In randomized phase 3 NORA trial (NCT03705156), niraparib maintenance therapy with an individualized starting dose (ISD) significantly improved PFS (PFS; primary endpoint) and provided a favorable OS (OS; secondary endpoint) trend versus placebo, in patients with platinum-sensitive recurrent ovarian cancer (PSROC). Evaluating OS in randomized controlled trials can often be confounded by bias introduced by subsequent therapy. Considerable numbers of patients in placebo arm received subsequent PARPi therapy. This updated analysis aims to describe the treatment effect of niraparib versus placebo on OS adjusted for subsequent PAPPi use in placebo arm. 265 Chinese patients with PSROC who achieved a CR or PR to last platinum-based chemotherapy were randomized (2:1) to receive niraparib (n = 177) or placebo (n = 88). A majority of patients (249/265) received niraparib or placebo with an ISD based on baseline body weight and platelet count (200 mg for patients with baseline body weight < 77 kg or platelet count < 150,000/μL; otherwise, 300 mg). Kaplan-Meier method was used to describe OS. Hazard ratio was estimated using a Cox proportional model. Inverse probability of censoring weighting (IPCW) method was used to estimate the effect of niraparib versus placebo adjusted for subsequent PARPi use in placebo arm. As of the data cut-off of Sep. 23, 2022, an ad hoc interim OS analysis was conducted at 44% (117/265) maturity. Detailed data are provided in the table. 43% (38/88) patients [54% (19/35) in gBRCAmut and 36% (19/53) in non-gBRCAmut] in the placebo group received subsequent PARPi therapy.Table: 35OOS summary for ITT population and by gBRCA statusAllgBRCAmutNon-gBRCAmutNiraparib N=177Placebo N=88Niraparib N=65Placebo N=35Niraparib N=112Placebo N=53ITT AnalysismOS (mo)46.3243.37NR47.6143.1038.41HR (95%CI)0.821 (0.558-1.207)0.764 (0.398-1.464)0.855 (0.529-1.381)Adjusted IPCW AnalysisTBUITT: intention to treat; gBRCAmut, germline BRCA mutation; HR, hazard ratio; CI: confidence interval; mOS: median overall survival; NR: not reached; TBU: to be updated. Open table in a new tab ITT: intention to treat; gBRCAmut, germline BRCA mutation; HR, hazard ratio; CI: confidence interval; mOS: median overall survival; NR: not reached; TBU: to be updated. Consistent with the OS results from the ITT analysis, the IPCW analysis further demonstrates favorable OS trend and supports positive benefit-risk profile of niraparib with ISD as maintenance therapy for PSROC.

Pembrolizumab plus chemotherapy +/- Bev has been approved as the 1L treatment for r/mCC patients (pts) with PD-L1 CPS ≥1. QL1706, a bifunctional Mabpair product of anti-PD-1 and anti-CTLA-4 antibodies, has shown good safety and promising efficacy in previously treated r/mCC pts in a phase Ib study. Here we report the latest efficacy and safety results from a Ph 2 study of QL1706 plus paclitaxel and cisplatin/carboplatin +/- Bev as 1L treatment of r/mCC. In this open-label, single arm, non-randomized, phase II study, eligible pts were pathologically confirmed r/mCC and had no prior systemic treatment. Pts were treated with QL1706 (5 mg/kg, IV, D1) plus paclitaxel (175 mg/m2 or 135 mg/m2, D1) and cisplatin (50 mg/m2, D1/D2)/carboplatin (AUC = 5, D1) (cohort 1) or with Bev (15 mg/kg, D1/D2) (cohort 2) once every 3 weeks for 6 cycles. Thereafter, treatment maintained with QL1706 +/- Bev, until disease progression, intolerable toxicity, or other discontinuation events. The primary and secondary endpoints were safety and efficacy, respectively. A total of 60 pts were enrolled. As of data cutoff (Apr 24, 2023), the median follow-up time was 14.0 months. Overall 58 pts had ≥1 post baseline tumor assessment and analyzed for efficacy. The ORR was 81% (95% CI, 68.6–90.1) (8 CRs and 39 PRs). The DCR was 98.3% (95% CI, 90.8–100.0). The mPFS was 14.3 months (95% CI, 9.2-NE). The mPFS was numerically longer in cohort 2 vs cohort 1 (16.4 vs 12.5 months). The mOS was not reached. TRAEs occurred in 60 (100%) pts. The most common TRAEs (≥30% in total population) were WBC count decreased (73.3%), neutrophil count decreased (58.3%), anemia (43.3%), platelet count decreased (38.3%), and alopecia (33.3%), Grade ≥3 TRAEs occurred in 43 (71.7%) pts. Treatment-related SAEs occurred in 20 (33.3%) pts. TRAEs leading to treatment discontinuation occurred in 16 (26.7%) pts. irAEs occurred in 36 (60%) pts (Grade ≥3, 13.3%). QL1706 plus platinum-based chemotherapy +/- Bev was well tolerated and showed promising antitumor activity as 1L treatment of r/mCC. Ph 3 study of QL1706 plus platinum-based chemotherapy +/- Bev as 1L treatment of r/mCC is ongoing.

Pts with R/M CC have poor prognoses with high unmet clinical needs and few treatment (tx) options. Dual targeting of solid tumors with anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and anti-PD-1 mAbs enhances antitumor activity in preclinical studies and clinical studies of other tumors. AdvanTIG-202 (NCT04693234) is investigating the efficacy and safety of TIS (anti-PD-1 mAb) ± OCI (humanized Fc-intact IgG1 anti-TIGIT mAb) in pts with R/M CC. Primary analysis results are reported here. Eligible pts with R/M CC had received ≥1 line of chemotherapy and were not amenable to curative tx. In Stage 1, 80 pts were randomized (1:1) to receive 200 mg TIS IV Q3W + 900 mg OCI IV Q3W (Cohort [C]1) or TIS monotherapy (C2) until disease progression, unacceptable toxicity, or withdrawal of consent. In Stage 2, C1 enrolled 98 additional pts. Primary endpoint: ORR per RECIST v1.1 by IRC for C1. Secondary endpoints: DoR, PFS, OS, and safety. As of June 16, 2022, 138 pts were enrolled and treated in C1 (median age 53.0 y); median study follow-up: 7.4 mo. In the safety analysis set (SS), the ORR was 22.5%, with 13 complete responses (CR; Table); 76.8% had a durable response of ≥6 mo. ORR was 26.2% in pts with PD-L1+ tumors (PD-L1 score ≥5%), with 10 CRs. Both analysis sets showed significant improvement in ORR vs historical control ORR of 15% in pts treated with anti-PD-1 therapy (P<0.05). Around 67% of pts experienced ≥1 tx-related adverse event (TRAE). Only 13% of pts experienced ≥grade 3 TRAEs; the most frequently reported were anemia (2%) and rash (1%). With limited enrollment in C2 (n=40), the ORR was 32.5%. Table: 744MOCohort 1Safety analysis seta (n=138)PD-L1 + (n=84)ORR, % (95% CI)22.5 (15.8, 30.3)26.2 (17.2, 36.9)n (%)Complete response Partial response Stable disease Progressive disease Not determined13 (9.4) 18 (13.0) 56 (40.6) 39 (28.3) 12 (8.7)10 (11.9) 12 (14.3) 34 (40.5) 20 (23.8) 8 (9.5)mDoR, mo 95% CINE (5.6, NE)NE (5.6, NE)mPFS, mo 95% CI3.5 (2.6, 4.9)4.2 (2.7, 6.9)mOS, mo 95% CI9.0 (8.1, 10.4)10.4 (8.1, NE)Data cutoff: June 16, 2022. Efficacy assessed by IRC. aPts who received ≥1 dose of any study drug. DoR, duration of response; IRC, independent review committee; m, median; mo, months; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Open table in a new tab . Data cutoff: June 16, 2022. Efficacy assessed by IRC. aPts who received ≥1 dose of any study drug. DoR, duration of response; IRC, independent review committee; m, median; mo, months; NE, not estimable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. OCI + TIS showed promising antitumor activity and durable responses, regardless of PD-L1 expression, and was well tolerated in pts with previously treated R/M CC.

Niraparib has previously shown efficacy in a phase 3 NORA trial, which demonstrated significantly improved PFS in patients with platinum-sensitive recurrent ovarian cancer (PSROC). The aim of this ad hoc interim analysis is to investigate the effect of niraparib on OS with individualized starting dose (ISD). This double-blind, placebo-controlled, randomized, phase 3 NORA trial enrolled 265 Chinese patients with PSROC who achieved a CR or PR to the last platinum-based chemotherapy (NCT03705156). A majority of patients (249/265) was randomized (2:1) to receive niraparib or placebo by individualized starting dose according to baseline body weight and platelet count (200 mg for patients with baseline body weight < 77 kg or platelet count < 150,000/μL; otherwise, 300 mg). OS analysis was adopted by an ITT method and a censoring method for patients in placebo who were switched to PARPi. Patients were randomized to receive niraparib (n = 177) or placebo (n = 88). Data cut-off occurred on Sep. 23, 2022. Median follow-up time for OS in niraparib and placebo arm was 45.7 and 44.5 mos, respectively. An ad hoc interim OS analysis was conducted at 44% (117/265) maturity. Using ITT method, mOS was numerically longer for patients receiving niraparib versus placebo in the ITT population: 46.3 [95% CI, 41.0-NE] versus 43.4 (95% CI, 33.1-NE) mos [HR =0.826; 95% CI, 0.56-1.21]. Forty three percent (38/88) patients in the placebo arm received subsequent PARPi therapy. A consistent OS trend was observed by censoring patients receiving PARPi in placebo arm, regardless of gBRCA status. Detailed data are provided in the table. No new safety signals were identified.Table: VP7-2022OS summary for ITT population and by gBRCA statusAllgBRCAmutNon-gBRCAmutNiraparib N=177Placebo N=88Niraparib N=65Placebo N=35Niraparib N=112Placebo N=53ITT AnalysismOS (mo)46.343.4NR47.643.138.4HR (95%CI)0.83 (0.56-1.21)0.77 (0.40-1.47)0.86 (0.53-1.39)Censoring Analysis∗Adjusted for patients in the placebo group who received subsequent PARP inhibitor therapy, [19/35 (54%) in gBRCAmut and 19/53 (36%) in non-gBRCAmut] received subsequent PARPi therapymOS (mo)46.334.3NR42.143.132.6HR (95%CI)0.70 (0.45-1.08)0.89 (0.39-2.03)0.63 (0.37-1.06)∗ Adjusted for patients in the placebo group who received subsequent PARP inhibitor therapy, [19/35 (54%) in gBRCAmut and 19/53 (36%) in non-gBRCAmut] received subsequent PARPi therapy Open table in a new tab NORA showed a potentially favorable OS trend irrespective of gBRCA status with niraparib maintenance treatment using an ISD regimen for patients with PSROC.

Objectives Traditionally ≥6 cycles of platinum-containing chemotherapy (Pt-chemo) are recommended for platinum-sensitive recurrent ovarian cancer (PSROC). PARP inhibitor maintenance treatment (MT) can be initiated upon clinical complete/partial response (CR/PR) after ≥4 cycles of chemotherapy. Shorter chemotherapy may improve patient experience without compromising efficacy. This study aims to compare the efficacy and safety of niraparib to placebo as MT administered after ≤4 or >4 cycles of Pt-chemo. Methods This is a post hoc analysis of the published NORA phase III study (NCT03705156). Adults with PSROC and CR/PR to most recent Pt-chemo were randomized 2:1 to niraparib or placebo. Primary endpoint was PFS by BICR. Subgroups comprised patients with ≤4 or >4 cycles of most recent Pt-chemo. Results Table 1 summarizes key baseline characteristics which were overall balanced between groups. Median (95% CI) PFS was 18.37 months (8.54–not estimable [NE], ≤4-cycle/niraparib) versus 3.88 months (3.68–7.43, ≤4-cycle/placebo; HR=0.36 [p=0.0016]), and was 18.33 months (10.28–NE, >4-cycle/niraparib) versus 5.49 months (3.71–5.75, >4-cycle/placebo; HR=0.33 [p<0.0001]) (figure 1). Overall safety profiles were comparable between ≤4-cycle/niraparib and >4-cycle/niraparib, with similar percentages of patients experiencing neutrophil count decrease (60.4%; 58.1%), anemia (50.0%; 55.0%), and platelet count decrease (45.8%; 58.1%). Composition of grade ≥3 TEAEs was consistent with the overall NORA results. Conclusions Similar niraparib-versus-placebo PFS benefits were observed after ≤4-cycle or >4-cycle Pt-chemo in CR/PR patients. The efficacy and safety of niraparib MT after shorter Pt-chemo remain to be verified in larger samples.

Niraparib, a potent inhibitor of PARP 1/2, maintenance therapy significantly improved the outcome of platinum-sensitive recurrent ovarian cancer (PSROC) in Caucasian and Chinese patients in NOVA and NORA studies. An individualized starting dose according to the baseline body weight and platelet count was utilized in the majority of patients in NORA trial aiming to decrease incidence of AE while maintaining efficacy. NORA was conducted in 32 hospitals in China. Eligible patients were women aged ≥ 18 years with PSROC who had either germline BRCA mutation or high-grade serous histologic features, and a complete or partial response after completion of the last round of platinum therapy. Patients were randomly allocated (2:1) to receive oral niraparib or placebo at 300mg once daily. After a protocol amendment in December 2017, the starting dose was subsequently changed to an individualized dosing regimen of 200 mg except for those with a baseline body weight >77kg and a platelet count >150K/μL in which case the starting dose is 300 mg. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. In total, 265 patients were randomized and included in the intent-to-treat (ITT) efficacy population. Of these, 249 patients (median body weight 61kg) received the individualized dosing of niraparib/placebo. Patients in the niraparib group had a significantly longer median PFS than did those in the placebo group, 18.3 vs. 5.4 months (HR=0.30; 95% CI, 0.21–0.43). The incidences of grade ≥3 treatment emergent AEs and ≥ 3 grade hematological AEs of neutrophil count decreased, platelet count decreased and anemia were 48.8% vs 20.5%, 19.9% vs 8.4%, 8.4% vs 1.2%, 13.9% vs 2.4% in niraparib group and placebo arm, respectively. This is the first study to demonstrate the efficacy and safety of niraparib in Chinese patients with PSROC. Individualized starting dosing of niraparib is effective and safe and should be considered standard clinical practice in this patient population, especially in Asian patients with low body weight.

Pamiparib, an investigational, selective inhibitor of PARP1/2, has PARP-DNA complex trapping capabilities. The first-in-human study (NCT02361723) established the pamiparib phase II dose as 60 mg po BID. Responses were reported in BRCA mutated or wild-type and platinum-sensitive/resistant aOC. Here we present phase II results from an ongoing phase I/II study in Chinese pts with advanced solid tumors (NCT03333915). Patients with platinum-sensitive (cohort 1) and platinum-resistant (cohort 2) aOC were enrolled. Patients with known/suspected deleterious germline BRCA1/2 mutation and ≥2 prior lines of chemotherapy were eligible. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (ORRIRC) per RECIST v1.1. As of 2 Feb 2020, 113 pts (cohort 1, n=90; cohort 2, n=23) were enrolled. Median age was 54 yr (range: 34-79), 25.6% (n=29) of pts had received ≥4 prior systemic chemotherapy lines, and 54.0% (n=61) of pts had an ECOG score of 1 at study entry. At data cutoff, median follow-up was 12.2 mo (range: 0.2-21.5). Across both cohorts, pamiparib showed preliminary antitumor activity (Table). In cohort 1, confirmed ORRIRC was 64.6%, median DoR was 14.5 mo (95% CI, 11.1-NE), progression-free survival (PFS) was 15.2 mo (95% CI, 10.35-NE), and median overall survival (OS) was not yet mature. In cohort 2, confirmed ORRIRC was 31.6%, median DoR was 11.1 mo (95% CI, 4.21-NE), median PFS was 6.2 mo (95% CI, 4.11-NE), and median OS was 13.6 mo (95% CI, 7.13-NE). Overall, the most common treatment-related AE was anemia (any grade, 89%; grade ≥3, 42%); following a per-protocol proposed dose modification algorithm, the incidence of grade ≥3 anemia was reduced to 25.6%.Table:Efficacy-evaluable populationCohort 1 (n=82)Cohort 2 (n=19)Best overall response, n (%)Complete response8 (9.8)0 (0)Partial response45 (54.9)6 (31.6)Stable disease25 (30.5)12 (63.2)Progressive disease4 (4.9)1 (5.3)Objective response rate, % (95% CI)Confirmed64.6 (53.3-74.9)31.6 (12.6-56.6)Disease control rate, % (95% CI)95.1 (88.0-98.7)94.7 (74.0-99.9)Clinical benefit rate, % (95% CI)74.4 (63.6-83.4)52.6 (28.9-75.6)Time to response, median mo (range)1.68 (1.3-6.3)1.38 (1.2-1.4)Duration of response, median mo (95% CI)14.5 (11.1-NE)11.1 (4.21-NE)PFS, median mo (95% CI)15.2 (10.35-NE)6.2 (4.11-NE)Abbreviations: NE, not estimable; PFS, progression-free survival. Open table in a new tab Abbreviations: NE, not estimable; PFS, progression-free survival. Promising antitumor activity was observed in pts with platinum-sensitive/resistant aOC. Pamiparib was generally tolerated, with no new safety signals. Pamiparib is being evaluated as monotherapy and combination therapy for other solid tumors.

Abstract Background Niraparib is a highly selective PARP-1/-2 inhibitor approved by FDA for the maintenance therapy of platinum-sensitive recurrent (PSR) ovarian cancer based on the significantly improved progression-free survival for niraparib-treated patients (pts) in the phase III NOVA study. A retrospective analysis of NOVA study suggests that pts with BW Methods The initial protocol adopted a fixed starting dose of 300 mg QD. After 16 patients were enrolled, the protocol was amended to start niraparib treatment at a dose of 200 mg QD in pts with BW Results A total of 265 pts had been enrolled, and 232 pts who have been followed up ≥ 90 days ending Mar 31, 2019 were included in this analysis. There were no major differences in key pts demographics or disease characteristics between both arms. Key safety data are presented in the table. More detailed safety data in all population will be disclosed. Conclusions The results indicate that niraparib tolerability will be improved with a starting dose based on body weight or platelet count. Clinical trial identification NCT03705156. Editorial acknowledgement Jun Wan and John Zhang of Zai Lab Writing and coordinated by Sean Li and Wendy Zhang of Zai Lab, Inc, funded by Zai Lab, Inc. (Shanghai,China). Legal entity responsible for the study Zai Lab (Shanghai) Co., Ltd. Funding Zai Lab (Shanghai) Co., Ltd. Disclosure J. Hou: Full / Part-time employment: Zai Lab (Shanghai) Co., Ltd C. Zhang: Full / Part-time employment: Zai Lab (Shanghai) Co., Ltd Y. Hei: Full / Part-time employment: Zai Lab (Shanghai) Co., Ltd. All other authors have declared no conflicts of interest. Table: 1004P . Pre-Amendment, Fixed starting dose (pooled niraparib and placebo arms) Post-Amendment, Individualized starting dose (pooled niraparib and placebo arms ) 300 mg (N = 16) 300 mg (N = 14) 200 mg (N = 202) Total (N = 216) Median BW, kg (min, max) 62 (40,76) 83 (78,94) 59 (37,82) 61 (37,94) Median plt count,109/L (min, max) 211 (124,336) 187(153,325) 184 (62,447) 184 (62,447) Any ≥ grade 3 TEAE, n(%) 9 (56.3) 4 (28.6) 56 (27.7) 60 (27.8) ≥Grade 3 thrombocytopenia, n(%) 3 (13.8) 1 (7.1) 6 (3.0) 7 (3.2) ≥Grade 3 anemia, n(%) 4 (25.0) 2 (14.3) 9 (4.5) 11 (5.1) ≥Grade 3 neutropenia, n(%) 2 (12.5) 0 25 (12.4) 25 (11.6) Any serious TEAE, n(%) 4 (25.0) 1 (7.1) 19 (9.4) 20 (9.3) TEAE leading to end of treatment, n (%) 1 (6.3) 0 3 (1.5) 3 (1.4)

The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.

PURPOSE:The N-myc downstream regulated gene 1 (NDRG1)/Cap43 is overexpressed in multiple cancer types, including lung cancer. In this study, we investigated the expression of NDRG1/Cap43 in lung cancer tissues and in serum from 90 lung cancer patients and 60 healthy controls. MATERIALS AND METHODS:Ninety patients with pathologically confirmed primary lung cancer who underwent surgical resections were recruited for the study. From resected sections, we dissected lung tumor tissues and adjacent noncancerous tissues that were used as controls and collected patient sera for NDRG1/Cap43 expression levels. Immunohistochemical staining was applied to detect NDRG1/Cap43-positive tumor cells, and real-time quantitative-PCR (RT-PCR) was used to determine mRNA transcript levels of NDRG1/Cap43 in lung cancer tissues. Serum levels of NDRG1/Cap43 were measured by Enzyme-linked immunosorbent assays (ELISA). Data comparison between two groups was performed by independent two sample test, and comparison between more than two groups was applied by the analysis of variance (ANOVA) test. RESULTS:Compared with adjacent normal tissues, lung cancer tissues had significantly increased expression of NDRG1/Cap43 (P < 0.05). Lung adenocarcinomas also had significantly higher NDRG1/Cap43 levels than lung squamous carcinomas (P < 0.01). RT-PCR analysis showed significantly higher levels of NDRG1/Cap43 mRNA transcripts in lung cancer tissues compared with matched adjacent noncancerous tissues (P < 0.05). mRNA expression of NDRG1/Cap43 was associated with the histological pattern of lung cancer. ELISA analysis for serum NDRG1/Cap43 levels revealed significantly higher levels in lung cancer patients (358.56 ± 233.82 ng/mL) compared with healthy controls (28.83 ± 10.51 ng/mL, P < 0.001). CONCLUSIONS:NDRG1/Cap43 overexpression may be of predictive value in determining the prognosis of lung cancer patients.