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Background: First-line treatments for nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have been evaluated in various clinical trials. However, it remains unclear which is the optimal treatment. Methods: A Bayesian network meta-analysis was used to assess the efficacy and safety profile of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, erlotinib plus bevacizumab and pemetrexed/carboplatin, or pemetrexed alone plus gefitinib. Literature was sourced from electronic databases. Data regarding objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs), treatment-related adverse event grades 3–5 (TRAE 3–5), specific TRAEs [diarrhea, rash, and elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT)] were extracted. The regimens were then ranked using the surface under the cumulative ranking curve (SUCRA). Results: A total of 19 studies involving 4607 EGFR-mutant NSCLC patients were analyzed. In regards to efficacy, pemetrexed/carboplatin (PC) plus gefitinib was superior in ORR and OS to chemotherapy and first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). All the TKI-based regimens had equivalent DCR and PFS. Patients with the L858R mutation treated with PC plus gefitinib achieved a better outcome than most EGFR TKI-related groups (except osimertinib) in the PFS subgroup. In regards to safety, no statistical significance for TRAEs was observed among the eight treatments. In regards to SUCRA, PC plus gefitinib ranked first in terms of PFS, OS, and TRAE grades 3–5. Conclusions: Pemetrexed/carboplatin plus gefitinib is a promising treatment option for EGFR-mutant NSCLC patients in the first-line setting.

Pembrolizumab monotherapy has become the preferred treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and a programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of at least 50%. However, little is known about the value of adding chemotherapy to pembrolizumab in this setting. Therefore, we performed an indirect comparison for pembrolizumab plus chemotherapy versus pembrolizumab, using the frequentist methods. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Data were retrieved from randomized trials comparing pembrolizumab plus chemotherapy or pembrolizumab monotherapy against chemotherapy. Five trials involving 1289 patients were included. Direct meta-analysis showed that both pembrolizumab plus chemotherapy (ORR: relative risk (RR) 2.16; PFS: hazard ratio (HR) 0.36; OS: HR 0.51) and pembrolizumab alone (ORR: RR 1.33; PFS: HR, 0.65; OS: HR 0.67) improved clinical outcomes compared with chemotherapy. Indirect comparison showed that pembrolizumab plus chemotherapy was superior to pembrolizumab alone, in terms of ORR (RR 1.62, 1.18–2.23) and PFS (HR 0.55, 0.32–0.97). A trend towards improved OS was also observed (HR 0.76, 0.51–1.14). In conclusion, the addition of chemotherapy to pembrolizumab further improves the outcomes of patients with advanced NSCLC and a PD-L1 TPS of at least 50%. Electronic supplementary material The online version of this article (10.1186/s40425-019-0600-6) contains supplementary material, which is available to authorized users.

Theranostics based on multifunctional nanoparticles (NPs) is a promising field that combines therapeutic and diagnostic functionalities into a single nanoparticle system. However, the major challenges that lie ahead are how to achieve accurate early diagnosis and how to develop efficient and noninvasive treatment. Sonodynamic therapy (SDT) utilizing ultrasound combined with a sonosensitizer represents a novel noninvasive modality for cancer therapy. Different ultrasound frequencies have been used for SDT, nevertheless, whether the effect of SDT can enhance synergistic HIFU ablation remains to be investigated.We prepared a nanosystem for codelivery of a sonosensitizer (methylene blue, MB) and a magnetic resonance contrast agent (gadodiamide, Gd-DTPA-BMA) based on hydrophilic biodegradable polymeric NPs composed of poly (lactic-co-glycolic acid) (PLGA). To enhance accumulation and penetration of the NPs at the tumor site, the surface of PLGA NPs was decorated with a tumor-homing and penetrating peptide-F3 and polyethylene glycol (PEG). The physicochemical, imaging and therapeutic properties of F3-PLGA@MB/Gd and drug safety were thoroughly evaluated both in vitro and in vivo. F3-PLGA@MB/Gd was evaluated by both photoacoustic and resonance imaging.F3-PLGA@MB/Gd NPs exhibited higher cellular association than non-targeted NPs and showed a more preferential enrichment at the tumor site. Furthermore, with good drug safety, the apoptosis triggered by ultrasound in the F3-PLGA@MB/Gd group was greater than that in the contrast group.F3-PLGA@MB/Gd can work as a highly efficient theranostic agent, and the incorporation of targeted multimodal and combined therapy could be an encouraging strategy for cancer treatment.

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood. Experimental Design: We performed genomic profiling of 78 patients with non–small cell lung cancer (NSCLC) who underwent anti–PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response. Results: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32–4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09–4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types. Conclusions: We identified novel genomic biomarkers that were predictive of response to anti–PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.

BackgroundPrior cancer is a common exclusion criterion in nasopharyngeal carcinoma (NPC) trials. However, whether a prior cancer diagnosis affects trial outcomes is still unknown. We aimed to determine the impact of prior cancer on survival in NPC.MethodsWe identified patients diagnosed with NPC between 2004 and 2009 in the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by chi-squared test and t-test as appropriate. Propensity score-adjusted Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of prior cancer on overall survival (OS).ResultsAmong 3,131 eligible NPC patients, 349 (11.15%) patients had a history of prior cancer. The Kaplan-Meier curves did not show a statistically significantly different OS (p=0.19). Subgroup analyses stratified by timing of prior cancer and AJCC TNM stage of index cancer displayed the same tendency, prior cancer didn’t adversely affect OS compared with patients without prior cancer (p>0.05). Furthermore, in propensity score–adjusted COX models analysis, patients with prior cancer had the same/non-inferior OS (hazard ratio [HR] = 1.12, 95% confidence interval= 0.88 to 1.42).ConclusionsAmong patients with nasopharyngeal carcinoma, prior cancer does not convey an adverse effect on clinical outcomes, regardless of the timing of prior cancer and AJCC TNM stage of index cancer. Broader inclusion trial criteria could be adopted in nasopharyngeal carcinoma patients with a history of prior cancer. However, further studies are still needed to confirm.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin’s effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression., Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.

Background: Dual blockade of the EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced anti-tumor efficacy versus a (v)EGFR inhibitor alone. This phase I study evaluated the safety, pharmacokinetic (PK) profile and antitumor activity of apatinib, an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI), plus gefitinib as a first-line treatment for EGFR-mutant advanced NSCLC. Methods: Advanced non-squamous NSCLC patients with the EGFR 19 deletion or the 21 L858R mutation who met this study's eligibility criteria were included. There were two cohorts. Cohort A: apatinib 500mg + gefitinib 250mg. Cohort B: apatinib 250mg + gefitinib 250mg. The primary endpoint was safety profile. Other endpoints included PK analysis, objective response rate (ORR) and progression free survival (PFS). Exploratory analysis was conducted using next generation sequencing of plasma circulating-tumor DNA with samples collected at baseline, best of response and after progression disease. Findings: Between July 2016 and April 2017, 13 patients with NSCLC were enrolled in this study. Six patients were enrolled in Cohort A and seven in Cohort B. Most adverse events (AEs) were grade 1-2 and the treatment-related AEs (TRAEs) were similar in both cohorts: rash (100% v 71.4%), diarrhea (66.7% v 71.4%), hypertension (66.7% v 71.4%), proteinuria (66.7% v 42.9%), and hand-foot skin reaction (33.3% v 28.6%). The area under the plasma concentration-time curve (AUC) for the steady state of apatinib was 2864.73 ± 2605.54 ng/ml*h in Cohort A and 2445.09 ± 1550.89 ng/ml*h Cohort B. Median follow-up was 29.7 months. The ORR was 80.0% and the median PFS was 19.2 months in Cohort and it 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a longer PFS compared with those with a detected concomitant mutation (20.99 months v 13.21 months, P=0.0624). The EGFR-T790M mutation remained the dominant resistance mechanism. Interpretation: Apatinib (500mg) plus gefitinib (250mg) had a tolerable safety profile and promising antitumor activity for EGFR-mutant NSCLC patients in the first-line setting. Phase III trials of apatinib (500mg) plus gefitinib (250mg) are warranted. Funding: This work was supported by National Key R&D Program of China (Grant number: 2016YFC0905500, 2016YFC0905503), The Science and Technology Planning Project of Guangdong Province of China (Grant number: 2017B020227001)，Natural Science Foundation of Guangdong Province of China (Grant number: 2018A0303130243) and The 5010 Clinical Research Foundation of Sun Yat-sen University (Grant number: 2016001). Li Zhang has received research support from the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12020101 to J.D.). Yan Huang has received research support from Science and Technology Program of Guangzhou (201704020072). Yunpeng Yang was supported by Outstanding Young Talents Program of Sun Yat-sen University Cancer Center (16zxyc03) and Central Basic Scientific Research Fund for Colleges-Young Teacher Training Program of Sun Yat-sen University (17ykpy85). Declaration of Interest: All authors declare no competing interests. Ethical Approval: This trial has been approved by the institutional review boards (ID: 2016-FXY-023) and the independent ethics committees of Sun Yat-sen University Cancer Center (Ethic approval ID: 5010-2016-03). And other participating centers have also obtained the approval from their institutional review boards/independent ethics committees before enrollment. All patients will be required to sign the informed consent form before enrollment.

Additional file 1: Table S1. Details of 6 patients receiving steroids for irAE.

Figure S1. The correlations of mutation numbers between panel sequencing and WES in three cohorts. (A) TCGA-LUAD, (B) TCGA-LUSC, (C) Geneplus. Abbreviations: TCGA The Cancer Genome Atlas, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, WES wholeexome sequencing. (PDF 124 kb)

Figure S3. The landscape of genomic alterations in enrolled non-small cell lung cancer patients. Integrated genomic data for 181 regions from 32 NSCLC patients. Overall number of mutations, as well as pathological type and typical mutant driver for each sample, were shown at the top. The group at the top and the patient No. at the bottom indicate contiguous regions from each patient. The percentage of NSCLC regions with an alteration was shown on the left in the order of the mutated genes as listed to the right of the panel. (PDF 276 kb)

Figure S2. The consistency of mutation numbers, ITH and phylogenetic trees between panel sequencing and WES in 4 randomly selected patients. (A) mutation numbers, (B) ITH, (C) phylogenetic trees. Abbreviations: ITH intratumor heterogeneity, WES wholeexome sequencing. (PDF 259 kb)

Supplemental material, Supplemental_Data_2_Supplemental_Table_and_Figure_changes_marked_yellow for Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis by Zhonghan Zhang, Kangmei Zeng, Shen Zhao, Yuanyuan Zhao, Xue Hou, Fan Luo, Feiteng Lu, Yaxiong Zhang, Ting Zhou, Yuxiang Ma, Yunpeng Yang, Wenfeng Fang, Yan Huang, Li Zhang and Hongyun Zhao in Therapeutic Advances in Medical Oncology

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH. Electronic supplementary material The online version of this article (10.1186/s12943-019-0939-9) contains supplementary material, which is available to authorized users.

Figure S1. The correlations of TMB value between panel sequencing and WES in published databases. Figure S2. The comparison of multi-region tTMB among different NSCLC subtypes. Figure S3. The comparisons and overlaps of tumor-derived mutational profiles among tumor tissues in each region and the corresponding ctDNA. (PDF 1439 kb)

Figure S5. The phylogenetic tree for each patientstratified by different non-small cell lung cancer subtype. Lengths of trunks and branches are proportional to the numbers of mutations acquired. Trunks and branches are shown in different colors. Genes with recurrent putative driver mutations are indicated beside the corresponding branches or trunks. The total number of mutations (n), patient No., and evolution pattern (linear [circle] or branch evolution [star]) are indicated below each tree. TNM stage of each patient is indicated by the colored track above each row of trees. (PDF 389 kb)

Supplementary Methods. (DOCX 21 kb)

Table S2. Clinical characteristics of the enrolled non-small cell lung cancer patients. (DOCX 14 kb)

Table S1. Clinical characteristics of the enrolled 32 NSCLC patients. Table S2. List of target regions of the pan-cancer 1021-gene panel. (DOCX 43 kb)

Figure S4. The comparison of commonly mutated genes in non-small cell lung cancer among three different cohorts. (PDF 59 kb)

Figure S6. Driver dominance score. Driver dominance score measures driver self-sufficiency for each driver gene calculated across 32 patients. It is plotted against the fraction of patients carrying the mutated driver. (PDF 179 kb)

Supplementary Methods. (DOCX 24 kb)

Supplemental Methods. Search strategies and number of studies yielded from each database. Table S1. Quality assessment: risk of bias by Cochrane Collaborationâ s tool. Figure S1. Trial Selection Process (PDF 337 kb)

Table S1. List of target regions of the pan-cancer 1021-gene panel. (DOCX 37 kb)

e15553 Background: PD-1 antibody monotherapy has shown durable response in colorectal cancer (CRC) patients (pts) with microsatellite instability (MSI) high status, who account for only 10–15% of all CRC pts. Preclinical studies revealed that inhibition of MAPK pathway with MEK inhibitors can increase T-cell infiltration into tumors and therefore might enhance the antitumor activity of immune checkpoint inhibitor. Thus, this study was conducted to evaluate the safety and antitumor activity of SHR7390, a MEK1/2 inhibitor, plus camrelizumab (anti-PD-1) in pts with CRC. Methods: In this single-arm, open-label, phase I study, pts with treatment-refractory advanced or metastatic CRC were enrolled to receive SHR7390 in an accelerated titration scheme at doses of 0.125, 0.25, and 0.5 mg orally qd, plus camrelizumab at a fixed dose of 200 mg IV q2w. Eligible pts were given a single dose of SHR7390, observed for 7–10 days, and then treated continuously with SHR7390 and camrelizumab in 28-day treatment cycles until disease progression, intolerable toxicities, or withdrawal of consent. A recommended dose for expansion was determined based on the safety and tolerability of the dose escalation stage. The primary endpoints were dose limiting toxicity (DLT) and maximum tolerated dose (MTD). This study is registered with ClinicalTrials.gov, number NCT03182673. Results: At data cutoff on May 30, 2020, 22 pts were enrolled. The median follow-up duration was 6 months. Seven pts had received ≥3 lines of prior treatment. MSI status were available in 21 pts (MSS/MSI-L, n = 18; MSI-H, n = 3). There were two pts each in the SHR7390 0.125 and 0.25 mg cohorts, and 0.5 mg cohort was expanded to 18 pts. One DLT (grade 3 rash) was reported in a pt in the 0.5 mg cohort and the MTD was not reached. Grade 3–4 treatment-related adverse events (TRAEs) were rash (n = 4), increased lipase, oedema peripheral, face oedema, and anemia (n = 1 each). One pt reported a grade 5 TRAE (increased intracranial pressure). Five pts (23%) achieved partial response (0.125 and 0.25 mg cohorts, n = 1 each; 0.5 mg cohort, n =3), including one out of three pts with MSS/MSI-L & BRAF mutant tumors (response lasting 13 months), one out of 15 pts with MSS/MSI-L & BRAF wild type tumors (response lasting 8 months), and all three pts with MSI-H tumors (responses lasting 31, 11, and 10 months, respectively). Three pts with MSS/MSI-L achieved stable disease, and the overall disease control rate reached 36%. Conclusions: SHR7390 plus camrelizumab showed a tolerable safety profile. Preliminary clinical activity was reported regardless of BRAF and MSI status, and future studies are warranted to further evaluate these results. Clinical trial information: NCT03182673.

Friction surfacing (FS) is one of the ideal solid-state cladding processes. Intermetallic particles were redistributed randomly after FS, and the microstructure of the coating was highly refined due to the continuous dynamic recrystallization, which also resulted in the evolution of the textures, as examined by scanning electron microscope and electron backscatter diffraction. The corrosion resistance of the coating was improved, which was tested by potentiodynamic polarization, electrochemical impedance spectroscopy and accelerated immersion. Different intermetallic distributions led to the different electrochemical processes in corrosion. The highly refined microstructure contributed to a strengthened passive film.

The lead‑tin solder has already been replaced by the lead-free solder gradually in most industrial applications according to the RoHS restriction. However, the reliability test duration and the failure mechanism of lead-free solders are always a concerned problem that must be addressed when designing a new electronic product. In this paper, a thermo-electric accelerated test (TEC) method, as well as its corresponding failure mechanism, was discussed to consider the feasibility of reducing the reliability test duration. Compared with the traditional thermal cycling (TC) test, the lifetime of the component boards decreased apparently in the thermo-electric accelerated test, including both the time-to-failure and the cycles-to-failure based on the Weibull distribution. The main failure mode in TEC test is the cracks propagating along the boundaries of the recrystallized grains at the corner of a solder joint, similar as the TC test. The higher acceleration rate of TEC test might be related to the intermetallic evolution both at the interface and in the solder bulk. Thus, it could be concluded that the thermo-electric test would be a valuable option to achieve highly accelerated reliability test for electronic products.

Laser welding-brazing of AA6061 alloys and press-hardened 22MnB5 steel in lap configuration was carried out with Zn-Al15 filler metal. The processing window in different defocused distances was investigated and its influence on microstructure and mechanical properties of Al/steel dissimilar joints was explored. The results revealed that good appearances could be acquired in different processing windows with variation of defocused distances. The processing window was enlarged with increase of laser spot diameters, from laser power of 2.1–2.3 kW in defocused distance of +20 mm (laser spot diameter of 1.4 mm) to 2.8–3.6 kW in defocused distance of +40 mm (laser spot diameter of 2.4 mm). The thickness of interfacial intermetallic layer increased gradually from 0.47 to 1.86 μm for defocused distance of +20 mm to 3.76–11.03 μm of +40 mm. The newly formed phase at the interface at defocused distance of +20 mm was identified as Fe2(Al, Zn)5 and those were identified as the mixture of Fe2(Al, Zn)5 and FeZn10 when the defocused distances were +30 mm and +40 mm. The tensile-shear test of laser welded-brazed joints produced in various processing windows showed two types of fracture modes occurred. The interfacial failure appeared with the defocused distance less than +30 mm. The maximum fracture load reached 2793 N, representing 84.6% joint efficiency in regard to aluminum alloys. However, when the defocused distance increased to +40 mm, the maximum tensile-shear force decreased to 2242 N and failure occurred in the softening region of HAZ in aluminum alloy caused by effect of large laser irradiation. At larger defocused distance, the weak position of the dissimilar joints would transfer from the interface to the HAZ of the aluminum alloy, resulting in a bottleneck to improve mechanical property of joints.

With the popularity of smartphones, many people use mobile phones to provide personalised recommendations in a smart city. Aggregate diversity is defined as recommending different categories of ite...

Highlights • A total of 346 patients were enrolled in this study. • Severe rash (grade 3&4) did not gain more bonification compare to grade 1&2 rash. • Gefitinib and its four metabolites were detected in patients’ plasma. • A specific and sensitive predictive model were established based on pharmacometabolomic profiling and pharmacogenomics approach., Background Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed. Methods The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort. Results The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958–11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067–72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032–33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710–0.951). Conclusions Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.

Background Small cell lung cancer (SCLC) is the most fatal malignancy for which more effective therapies are urgently needed. Overexpression of myeloid cell leukemia-1 (Mcl-1) has been demonstrated to be one of the most common genetic alterations among different types of tumor/cancer, which induces resistance against various anti-cancer therapies including cisplatin. The study aimed to explore the role of Mcl-1 in the prognosis and resistance to anti-cancer therapy in patients with SCLC. Methods Patients with SCLC were recruited from those enrolled/treated in Sun Yat-sen University Cancer Center. Their specimens were collected for immunohistochemical evaluation. We compared the baseline characteristics, response to chemotherapy and overall survival (OS) of the patients with different expression levels of Mcl-1. Results The expression level of Mcl-1 was significantly lower in patients with limited stage SCLC than in those with extensive stage SCLC (P=0.014). Based on the median value of Mcl-1 expression level, the patients were divided into high and low Mcl-1 groups, respectively. Univariate analysis revealed that low Mcl-1 expression was associated with a significant improvement in OS, with a hazard ratio (HR) of 0.538. Multivariate analysis confirmed the independent prognostic value of Mcl-1 expression level (P=0.014). Moreover, we found a significantly close relationship between higher Mcl-1 expression level and shorter time to progression (TTP) of the patients received chemotherapy (P=0.040). Conclusions Our findings demonstrated that Mcl-1 expression level was a prognostic biomarker for survival outcomes and cancer progression in the patients with SCLC. Thus, it could be used as a valuable biomarker in identifying those patients with high risk of treatment failure.

AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non–small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation. Mol Cancer Ther; 15(11); 2586–97. ©2016 AACR.

An amorphous coating was synthesized on low carbon steel by laser cladding Co-based self-fluxed alloy powder successfully. The microstructure, thermal stability property of the fabricated amorphous coating was investigated. The thickness of amorphous coating was 400 µm while the dendrite zone was only 10 µm height near the interface. The volume fraction of amorphous was 85.1% approximately. DSC curve showed that the glass transition temperature and the crystallization temperature were 298 °C and 342 °C, respectively. The supercooling liquid region was 44 °C which ensured the high thermal stability of amorphous coating against crystallization.

Skin rash, diarrhea and hepatotoxicity are the most common toxicities of Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study investigated the effects of genetic polymorphisms of drug target, metabolizing enzymes and transporters on Gefitinib toxicities. Thirty single-nucleotide polymorphisms, including EGFR, cytochromes P450 and ATP-binding cassette (ABC), were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform in 59 non-small cell lung cancer patients treated with Gefitinib. Correlation analyses were performed to evaluate their effects on Gefitinib-induced toxicities. ABCB1 rs1128503 TT genotype was a significant high-risk determinant of both skin rash and diarrhea, with 15.78- and 10.78-fold of incident risk increased, respectively. (odds ratio (OR)=15.78, 95% confidence interval (CI) 2.01-124.1, P=0.0087; OR=10.78, 95% CI 1.54-75.40, P=0.0166 vs non-TT genotypes). Patients with ABCB1 rs1128503 TT genotype had greater risk of skin rash and diarrhea. Therefore, polymorphism analyses of ABCB1 might be beneficial to optimize Gefitinib treatment.

// Qilong Ma 1,* , Wengao Liu 1,* , Ran Jia 1,* , Hao Long 1 , Lanjun Zhang 1 , Peng Lin 1 , Hongyun Zhao 1 and Guowei Ma 1 1 Sun Yat-sen University Cancer Center, Guangdong Esophageal Cancer Institute, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Hongyun Zhao, email: // Guowei Ma, email: // Keywords : alcohol consumption, postoperative survival, esophageal carcinoma, Chinese cohort Received : October 11, 2015 Accepted : March 31, 2016 Published : April 15, 2016 Abstract Background: The association between esophageal cancer and prediagnosis alcohol consumption is well established. However, evidence that prediagnosis alcohol consumption affects postoperative survival in patients with lymph node-negative esophageal squamous cell carcinoma (ESCC) is lacking. We conducted a retrospective study on the effect of prediagnosis alcohol consumption on the postoperative survival of patients with lymph node-negative ESCC in China. Methods: We enrolled 643 ESCC patients with negative lymphatic metastasis who had undergone esophagectomy between 1990 and 2005 at the Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China, and reviewed their demographic, pathologic, preoperative, and cancer outcome data obtained from medical records. These data were analyzed using life table and Kaplan–Meier analyses and multivariate Cox regression. Results: There was a significant reduction in 3- and 5-year survival in drinkers with lymph node-negative ESCC. For drinkers, 3- and 5-year survival rates were 43% and 36% respectively, whereas, for nondrinkers, the corresponding values were 63% and 58%, respectively ( p < 0.05). Multivariate Cox regression showed that drinking ( p = 0.001, relative risk =1.583) was an independent factor for survival in patients with lymph node-negative ESCC. Striated analysis revealed that drinking was an independent factor for survival in patients with stage II A ( p = 0.008, relative risk =1.679), stage IB ( p = 0.044, relative risk=1.517), and well ( p =0.011, relative risk =1.783) and moderately ( p = 0.002, relative risk = 1.915) differentiated ESCC. Conclusions: Prediagnosis alcohol consumption is an independent prognostic factor for postoperative survival in patients with lymph node-negative ESCC.

Two new species, Cretohypna puncta sp. nov. and Cretohypna robusta sp. nov., of Glaphyridae are described and illustrated. These fossils were collected from the Jehol Biota, Lower Cretaceous Yixian Formation of Liutiaogou Village in Ningcheng, Inner Mongolia, China. Up to date, 18 fossil species in 6 genera of Glaphyridae have been reported, among which ten species are from China. Respective keys to the Mesozoic genera of Glaphyridae and to species of Cretohypna Yan, Nikolajev & Ren, 2012 are provided. This is the first report of spiracles in fossil Glaphyridae leading to a hypothesis that the character of the 7th abdominal spiracles present in pleural membrane is a plesiomorphy for Glaphyridae.

// Yaxiong Zhang 1, 2, 3, * , Jin Sheng 1, 2, 3, * , Yunpeng Yang 1, 2, 3, * , Wenfeng Fang 1, 2, 3 , Shiyang Kang 2, 3, 4 , Yang He 5 , Shaodong Hong 1, 2, 3 , Jianhua Zhan 1, 2, 3 , Yuanyuan Zhao 1, 2, 3 , Cong Xue 1, 2, 3 , Yuxiang Ma 1, 2, 3 , Ting Zhou 1, 2, 3 , Shuxiang Ma 1, 2, 3 , Fangfang Gao 1, 2, 3 , Tao Qin 1, 2, 3 , Zhihuang Hu 1, 2, 3 , Ying Tian 1, 2, 3 , Xue Hou 1, 2, 3 , Yan Huang 1, 2, 3 , Ningning Zhou 1, 2, 3 , Hongyun Zhao 1, 2, 3 , Li Zhang 1, 2, 3 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China 2 State Key Laboratory of Oncology in South China, Guangzhou, China 3 Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, China 5 Lau Luen Hung Private Medical Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Li Zhang, e-mail: zhangli6@mail.sysu.edu.cn Keywords: EGFR-TKI, NSCLC, gefitinib, erlotinib, afatinib Received: January 21, 2016 Accepted: February 18, 2016 Published: February 25, 2016 ABSTRACT Background: To answer which epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the best choice for advanced non-small cell lung cancer (NSCLC) EGFR mutants. Results: 16 phase III randomized trials involving 2962 advanced NSCLC EGFR mutants were enrolled. Multiple treatment comparisons showed different EGFR-TKIs shared equivalent curative effect in terms of all outcome measures among the overall, chemo-naive and previously treated patients. Rank probabilities showed that erlotinib and afatinib had potentially better efficacy compared with gefitinib in both of the overall and chemo-naive patients. Potentially survival benefit of erlotinib was also observed in previously treated patients compared with gefitinib. Additionally, EGFR-TKI showed numerically greater survival benefit in 19 Del compared with chemotherapy, while it was opposite in 21 L858R. Furthermore, afatinib, erlotinib and gefitinib had high, moderate and low risk of rash & diarrhea, respectively, while the occurrence of elevated liver transaminase was more common in gefitinib. Methods: Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were extracted from included studies. Efficacy and toxicity of all included treatments were integrated by network meta-analyses. Conclusion: Our study indicated a high efficacy-high toxicity pattern of afatinib, a high efficacy-moderate toxicity pattern of erlotinib and a medium efficacy-moderate toxicity pattern of gefitinib. Recommended EGFR-TKI should be suggested according to patients’ tolerability and therapeutic efficacy in clinical practice. Moreover, the treatment for advanced EGFR-positive NSCLC might be different between 19 Del and 21 L858R.

Laser oscillating welding of AZ91 and Ti-6Al-4V was carried out and the influence of oscillating parameters on morphology and mechanical property was investigated. The joint strength obtained with beam oscillating was enhanced compared that without oscillating. With oscillating frequency increased, welding width of Mg improved while the melting amount of Ti decreased. The tensile strength improved initially and then decreased when oscillating frequency increased.

Background: Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients. Methods: Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity. Results: Between March, 2017 and August, 2018, 48 patients were enrolled. 43 patients were locally detected ALK positive by FISH or IHC (VANTANA), 5 patients harbored with ROS1 fusion. In 43 ALK positive patients, 32 patients were ALK TKI-naïve while 11 patients progressed on prior molecular targeted therapy (including 10 crizotinib-treatment and 2 ceritinib- or alectinib-treatment). Two DLTs were observed in the 250 mg dose cohort (grade 3 rash). All patients experienced at least one treatment-related adverse event, in which 19 (39.6%) had grade 3 or higher events with skin rash (16.7%) as the most common one. Ensartinib was moderately absorbed (median time to max concentration: 3.00-4.00 h) and slowly eliminated (mean half-life: 21.0-30.2 h). In multiple dose administration, a steady-state concentration of ensartinib was reached after 8-15 days. The geometric mean AUC0-tau and Cmax of ensartinib at 225 mg were 6950 h*ng/mL and 435 ng/mL, respectively. The ratio of drug concentration in cerebrospinal fluid (CSF) to that in plasma was 1.31-2.05% in 6 patients treated with ensartinib. Objective tumor responses were observed across all dose cohorts. In 46 evaluable patients, the objective response rates (ORR) and disease control rates (DCR) were 71.7% (1 CR and 32 PR) and 84.8% (6 SD), respectively. In ALK positive patients, the ORR and DCR were 80.5% (33/41) and 87.8% (36/41). The ORRs and DCRs at ≥225mg were 68.6% (24/35) and 85.7% (30/35), respectively. The confirmed ORR was 90.0% (27/30) in ALK TKI-naive patients compared to 54.5% (6/11) in ALK TKI-resistant patients. The ORR and DCR in 16 patients with baseline brain metastases were 75% and 75%, respectively. At data cut-off (07-Nov-2019), the median PFS for all 46 evaluable patients was 17.1 months (95% CI 6.3-27.9), and was 20.4 months (95% CI 13.2-27.6) for ALK positive patients, 8.6 months (95% CI 0-24.8) for ROS1 fusion patients. The median PFS was 24.5 months (95% CI 17.4-31.6) and 4.2 months (95% CI 0-8.9) for ALK TKI-naive and ALK TKI-resistant patients, respectively. Conclusions: Ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartinib could penetrate the blood-brain barrier with a CSF/plasma concentration ratio of 1.65%, supporting its remarkable intracranial efficacy. A global randomized phase 3 trial of ensartinib versus crizotinib in NSCLC patients who have not previously been treated with ALK TKIs is underway (NCT02767804). Citation Format: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang. Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 579.

Background: Blood-based detection of circulating tumor DNA (ctDNA) is a non-invasive and clinical accessible source of biomarkers that enables selection of non-small-cell lung cancer (NSCLC) patients for treatment with anti-PD-(L)1 therapies. However, new approaches are necessary to improve enrichment of responders. Patients and Methods: Pretreatment plasma ctDNA from 97 advanced-stage NSCLC patients who underwent anti-PD-(L)1 therapy from December 2015 to August 2017, with matched tissue samples from 66 patients, were profiled using a targeted next-generation sequencing (NGS) panel (Geneseeq) encompassing 422 cancer-relevant genes. External validation was performed using two large randomized trials, POPLAR and OAK. Results: In the 72 patients with adequate ctDNA release (maximum somatic allele frequency, MSAF ≥2%), high blood tumor mutational burden (bTMB) was associated with significantly prolonged median PFS (110 vs 60 days, HR=0.54 [95%CI, 0.31-0.92]; log-rank p = 0.02) and a trend towards improved DCB (34.8% vs 22.5%, p=0.39). While a high concordance was observed between bTMB and tTMB (Spearman's ρ= 0.71), the greatest progression-free survival (PFS) improvement was achieved with concomitantly high bTMB and tTMB (mPFS, 156 vs 59 days, HR=0.47 [95%CI, 0.24-0.91], log-rank p=0.02). Remarkably, the subset of patients with low ctDNA release (MSAF Conclusions: Our findings validated panel-assessed bTMB as a promising biomarker that demonstrated added value over tissue testing alone for benefit with anti-PD-(L)-1 therapies. Our findings also provided the first clinical evidence suggesting that matched tissue and blood testing might be necessary to refine the predictive value of TMB. Moreover, we identified low ctDNA MSAF as an important and robust predictor of improved immunotherapy outcome. Citation Format: Wenfeng Fang, Yuxiang Ma, Jiani C. Yin, Huaqiang Zhou, Fufeng Wang, Hua Bao, Ao Wang, Xue Wu, Shaodong Hong, Yunpeng Yang, Yan Huang, Hongyun Zhao, Yang W. Shao, Li Zhang. Combinatorial assessment of ctDNA release and mutational burden predicts clinical outcome from anti-PD-(L)1 therapies in non-small-cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 707.

The purpose of this paper is to make a comprehensive understanding of the trends between the lifetime and the thermomechanical test setup parameters, based on the physical failure mechanism of SnAgCu solder interconnections in the component boards. The thermomechanical tests, including thermal cycling and thermal shock, were employed to investigate the failure of the component boards under different loading conditions. The in situ observation during the thermomechanical tests was employed to study the microstructure evolution and the crack propagation of solder interconnections. Electrical failures of the component boards under all setup conditions are mainly caused by the cracks, which propagate along the continuous network of the high-angle grain boundaries produced by the distinguished recrystallization of solder interconnections. The propagation of cracks is highly dependent on the expansion of the recrystallized volume in the solder interconnections. In addition, the expansion of the recrystallization would be influenced by the setup parameters of the thermomechanical test. The paper discusses the relationship among the four factors of the lifetime, the crack growth, the restoration phenomenon and the test setup parameters, in order to explain the complicated trend between the component board lifetime and the setup parameters.

3020 Background: KN046 is a bispecific antibody that blocks PD-L1 and CTLA-4 by interaction with PD1 and CD80/CD86. KN046-CHN-001 (NCT03529526) is a, dose escalation and expansion phase Ia/Ib clinical trial in China. Here we reported safety, tolerability and preliminary efficacy in patients failed on prior immune checkpoint inhibiters (ICIs) treatment. Methods: Patients progressed on ICIs (including but not limited to antibodies targeting PD-1, PD-L1, OX40, et al) with pathologically confirmed solid tumor, ECOG 0-1, measurable lesion per RECIST v1.1, no immune-related adverse events (IRAEs) led to ICIs discontinuation, were enrolled and received intravenous KN046 treatment across four dose levels including 3.0 mg/kg (n = 3) and 5.0 mg/kg (n = 20) Q2W; and 5.0 mg/kg (n = 4), 300.0 mg flat dose (n = 2) Q3W. Safety and tolerability were assessed per NCI-CTCAE v5.0. Treatment-emergent AEs (TEAEs) and IRAEs were decided by investigators. Efficacy was evaluated by investigators per RECIST 1.1 every 6 weeks. Results: Twenty-nine who progressed on prior ICIs therapy were enrolled (25anti-PD-1 antibody; 3 anti-OX40 antibody; and 1 anti-CD137 antibody) and were included in the current analysis. Among 29 patients, 19 were nasopharyngeal cancer (NPC) and 9 were non-small cell lung cancer (NSCLC). The median duration of the exposure of KN046 was 12 weeks (range 2 to 40). Eleven patients remained on the treatment and 18 discontinued due to disease progression (n = 13), AE (n = 1), death (n = 1) and others (n = 3). Twenty-six (89.7%) patients experienced TRAEs of all grades and 2 (6.9%) experienced grade≥3 TRAEs (1 grade 3 anemia and 1 grade 3 infusion-related reaction). The most common (≥10%) TRAEs were pruritus (8, 27.6%), rash (8, 27.6%), asthenia (6, 20.7%), fatigue (6, 20.7%), pyrexia (5, 17.2%), infusion related reaction (4, 13.8%), alanine aminotransferase elevation (3, 10.3%) and white blood cell count elevation (3, 10.3%). Eleven (37.9%) patients experienced irAEs (with no grade≥3). Objective responses were occurred in 3 (12.0%, 25 evaluable) patients, disease control rate was 52.0% (10 stable disease). Median progression free survival was 2.69 (95%CI 1.31,5.52) months. Median overall survival was not reached. PFS rates for 3 and 6 Months were 41.0% (95%CI 18.5, 62.5) and 21.9% (95%CI 4.6, 47.3). OS rates for 6 and 9 months were88% (95%CI 57.2, 97.1) and 58.7% (95%CI 8.3, 89.2), respectively. Conclusions: Overall, KN046 showed a favorable safety profile and promising clinical benefit in advanced solid tumor patients who failed on prior ICIs therapy. Clinical trial information: NCT03529526 .

3105 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody, targeting a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 ligand antagonism and potent cross-linking via FcgRIIb. This phase 1 study was conducted to assess its safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and preliminary efficacy. Methods: Eligible patients with age 18 to 75, ECOG ≤1, measurable lesion received intravenous infusion of ADG106 every 3 weeks for a maximum of 24 months. Accelerated titration was applied in 0.1mg/kg dose level and traditional Fibonacci 3+3 method was applied in 0.5, 1.5, 3.0, 5.0 and 10.0 mg/kg dose levels. A dose-expansion cohort will be started for dose levels that have been proved tolerable and with evidence of clinical or biological activity. Results: Data cutoff at Jan 17 2020, 15 patients [5 adenoid cystic carcinoma (ACC), 5 non-small cell lung cancer (NSCLC), 3 nasopharyngeal carcinoma, 1 malignant pleural mesothelioma and 1 follicular lymphoma] were enrolled and received treatment: 0.1mg/kg (n = 1), 0.5mg/kg (n = 3), 1.5mg/kg (n = 5), 3mg/kg (n = 3), and 5mg/kg (n = 3). Of these 15 patients, 6 with ongoing treatment, 9 discontinued (8 progression disease, 1 lack of clinical benefit). Medium treatment duration was 2 cycles (range 2-8). No dose limiting toxicities were observed. Seven (47%) patients experienced treatment-related AEs (TRAEs): rash (13%), pruritus (13%), nausea (7%), pyrexia (7%), hemoptysis (7%), mouth ulceration (7%), vomiting (7%), chest discomfort (7%), LDH increased (7%). All TRAEs were grade 1, no grade ≥3 occurred. One serious adverse event (anemia, not related) was observed. Pharmacokinetic analysis of ADG106 showed a half-life ranging from 5~10 days, with dose-dependent increase of systemic exposure. Treatment induced anti-drug antibodies were developed in 3 (20%) patients. No objective response was observed among the 14 evaluated patients. Disease control rate was 57% (8 stable disease), tumor shrinkage was observed in 3 (21%) patients (2 ACC, 1 NSCLC). Conclusions: ADG106 is safe and tolerable at doses up to 5 mg/kg in solid tumors and non-Hodgkin lymphoma. The dose expansion cohorts have started at selected doses. Clinical trial information: NCT03802955 .

3062 Background: With the proven success of PD-1 and PD-L1 monoclonal antibodies, exploiting antibody based immune checkpoint strategies has potential to reduce disease burden and improve patient survival outcome. IBI318, as a first-in-class anti-PD-1/PD-L1 bispecific antibody, could provide more potent anti-tumor activity and more durable response. Here we report preliminary results from an ongoing phase 1a/1b study of IBI318 in advanced tumors. Methods: In the dose escalation of Phase 1a, patients with advanced and/or refractory solid tumors or hematological malignancies were enrolled to receive IBI318. Dose escalation was from 0.3 mg to 600 mg (8 cohorts) via an accelerated titration followed by a modified toxicity probability interval-2 design with a 28-day dose-limiting toxicity (DLT) observation period. Patients without DLT will receive IBI318 every two week (Q2W). Tumor assessments were performed every 6 weeks. Results: As of Jan 10, 2020, 15 pts who had failed at least one line of treatment had been enrolled (1 pt each in 0.3 mg, 1 mg, 3 mg and 10 mg; 3 pts in 30 mg; 3 pts in 100 mg, 3 pts in 300 mg and 2 pts in 600 mg) for dose escalation and received at least 1 dose of treatment. Median duration of treatment was 6.1 (range: 2.1-24.7) weeks. IBI318 had been well tolerated with no DLT from 0.3mg to 300mg group. 11 of 15 pts had treatment related AEs (TRAEs) and the most common (≥10%) TRAEs were pyrexia (20.0%, G1/2) and infusion-related reaction (20.0%, G1/2). 1 patient in 300 mg had an immune-related AE (G2 arthritis). No ≥G3 TRAE had been observed. 12 pts had at least one on-study tumor assessment. 3 of 9 pts receiving dose level ≥10mg had achieved partial response (1 confirmed, 1 pending confirmation and the other PD after the first PR scan). A total of 10 pts discontinued treatment due to disease progression (8) and AE (2, G4 lung infection and G4 upper gastrointestinal hemorrhage, both were not related to treatment). Conclusions: IBI318 has shown an acceptable safety profile. Preliminary efficacy results are promising in advanced cancer patients. The study is currently ongoing at dose level of 600 mg Q2W. Clinical trial information: NCT03875157 .

9585 Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. Methods: Patients with advanced NSCLC and failed at least one systemic anti-cancer treatment were enrolled. TQ-B3139 was administered orally from 50mg~100mg qd and 200, 300, 400, 500, 600 and 800mg bid, using a PK-guided modified Fibonacci 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles, dose limited toxicities (DLTs) was observed at first cycle. Dose-expansion phase started at dose level which objective response occurs. Treatment was continued until disease progression, death or unacceptable toxicity. Results: Between July 2017 and May 2019, totally 63 patients (59 ALK+, 4 ROS1+) were enrolled. Sixteen patients had prior ALK inhibitor therapy (11 Crizotinib, 5 Ensartinib), and 23 (36.5%) with baseline brain metastasis. Totally, 62 (98.4%) patients experienced treatment-related adverse events (TRAEs), grade 3-4 TRAEs were observed in 21 (33.3%) patients. One DLT occurred in the 800mg bid dose cohort (grade 3 nausea and vomiting). Top 3 common TRAEs were nausea (all grade 87.3%; grade 3-4 3.2%), diarrhea (84.1%, 6.4%), transaminase elevation (65.1%, 4.8%). AUC and Ctrough at steady state increased proportionally from 200mg to 600mg bid. Absorption saturation was observed in 800mg bid. Base on the safety and PK results, PR2D was decided at 600mg bid. Overall ORR was 73.0% (2 CR, 44 PR); DCR was 85.7% (8 SD). Objective response was observed from dose level 200mg bid cohort, ORR and DCR at ≥200mg bid was 78.0% and 89.8%. For ALK TKI-naïve and -resistant patients, the ORR was 78.7% (37/47) and 56.3% (9/16) respectively. For patients with measurable baseline brain metastasis, the ORR for brain lesions was 80.0% (8/10). At data cut-off (23 Jan 2020), 32 events (50.8%) occurred, the median PFS for all patients was 12.1 months (95%CI 8.5-15.6), for patients at ≥200mg bid dose was 12.2 months. The median PFS was not reached for -naive patients (6 months PFS rate 74.5%, 95%CI 68.1-80.9), and 5.6months (95%CI 1.6-9.5) for ALK TKI-resistant patients. Conclusions: TQ-B3139 was well tolerated in Chinese NSCLC patients with high antitumor activity. RP2D was established at 600mg bid. A randomized phase III trial of TQ-B3139 versus Crizotinib in advanced ALK-TKI naïve NSCLC patients is underway. Clinical trial information: NCT03099330 .

9583 Background: Ningetinib is a novel tyrosine kinase inhibitor, targeted at c-Met, Axl, VEGFR-2, Mer and Flt3. This phase Ib trial (NCT03758287) evaluated the safety, determined the recommended phase II dose (RP2D), and further explored the pharmacokinetic and efficacy of Ningetinib + Gefitinib in EGFR-TKIs acquired resistant NSCLC patients (pts) with T790M negative. Methods: Chinese Pts with advanced or metastatic NSCLC, acquired resistant to at least one EGFR-TKI, T790M negative were enrolled. Pts received Ningetinib 30, 40, 60 mg + Gefitinib 250mg orally once daily in dose-escalation (n = 12) by a Fibonacci 3+3 design. Expansion phase (n = 74, enrollment is ongoing) started at tolerated dosage. Safety, RP2D were primary endpoints; PK, antitumor activity were secondary endpoints. Non-mandatory tumor samples at baseline were collected for exploratory objectives. Results: Totally, 86 eligible pts were enrolled between Nov 2016 and Dec 2019, and received treatment (Ningetinib 30 mg, n = 36; 40 mg, n = 46; 60 mg, n = 4), with median age 56.7 years, 36% with baseline brain metastasis, 66%/33%/1% prior 1/2/3 lines EGFR-TKI treatment, respectively. Treatment-related adverse events (TRAEs) occurred in 82 (95%) pts, grade 3/4 in 32 pts (37%). Most common TRAEs (≥30%) were myocardial enzyme elevation (all grade 74.4%; grade 3-4 0%), transaminase elevation (73.3%; 2.3%), skin rash (60.5%; 3.5%), albuminuria (44.2%; 0%), coagulation abnormalities (mostly asymptomatic Fbp decrease; 37.2%; 15.1%), diarrhea (33.7%; 2.3%) and hypertension (32.6%; 11.6%). Two Dose limited toxicities were observed at 60 mg dosage (both were grade 3 Fbg decrease), RP2D was decided at 40 mg. Of 84 efficacy evaluable pts, ORR was 19.1% (16 PR), DCR was 91.7% (61 SD, 7 PD). Totally, 65 (75.6%) progression events occurred at data cut-off (9 Jan 2020), the median PFS for all pts was 4.4 months (95%CI 3.7-4.6). No PFS differences were found between pts grouped by 3rd TKIs history or brain metastasis. C-Met gene amplification by FISH was conducted in 72 pts (83.7%). Pts with higher gene copy number (GCN) responded better in treatment, ORR in the GCN ≥6 (n = 11), GCN ≥5 (n = 16) and GCN ≥3 (n = 37) subgroups was 36.4%, 25.0% and 21.6% respectively. Conclusions: Ningetinib was well tolerated at 30 mg and 40 mg dosage with Gefitinib 250 mg, the RP2D for Ningetinb was 40 mg. This combination therapy showed promising anti-tumor activity in prior EGFR-TKIs acquired resistant NSCLC pts with T790M negative. C-Met GCN was the potential efficacy biomarker. Clinical trial information: NCT03758287 .

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

The effect of laser process parameters including single pulse energy (E), dimples per square millimetre (D) and laser incidence angle (θ) on the properties of 30CrMnSiA steel substrate and the tensile shear strength of adhesively bonded joints was investigated. The characterization of the substrate was established by surface morphology, the dimension (diameter and depth) of dimples and surface roughness (Ra and Rz). Single lap joints were fabricated and tensile tests were then performed. The fracture surfaces were observed and analyzed. The results indicated that the dimple dimension and surface roughness increased as the single pulse energy increased. The increase of dimples per square millimetre made surface roughness improve. The larger incidence angle reduced the actually absorbed energy changing the shape and size of dimples. The diameter of dimples increased while the depth decreased as incidence angle increased. The modified substrate morphology as well as increased dimple dimension expanded the contact area between the adhesive and adherend. The shear strength was enhanced and the maximum value was 24.67 MPa increasing by 363% compared to the adhesive joints without surface treatment. The mechanical interlocking between the adhesive and laser textured morphology was discovered in the fracture surface demonstrating the improvement of shear strength.

This article outlines the ongoing phase I studies of immune checkpoint inhibitors (ICI) in China, shedding light on the status quo of ICI research and development in China and identifying challenges for future early‐phase studies in the era of immuno‐oncology., Background. Cancer immunotherapy targeting immune checkpoint inhibitors (ICIs) has been shown to be a promising strategy in the treatment of various malignancies. Despite the proven efficacy and tolerability of ICIs based on 113 clinical trials globally, data regarding the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ICIs in the Chinese population are lacking. As of June 1, 2018, not a single ICI has been approved by the China Food and Drug Administration. Materials and Methods. Currently, there are 26 ongoing phase I studies actively investigating the safety, antitumor activity, and PK/PD profiles of six multinational corporation (MNC)‐developed ICIs and eight domestic‐developed ICIs in the Chinese population. Data regarding study designs, treatment interventions, targeted populations, and the current states of these studies were collected and summarized. Results. We outlined 8 phase I studies assessing MNC‐developed ICIs and 18 phase I studies assessing domestic‐developed ICIs in the Chinese population in this article, in order to provide researchers with a clear picture of the status quo of ICI research and developments in China. Conclusion. Immuno‐oncology in China remains at a preliminary stage. Despite the substantial amount of phase I studies of ICIs, early‐phase studies with designs incorporating characteristics of Chinese patients are still lacking. Implications for Practice. Cancer immunotherapy targeting immune checkpoint inhibitors (ICIs) has led to a paradigm shift in the treatment of various malignancies. However, data regarding the pharmacokinetic and pharmacodynamic profiles of ICIs in the Chinese population are lacking. Currently, there are 26 phase I studies actively investigating 14 ICIs in China. In this article, we outlined all the ongoing phase I studies of multinational corporation‐developed ICIs and domestic‐developed ICIs targeting the Chinese population, hoping to shed some light on the status quo of ICI research and developments in China.

Background Observational studies have shown that excessive dietary fat may be associated with lung carcinogenesis. However, findings from previous studies are inconsistent and it remains unclear whether docosapentaenoic acid (DPA), a kind of polyunsaturated fatty acid, is linked to the risk of lung cancer. The aim of this study is to investigate the causal effect of DPA on lung cancer with Mendelian randomization (MR) method. Methods With a two‐sample MR approach, we analyzed the summary data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, 8866 individuals of European ancestry) Consortium and International Lung Cancer Consortium (ILCCO, 11 348 lung cancer cases and 15 861 controls; European ancestry) to assess the possible causal relationship of DPA on the risk of lung cancer. Results Our results indicated that genetically predicted higher DPA level has a positive association with lung cancer, where 1% higher DPA was associated with a 2.01‐fold risk of lung cancer (odds ratio [OR]: 2.01, 95% CI = 1.34‐3.01; P = 7.40 × 10−4). Additionally, lung cancer was not a causal factor for DPA. The results of MR‐Egger regression analysis showed that there was no evidence for the presence of directional horizontal pleiotropy. Conclusions Genetically elevated DPA is positively associated with risk of lung cancer, and more work is needed to investigate the potential mechanisms.

Background Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors. Methods We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. Results Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57–0.67; P