IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

High-Performance Solar-Blind Photodetector Based on (010)-Plane ß-Ga2O3 Thermally Oxidized from Nonpolar (110)-Plane GaN.

A high-performance planar structure metal-semiconductor-metal-type solar-blind photodetector (SBPD) was fabricated on the basis of (010)-plane ß-Ga2O3 thermally oxidized from nonpolar (110)-plane GaN. A full width at half maximum of 0.486° was achieved for the X-ray rocking curve associated with (020)-plane ß-Ga2O3, which is better than most reported results for the heteroepitaxially grown (-201)-plane ß-Ga2O3. As a result of the relatively high crystalline quality, a dark current as low as 6.30 × 10-12 A was achieved at 5 V, while the photocurrent reached 1.86 × 10-5 A under 254 nm illumination at 600 µW/cm2. As a result, the photo-to-dark current ratio, specific detectivity, responsivity, and external quantum efficiency were calculated to be 2.95 × 106, 2.39 × 1012 Jones, 3.72 A/W, and 1815%, respectively. Moreover, the SBPD showed excellent repeatability and stability in the time-dependent photoresponse characteristics with fast relaxation time constants for the rise and decay processes of only 0.238 and 0.062 s, respectively. This study provides a promising approach to fabricate the device-level (010)-plane ß-Ga2O3 film and a new way for the epitaxial growth of (010)-plane ß-Ga2O3 and (110)-plane GaN as mutual substrates.

PD-L1 mRNA derived from tumor-educated platelets as a potential immunotherapy biomarker in non-small cell lung cancer.

Background: To date, the role of programmed death ligand-1 (PD-L1) messenger RNA (mRNA) derived from tumor-educated platelets (TEPs) has not been well investigated in patients with advanced non-small cell lung cancer (NSCLC). A few reports have examined whether mRNA in TEPs can predict the clinical responses of patients with advanced NSCLC following immunotherapy. This study aimed to identify novel biomarkers to improve the clinical benefits and outcomes of NSCLC patients. Methods: Advanced NSCLC patients receiving a combination of immunotherapy and chemotherapy, or immunotherapy alone as a first- or second-line treatment at the Fudan University Shanghai Cancer Center were enrolled in this study. All the patients had wild-type epidermal growth factor receptor/anaplastic lymphoma kinase. The patients were enrolled in clinical trials for immune checkpoint inhibitors (ICIs), including nivolumab, pembrolizumab, atezolizumab, durvalumab, tremelimumab, and camrelizumab. Tumoral PD-L1 expression was tested by immunohistochemistry (PD-L1 22C3 pharmDx kit, Agilent, Santa Clara, CA, USA) in archived tissue samples, when available, to calculate the tumor proportion scores (TPSs). RNA and exosomal RNA of blood were isolated before immunotherapy using the Yunying RNA extraction kit (Yunying Medicine, Shanghai, China). The concentration and quality of the RNA was determined using a Qubit fluorometer (Life Technologies, Carlsbad, CA, USA). Finally, we analyzed the predictive value of TEP-derived PD-L1 mRNA expression and association with the level of the tumoral PD-L1 expression. Results: In total, 72 patients were enrolled in this study. Most of the patients were male (n=54, 75.0%), had adenocarcinoma (n=49, 68.1%). We found there was no significant correlation between the TEP-derived mRNA of PD-L1 and tumoral PD-L1 expression based on the results of the Pearson Correlation test (r=-0.19, P=0.233). Based on the median of PD-L1 mRNA, 72 patients were divided into a high PD-L1 group and a low PD-L1 group. We found that 19 patients (44.4%) responded to immunotherapy [partial response or progression-free survival (PFS) >6 months] in the high PD-L1 group, but only five patients (13.9%) responded to immunotherapy in the low PD-L1 group (P<0.01). The median PFS of the low PD-L1 group was lower than that of the high PD-L1 group (2.8 vs. 8.3 months, P<0.001). For the patients who were treated with immunotherapy alone (n=64), a similar PFS advantage was observed in the high PD-L1 group (2.8 vs. 8.0 months, P=0.002). Conclusions: This article presented the first data on TEP-derived PD-L1 mRNA in advanced NSCLC patients following immunotherapy and showed the potential advantage of using it as the surrogate biomarker for predicting the PFS and overall survival of patients following immunotherapy.

Spatiotemporal evolution of ultrafast photocarrier dynamics across WS2-ReS2 lateral interface.

2D lateral heterostructures possess atomically sharp lateral interfaces, while understanding of their ultrafast photocarrier dynamics from a spatiotemporal viewpoint is rather elusive. In this study, we have investigated the spatiotemporal evolution of photocarrier dynamics across the 1D lateral interface of a WS2-ReS2 2D lateral heterostructure utilizing femtosecond laser pump-probe. The nontrivial band offset across the 1D lateral interface markedly mediates the spatiotemporal photocarrier transfer and transport processes. Subsequently, a hole accumulation region on the WS2 side and an electron accumulation region (1DEG) on the ReS2 side have been spatially identified by correlating ultrafast photocarrier signals. The measured width of the unilateral depletion region is 1360 ± 160 nm. Our work has provided substantial insights into mediated photocarrier dynamics in the 2D lateral heterostructure, which will benefit explorations in 2D interfacial physics and 2D lateral optoelectronic devices.

Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis.

BACKGROUND: MET and AXL dysregulations are implicated in acquired resistance to EGFR-TKIs in NSCLC. But consensus on the optimal definition for MET/AXL dysregulations in EGFR-mutant NSCLC is lacking. Here, we investigated the efficacy and tolerability of ningetinib (a MET/AXL inhibitor) plus gefitinib in EGFR-mutant NSCLC, and evaluated the clinical relevance of MET/AXL dysregulations by different definitions. METHODS: Patients in this phase 1b dose-escalation/dose-expansion trial received ningetinib 30 mg/40 mg/60 mg plus gefitinib 250 mg once daily. Primary endpoints were tolerability (dose-escalation) and objective response rate (dose-expansion). MET/AXL status were analyzed using FISH and IHC. RESULTS: Between March 2017 and January 2021, 108 patients were enrolled. The proportion of MET focal amplification, MET polysomy, MET overexpression, AXL amplification and AXL overexpression is 18.1 %, 5.6 %, 55.8 %, 8.1 % and 45.3 %, respectively. 6.8 % patients have concurrent MET amplification and AXL overexpression. ORR is 30.8 % for tumors with MET amplification, 0 % for MET polysomy, 24.1 % for MET overexpression, 20 % for AXL amplification and 27.6 % for AXL overexpression. For patients with concurrent MET amplification and AXL overexpression, ningetinib plus gefitinib provides an ORR of 80 %, DCR of 100 % and median PFS of 4.7 months. Tumors with higher MET copy number and AXL expression tend to have higher likelihood of response. Biomarker analyses show that MET focal amplification and overexpression are complementary in predicting clinical benefit from MET inhibition, while AXL dysregulations defined by an arbitrary level may dilute the efficacy of AXL blockade. CONCLUSIONS: This study demonstrates that combined blockade of MET, AXL and EGFR is a feasible strategy for a subset of EGFR-mutant NSCLC. TRIAL REGISTRATION: Chinadrugtrials.org.cn, CTR20160875.

Impact of BMI on the survival outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis.

OBJECTIVES: ICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs. METHODS: A systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I2 tests. RESULTS: Nine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777-1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789-1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760-0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741-0.902, p<0.0001). CONCLUSION: Overweight and obese NSCLC patients tend to achieve prolonged survival time with ICI regimens. Further prospective studies are needed to strengthen the association between ICI outcomes and BMI levels.

Safety and efficacy of atezolizumab in Chinese patients with previously treated locally advanced or metastatic non-small cell lung cancer: An open-label, single-arm, multicenter study.

OBJECTIVES: To evaluate the long-term safety and efficacy of atezolizumab monotherapy in Chinese patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this open-label, single-arm, multicenter study, patients received atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle. The primary endpoint was incidence of atezolizumab-related serious adverse events (SAEs). Secondary endpoints included other safety and efficacy measures. Patients with available tumor tissue and blood samples underwent biomarker analyses. Patients with available tumor biopsies underwent exome sequencing. RESULTS: The safety and evaluable populations included 101 and 97 patients, respectively. Exome sequencing data were available for 31 patients. Median follow-up time was 27.43 months. Atezolizumab-related SAEs and immune-related adverse events occurred in 25.7% and 47.5% of the safety population, respectively, and in the following subgroups: central nervous system metastases (n = 14), 35.7% and 35.7%; squamous NSCLC (n = 39), 33.3% and 53.8%. The 24-month overall survival rate was 37.4%. Median overall survival and progression-free survival by RECIST v1.1 were 15.31 and 2.86 months, respectively; objective response rate was 16.5% in the evaluable population. PRRC2C (odds ratio: 12.780, P = 0.014) and ZMYND8 (odds ratio: 19.963, P = 0.016) gene mutations were significantly enriched in atezolizumab responders vs non-responders. Patients with CD8+ TILs > 10% vs ≤ 10% were significantly more likely to be atezolizumab responders. CONCLUSION: No new safety concerns were raised, and clinically meaningful benefits of atezolizumab monotherapy were shown. The results of the biomarker analyses may guide future therapeutic strategies.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

BACKGROUND: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. METHODS: Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. RESULTS: Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. CONCLUSION: Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. CLINICAL TRIAL REGISTRATION: NCT03037385.

Consensus Statements on Precision Oncology in the China Greater Bay Area.

BACKGROUND: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. METHODS: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. RESULTS: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. CONCLUSION: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Comparative study on left-sided versus right-sided hepatectomy for resectable peri-hilar cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: Peri-hilar cholangiocarcinoma (pCCA) is a unique entity, and radical surgery provides the only chance for cure and long-term survival. But it is still under debate which surgical strategy (i.e., left-sided hepatectomy, LH or right-sided hepatectomy, RH) should be followed and benefitted. METHODS: We performed a systematic review and meta-analysis to analyze the clinical outcomes and prognostic value of LH versus RH for resectable pCCA. This study followed the PRISMA and AMSTAR guidelines. RESULTS: A total of 14 cohort studies include 1072 patients in the meta-analysis. The results showed no statistical difference between the two groups in terms of overall survival (OS) and disease-free survival (DFS). But compared to the LH group, the RH group exhibited more employment of preoperative portal vein embolization (PVE), higher rate of overall complications, post-hepatectomy liver failure (PHLF), and perioperative mortality, while LH was associated with higher frequency of arterial resection/reconstruction, longer operative time, and more postoperative bile leakage. There was no statistical difference between the two groups in terms of preoperative biliary drainage, R0 resection rate, portal vein resection, intraoperative bleeding, and intraoperative blood transfusion rate. CONCLUSIONS: According to our meta-analyses, LH and RH have comparable oncological effects on curative resection for pCCA patients. Although LH is not inferior to RH in DFS and OS, it requires more arterial reconstruction which is technically demanding and should be performed by experienced surgeons in high-volume centers. Selectin of surgical strategy between LH and RH should be based on not only tumor location (Bismuth classification) but also vascular involvement and future liver remnant (FLR).

BRF2 is mediated by microRNA-409-3p and promotes invasion and metastasis of HCC through the Wnt/ß-catenin pathway.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Its invasiveness and ability to metastasize contributes to an extremely high patient mortality. However, the molecular mechanisms that underlie the characteristics of HCC progression are not well understood. BRF2 has been shown to be an oncogene in a number of tumors; however, its role in HCC has not yet been thoroughly examined. In this study, we identified and validated BRF2 as an oncogene in HCC, providing a new insight into HCC pathogenesis and therapeutic possibilities. We showed that BRF2 expression was significantly upregulated in HCC cell lines and tissues, while BRF2 depletion suppressed HCC metastasis and invasion. We then examined the upstream regulation of BRF2 and identified miR-409-3p as being predicted to bind to the 3' UTR of BRF2. We used a luciferase activity assay and functional verification to show that BRF2 is downregulated by miR-409-3p. Finally, we used bioinformatic analysis to show that BRF2 may be related to early HCC development through the Wnt/ß-catenin signaling pathway.

NEPTUNE China cohort: First-line durvalumab plus tremelimumab in Chinese patients with metastatic non-small-cell lung cancer.

OBJECTIVES: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. MATERIALS AND METHODS: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). RESULTS: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. CONCLUSIONS: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals.

Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial.

INTRODUCTION: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. METHODS: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. RESULTS: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

Label-Free Sensing of Biomolecular Adsorption and Desorption Dynamics by Interfacial Second Harmonic Generation.

Observing interfacial molecular adsorption and desorption dynamics in a label-free manner is fundamentally important for understanding spatiotemporal transports of matter and energy across interfaces. Here, we report a label-free real-time sensing technique utilizing strong optical second harmonic generation of monolayer 2D semiconductors. BSA molecule adsorption and desorption dynamics on the surface of monolayer MoS2 in liquid environments have been all-optically observed through time-resolved second harmonic generation (SHG) measurements. The proposed SHG detection scheme is not only interface specific but also expected to be widely applicable, which, in principle, undertakes a nanometer-scale spatial resolution across interfaces.

Multiplexed imaging of tumor immune microenvironmental markers in locally advanced or metastatic non-small-cell lung cancer characterizes the features of response to PD-1 blockade plus chemotherapy.

BACKGROUND: Although programmed cell death 1 (PD-1) blockade plus chemotherapy can significantly prolong the progression-free survival (PFS) and overall survival (OS) in first-line settings in patients with driver-negative advanced non-small-cell lung cancer (NSCLC), the predictive biomarkers remain undetermined. Here, we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy. METHODS: Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone. Tumor immune microenvironmental markers, including PD-1 ligand (PD-L1), CD8, CD68, CD4 and forkhead box P3, were assessed using multiplex immunofluorescence (mIF) assays. Kaplan-Meier curves were used to determine treatment outcome differences according to their expression status. Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations. RESULTS: Responders had significantly higher CD8/PD-L1 (P = 0.015) or CD68/PD-L1 co-expression levels (P = 0.021) than non-responders in the camrelizumab plus chemotherapy group, while no difference was observed in the chemotherapy group. Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS (P = 0.002, P = 0.024; respectively) and OS (P = 0.006, P = 0.026; respectively) than those with low co-expression in camrelizumab plus chemotherapy group. When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification, significantly better PFS (P = 0.003) and OS (P = 0.032) were observed in high co-expression subgroups. The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features. Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression, the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups (both 13.0% vs. 0.0%, P = 0.023). Notably, enriched PI3K (P = 0.012) and cell cycle pathway (P = 0.021) were found in the CD8/PD-L1 co-expression group. CONCLUSION: Tumor immune microenvironmental marker expression, especially CD8/PD-L1 or CD68/PD-L1 co-expression, was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.

An open label, safety study of Asian patients with advanced non-small-cell lung cancer receiving second-line nivolumab monotherapy (CheckMate 870).

Background: Nivolumab has been approved in China as second-line treatment for advanced non-small-cell lung cancer (NSCLC) via weight-based infusion, based on the CheckMate 078 study. We investigated the safety and efficacy of 240 mg flat-dose nivolumab in patients with advanced NSCLC, including those with hepatitis B virus (HBV) and epidermal growth factor receptor (EGFR) mutation/ALK receptor tyrosine kinase (ALK) translocation due to high prevalence in China. Methods: CheckMate 870 was a single-arm, open-label, phase IIIb trial in Asian (primarily Chinese) patients with previously treated advanced NSCLC. Patients received flat-dose nivolumab 240 mg every 2 weeks (Q2W) for up to 2 years. The primary endpoint was the incidence and severity of treatment-related select adverse events (TRsAEs) in non-HBV patients; secondary and exploratory endpoints included severity of high-grade TRsAEs in HBV-infected patients, and safety, efficacy and patient-reported outcomes (PROs) in the whole population. Results: Out of 404 patients enrolled, 400 received treatment. Median (standard deviation) age was 60.5 (8.68) years and the majority were male (78.5%). At a median follow-up of 37.6 months, no Grade 5 TRsAEs were reported, and the frequency of Grade 3-4 TRsAEs was low (0.0-5.9%) in non-HBV and HBV NSCLC patients. Median overall survival (OS) and progression-free survival (PFS) in all treated patients were 14.7 (12.3-18.1) and 3.6 (2.3-3.8) months, respectively. Median OS was 14.2 (12.3-18.1) and 22.3 (10.0-NA) months for non-HBV and HBV-infected patients, 19.3 (11.2-31.7) and 13.7 (11.5-18.1) months for EGFR-positive and wild-type subgroups, and 19.3 (12.9-23.5) and 13.3 (10.9-17.7) months for those with programmed death-ligand 1 (PD-L1) expression ⩾1% and <1%, respectively. No notable changes from baseline were observed in PROs throughout the study. Conclusion: Nivolumab 240 mg infusion Q2W was well tolerated, efficacious, and maintained health status and quality of life in Asian patients with previously treated advanced NSCLC regardless of HBV, EGFR, or PD-L1 status.

Effective switching of an all-solid-state mode-locked laser by a graphene modulator.

Although sophisticated novel saturable absorber materials are available for the development of ultrafast lasers, innovative approaches and devices play an increasingly important role in continuously adjusting mode-locked lasers with electrical gating. In this study, electrically switched operational regimes of an Nd:YVO4 all-solid-state mode-locked laser with a high modulation ratio (from 900 ns to 15 ps) are demonstrated for the first time. The laser can automatically switch multiple operation regimes with the assistance of electrical signals using techniques such as Q-switching, Q-switched mode-locking (QML), and continuous-wave mode-locking (CWML). The device is operated at an ultralow electrical modulation power (0.1 nW) to generate sub 15 ps pulses with a high average output power (as much as 800 mW) from a mode-locked laser operating at 1064 nm. The results verify the reversible switching of the operational regimes from QML to CWML and provide a basis for exploring their applications in electro-optical devices.

Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial.

Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion-positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35-77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib's potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors.

Sarcopenia Was a Poor Prognostic Predictor for Patients With Advanced Lung Cancer Treated With Immune Checkpoint Inhibitors.

Background: It remains not well known whether skeletal muscle mass (SMM) loss has any impact on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer. We aimed to evaluate the association between SMM and clinical outcome of patients with advanced lung cancer receiving ICIs as first line or second line. Materials and Methods: From March 1st, 2019 to March 31st, 2021 at our hospital, 34 patients with advanced lung cancer treated with first-line or second-line ICIs were enrolled retrospectively. The estimation of skeletal muscle index (SMI) for sarcopenia was assessed at the level of the third lumbar vertebra (L3) on computed tomography (CT) images obtained within 4 weeks before initiation of ICIs treatment. The impact of sarcopenia (low SMI) on progression free survival (PFS) was analyzed using Kaplan-Meier method and log-rank tests. The effect of various variables on PFS was evaluated using Cox proportional hazards regression model with univariate and multivariate analysis. The impact on treatment response including objective response rate (ORR) and disease control rate (DCR) and immunotherapy related adverse events (irAEs) between patients with and without sarcopenia was compared by the chi-squared test. The comparison of SMI value between patients with objective response (OR), disease control (DC) and those without OR and DC was used student t-test or Mann-Whitney U test. Results: Both in univariate and multivariate analysis, sarcopenia and treatment lines were the predictive factors for PFS (p < 0.05). Patients with sarcopenia had significantly shorter PFS than that of non-sarcopenic ones [6.57 vs. 16.2 months, hazard ratios (HR) = 2.947 and 3.542, and 95% confidence interval (CI): 1.123-13.183 and 1.11-11.308, p = 0.022 and 0.033]. No significant difference in ORR and irAEs was found. Patients with sarcopenia had lower DCR than those without sarcopenia. The mean SMI value of DCR group and non-DCR group was 32.94 ± 5.49 and 44.77 ± 9.06 cm2/m2, respectively (p = 0.008). Conclusion: Sarcopenia before immunotherapy might be a significant predictor for poor prognosis including shorter PFS and lower DCR in patients with advanced lung cancer treated with ICIs as first line or second line.

Multiparameter measurement sensor based on no-core fiber.

This paper proposes a no-core-single-mode-no-core Mach-Zehnder fiber sensor. In this sensor, two no-core fibers serve as input and output couplers, and the middle single-mode fiber serves as a sensing arm. Using finite element simulation and theoretical analysis, the optimal length of the couplers and the sensing arm are determined. High-order modes excited by no-core optical fiber propagate through the cladding of the single-mode fiber, which is affected by the ambient temperature and applied force. The trough of different interference orders of the transmission spectrum is selected as a research object to realize the measurement of curvature and temperature, strain and temperature with the sensing matrix.