impacts upon response to PD‐1/L1 inhibitors in non–small‐cell lung cancer with PD‐L1 tumor proportion score < 50

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD‐L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)‐A, D and PDGF‐AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non–small‐cell lung cancer with PD‐L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).     

DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor‐infiltrating T cells through IL‐18

Immunotherapies represented by programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1) immune checkpoint inhibitors have made great progress in the field of anticancer treatment, but most colorectal cancer patients do not benefit from immunotherapy. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, is activated by collagen binding and overexpressed in various malignancies. However, the role of DDR1 in colorectal cancer and immunoregulation remains unclear. In this study, we found DDR1 is highly expressed in colorectal cancer tissues and negatively associated with patient survival. We demonstrated that DDR1 promotes colorectal tumor growth only in vivo. Mechanistically, DDR1 is a negative immunomodulator in colorectal cancer and is involved in low infiltration of CD4⁺ and CD8⁺ T cells by inhibiting IL‐18 synthesis. We also reported that DDR1 enhances the expression of PD‐L1 through activating the c‐Jun amino terminal kinase (JNK) signaling pathway. In conclusion, our findings elucidate the immunosuppressive role of DDR1 in colorectal cancer, which may represent a novel target to enhance the efficacy of immunotherapy in colorectal cancer.     

Cancer‐associated fibroblast migration in non‐small cell lung cancers is modulated by increased integrin α11 expression

Cancer‐associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer–stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non‐small‐cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC‐associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer–stroma interactions may serve as a novel, promising anti‐tumor strategy.     

USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer

Deubiquitinating enzymes (DUBs) serve to maintain cellular homeostasis via protein ubiquitination and exert diverse regulatory functions in cancers and other diseases. Much progress has been made in characterizing biological roles of DUBs over the decades, yet the specific functions of many subclass members remain largely unexplored. It was not until recent years that the role of ubiquitin‐specific‐processing protease 35 (USP35) in cancers began to be understood. Here, we focus on delineating the roles and underlying mechanisms of USP35 in non‐small cell lung cancer (NSCLC). The isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach were employed to identify differentially expressed proteins (DEPs) in H1299 cells induced by USP35 overexpression or silencing. Among the potential interactome of USP35, ribosome‐binding protein 1 (RRBP1), a membrane‐bound protein in endoplasmic reticulum (ER), captured our attentions. RRBP1 expression was found to positively correlate with USP35 levels in both genetically modified cells and human NSCLC tissues. Concordantly, both RRBP1 expression and USP35 expression were found to positively correlate with poor prognoses in lung adenocarcinoma patients. At the molecular level, USP35 was verified to directly interact with RRBP1 to prevent it from proteasomal‐dependent degradation. Functionally, USP35 alleviated ER stress‐induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. Collectively, these findings indicate that USP35 plays a critical role in resisting ER stress‐induced cell death through deubiquitinating RRBP1, hence providing a rationale to target the USP35‐RRBP1 axis as an alternative therapeutic option for NSCLC.     

Adjuvant atezolizumab in Japanese patients with resected stage IB‐IIIA non‐small cell lung cancer (IMpower010)

The global phase 3 IMpower010 study evaluated adjuvant atezolizumab versus best supportive care (BSC) following platinum‐based chemotherapy in patients with resected stage IB–IIIA non‐small cell lung cancer (NSCLC). Here, we report a subgroup analysis in patients enrolled in Japan. Eligible patients had complete resection of histologically or cytologically confirmed stage IB (tumors ≥4 cm)–IIIA NSCLC. Upon completing 1–4 cycles of adjuvant cisplatin‐based chemotherapy, patients were randomized 1:1 to receive atezolizumab (fixed dose of 1200 mg every 21 days; 16 cycles or 1 year) or BSC. The primary endpoint of the global IMpower010 study was investigator‐assessed disease‐free survival, tested hierarchically first in patients with stage II–IIIA NSCLC whose tumors expressed programmed death‐ligand 1 (PD‐L1) on ≥1% of tumor cells, then in all randomized patients with stage II–IIIA NSCLC, and finally in the intention‐to‐treat (ITT) population (stage IB–IIIA NSCLC). Safety was evaluated in all patients who received atezolizumab or BSC. The study comprised 149 enrolled patients in three populations: ITT (n = 117; atezolizumab, n = 59; BSC, n = 58), all‐randomized stage II–IIIA (n = 113; atezolizumab, n = 56; BSC, n = 57), and PD‐L1 tumor cells ≥1% stage II–IIIA (n = 74; atezolizumab, n = 41; BSC, n = 33). At the data cutoff date (January 21, 2021), a trend toward disease‐free survival improvement with atezolizumab vs BSC was observed in the PD‐L1 tumor cells ≥1% stage II–IIIA (unstratified hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.25–1.08), all‐randomized stage II–IIIA (unstratified HR, 0.62; 95% CI, 0.35–1.11), and ITT (unstratified HR, 0.61; 95% CI, 0.34–1.10) populations. Atezolizumab‐related grade 3/4 adverse events occurred in 16% of patients; no treatment‐related grade 5 events occurred. Adjuvant atezolizumab showed disease‐free survival improvement and a tolerable toxicity profile in Japanese patients in IMpower010, consistent with the global study results.