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Background Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumours have a high response rate to immunotherapy. Antitumour activity and safety of serplulimab, a novel humanised anti-PD-1 monoclonal antibody, were evaluated in this phase II study. Methods In this ongoing, single-arm, open-label, phase II trial, patients with previously treated unresectable or metastatic MSI-H/dMMR solid tumours received intravenous serplulimab 3 mg/kg every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included additional efficacy measures, safety, and tolerability. Results As of 9 January 2021, 108 patients were enrolled, and 68 patients with confirmed MSI-H solid tumours were included in the main efficacy analysis population (MEAP). The median follow-up duration in the MEAP was 7.7 months, with an ORR of 38.2% (95% confidence interval, 26.7–50.8). Of the 108 patients, grade ≥3 treatment-emergent adverse events were reported in 53 (49.1%) patients; immune-related adverse events occurred in 52 (48.1%) patients. Conclusions Serplulimab demonstrates a durable antitumour effect and a manageable safety profile in previously treated patients with MSI-H solid tumours. Serplulimab is a promising tissue-agnostic treatment for previously treated MSI-H solid tumours. Trial registration NCT03941574.

Restoration of REDD1 expression counteracts miR-22-mediated Taxol sensitivity. EJ and BIU87 cells were treated with Taxol and combinations of miR-22 mimics, miR-22 antagonist, shRNA-REDD1, and REDD1 overexpression vector. (A) Protein expression of REDD1, EEF2K, c-caspase 3, c-PARP, and LC3-I/II was determined by western blot. (B) CCK-8 was used to determine treatment effect on cell proliferation. (C) Flow cytometry was used to detect cell apoptosis. (D) Autophagy was assessed by immunofluorescence of LCB3 and quantification by flow cytometry. ***P

(A-B) The autophagy inhibitors intensified Taxol sensitivity in RT4 cells. Immunofluorescence for the autophagy marker LC3B was quantitated with flow cytometry. (C-D) CCK-8 was used to determine treatment effect on cell proliferation. (E-F) Restoration of REDD1 expression counteracts miR-22-mediated Taxol-induced inhibition of clone formation. T24 cells were treated with Taxol and combinations of miR-22 mimics, or REDD1 overexpression vector, or both. RT4 cells were treated with Taxol and combinations of miR-22 antagonist, or shRNA-REDD1, or both. ****P

Purpose: Regulated in development and DNA damage response-1 (REDD1) is a stress-related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified.Experimental Design: The expression of REDD1 in BUC was detected by Western blot analysis and immunohistochemistry (IHC). The correlation between REDD1 expression and clinical features in patients with BUC were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both in vitro and in vivo. Then the targeted-regulating mechanism of REDD1 by miRNAs was explored.Results: Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is first reported as an independent prognostic factor in patients with BUC. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. In addition, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 in vitro, which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1–EEF2K–autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Finally, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant carcinoma model in vivo.Conclusions: REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel. Clin Cancer Res; 24(2); 445–59. ©2017 AACR.

(A) The mutation sites in the REDD1 3'UTR reporter construct. (B) The cytotoxicity test of Taxol in T24 and RT4 cells. Cell proliferation was determined in T24 and RT4 cells using the CCK-8 method.

Effects of REDD1 and miR-22 on Taxol chemosensitivity in EJ and BIU87 cells in nude mice. (A-B) Tumor tissues isolated from indicated mice at day 35 post-transplant. (C-D) The tumor volumes were calculated at day 35 post-transplant. (E-F) Tumor cells apoptosis was tested by TUNEL assay. ****P

REDD1 regulates cell proliferation, apoptosis, and autophagy in EJ and BIU87 cells. (A-B) Western blot analysis of REDD1, C-caspase 3, c-PARP, LC3-I/II, and EEF2K in EJ cells transfected with REDD1-shRNA (sh-3), and BIU87 cells transfected with REDD1 over-expression plasmid. (C) Cell proliferation was determined in EJ and BIU87 cells using the CCK-8 method. (D) Expression of the autophagy marker LC3B was detected by immunofluorescence, and analyzed with flow cytometry. (E) Apoptosis of EJ and BIU87 cells with modulation of REDD1 expression was detected by flow cytometric analysis of annexin V and propidium iodide staining. (F) Cell cycle in EJ and BIU87 cells was analyzed by flow cytometry analysis. Proliferation index (PI) = (S+G2/M)/(S+G2/M+G0/G1). (G-H) The levels of p-AKT, AKT, p-mTOR, mTOR, p-S6K1, S6K1, EEF2K, and LC3-I/II were examined by western blot. The time point of "o min" was identified beginning at 24 hours after sh-REDD1 or REDD1 plasmid transfecting. ****P

Suppl. Table 1: Univariate analysis of different prognostic parameters in 112 patients with BUC. Suppl. Table 2. Multivariate cox regression analysis of the association of various clinicopathological features with survival in 112 patients with BUC. Suppl. figure 1-7 legends

miR-22 regulates cell proliferation, apoptosis, and autophagy in EJ and BIU87 cells. (A) EJ cells were transfected with miR-22 mimics, and BIU87 cells with miR-22 inhibitors and Protein expression of REDD1, C-caspase 3, c-PARP, and LC3-I/II was detected by western blot after intervention on miR-22 expression. (B) the CCK-8 method was used to detect cell proliferation. (C) Immunofluorescence for the autophagy marker LC3B was quantitated with flow cytometry. (D) The effects of miR-22 mimics or inhibitors on apoptosis of EJ or BIU87 cells were assessed through annexin V staining and flow cytometry analysis. (E) Cell cycle was analyzed by flow cytometry. ***P

Cisplatin is the most widely used chemotherapeutic agent due to its efficacy in the treatment of a broad range of cancer types; while the side effects and drug resistance of cisplatin limit its clincial application. Combination therapy, which contains several types of free drugs, exhibits promising potential in clinical practice. Nevertheless, current combination chemotherapy cannot accurately deliver different drug components into a single tumor cell at the same time. Herein, we report a triple-action nanoplatinum drug based on artesunate and cantharidin to overcome the influence of pharmacokinetics and distribution variation in different drugs. The results show that the triple action nanoplatinum drug enhances ROS generation, leads to DNA damage, and inhibits DNA repair. Therefore, a high-efficiency killing effect is achieved with a triple-action platinum drug in a single tumor cell.

Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy.This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156.A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively.Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Background: In patients (pts) with previously treated aHCC, pembro demonstrated comparable efficacy and safety vs placebo (pbo) in the phase 3 KEYNOTE-240 (NCT02702401) and KEYNOTE-394 (NCT03062358) studies in global and Asian populations, respectively. The hazard ratio ([HR]; 95% confidence interval [CI]) for OS was 0.781 (0.611-0.998) in KEYNOTE-240 and 0.79 (0.63-0.99) in KEYNOTE-394; HR (95% CI) for PFS was 0.78 (0.61-0.99) and 0.74 (0.60-0.92), respectively. ORR differences with pembro vs pbo were similar in KEYNOTE-240 (13.8% [95% CI, 7.7-19.5]) and KEYNOTE-394 (11.4% [95% CI, 6.7-16.0]). We performed a prespecified meta-analysis of KEYNOTE-240 and KEYNOTE-394 to obtain a more precise estimate of the pembro treatment effect. Methods: In KEYNOTE-240 and KEYNOTE-394, pts with confirmed aHCC and progression or intolerance to sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only) were randomized 2:1 to pembro (200 mg IV Q3W) or pbo for ≤35 cycles, both with best supportive care. Inclusion/exclusion criteria were similar. Meta-analysis of pt data pooled from the ITT population of the pembro and pbo arms of each study was completed. OS, PFS (blinded independent central review [BICR] per RECIST 1.1), and ORR (BICR per RECIST 1.1) were assessed. Results: In total, 578 pts who received pembro and 288 who received pbo were included. The HR for OS and PFS and the difference in ORR for pembro vs pbo in all pts was 0.79 (95% CI, 0.67-0.93), 0.76 (0.64-0.89), and 12.5 (8.8-16.2), respectively (Table). Results were consistent across subgroups, including viral etiology, BCLC stage, and age. Conclusions: This meta-analysis of two studies with similar design, inclusion/exclusion criteria, and endpoints, showed improvement in OS, PFS, and ORR with pembro vs pbo across studies. These data also show consistent outcomes between the studies, providing further evidence for the benefit of second-line pembro for aHCC globally. All Patients Patients With Sorafenib-Treated aHCC Pembrolizumab(n = 578) Placebo(n = 288) Pembrolizumab(n = 550) Placebo (n = 274) OS, median (95% CI), mo 14.2 (12.8-16.2) 12.5 (10.2-13.6) 14.2 (12.8-16.0) 12.5 (10.4-13.6) HR (95% CI)a,b 0.79 (0.67-0.93) 0.78 (0.66-0.92) PFS, median (95% CI), mo 2.8 (2.7-2.9) 2.7 (1.6-2.8) 2.8 (2.7-2.9) 2.7 (1.6-2.8) HR (95% CI)a,b 0.76 (0.64-0.89) 0.76 (0.64-0.90) ORR, % (95% CI) 15.4 (12.6-18.6) 2.8 (1.2-5.4) 15.6 (12.7-18.9) 2.9 (1.3-5.7) Estimated treatment difference, (95% CI)b,c 12.5 (8.8-16.2) 12.6 (8.8-16.4) aHCC, advanced hepatocellular carcinoma; CI, confidence interval; HR, hazard ratio.aStratified Cox proportional hazard model with treatment as a single covariate and Efron’s method of tie handling was used to estimate the OS and PFS HR and its 95% CI.bStratification was performed per protocol and within each protocol, by strata used in the analysis of the respective protocol.cMiettinen & Nurminen method was used to estimate the difference in ORR and its 95% CI. Citation Format: Richard S. Finn, Kangsheng Gu, Xi Chen, Philippe Merle, Kyung-Hun Lee, Mohamed Bouattour, Peiguo Cao, Wei Wang, Ann-Lii Cheng, Liangjun Zhu, Ho Yeong Lim, Masatoshi Kudo, Yueyin Pan, Ting-Tsung Chang, Julien Edeline, Wei Li, Ping Yang, Chen Li, Jianfeng Li, Abby B. Siegel, Shukui Qin. Pembrolizumab (pembro) for previously treated advanced hepatocellular carcinoma (aHCC): Meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT222.