8505 Background: Monoclonal antibodies against programmed death-ligand 1 (PD-L1) have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy. However, whether a programmed death 1 (PD-1) inhibitor provides similar survival benefit in this patient population remains unclear. In this study, the efficacy and safety of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, were assessed in combination with chemotherapy in previously untreated ES-SCLC patients. Methods: In this international, randomized, double-blind, multicenter, phase 3 trial (NCT04063163), patients with ES-SCLC who had not received prior systemic therapy were randomized (2:1) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Between September 12, 2019 and April 27, 2021, 585 patients were randomized (serplulimab group, n = 389; placebo group, n = 196). At interim analysis, the median follow-up duration was 12.3 months. Median OS was significantly prolonged in the serplulimab group than the placebo group (15.4 vs.10.9 months; hazard ratio [HR] 0.63, 95% CI 0.49–0.82; P < 0.001). Median PFS assessed by the independent radiology review committee (IRRC) per RECIST v1.1 was significantly longer in the serplulimab group than the placebo group (5.8 vs. 4.3 months; HR 0.47, 95% CI 0.38–0.59; P < 0.001). Efficacy improvements were also observed in ORR (80.2% vs. 70.4%) and DoR (5.6 vs. 3.2 months) as assessed by IRRC per RECIST v1.1. Grade ≥3 treatment-emergent adverse events (TEAEs) related to serplulimab or placebo were reported in 129 (33.2%) and 54 (27.6%) patients in the respective groups. Incidence of immune-related TEAEs was higher in the serplulimab group compared to the placebo group (37% vs. 18.4%), with the largest difference in endocrine disorders (18.3% vs. 4.6%), which are commonly reported with anti-PD-1/PD-L1 therapies. Four deaths (1 acute coronary syndrome, 1 pyrexia, and 1 platelet count decreased in the serplulimab group; 1 thrombocytopenia in the placebo group) that might be related to study drugs were reported. Conclusions: Serplulimab plus chemotherapy as first-line treatment provided significant benefits and a manageable safety profile compared with chemotherapy alone in ES-SCLC patients. For the first time, OS benefits was demonstrated with a PD-1 inhibitor in a global phase 3 study among previously untreated ES-SCLC patients. Clinical trial information: NCT04063163.

1102 Background: MRG002 is a novel HER2-targeted ADC, composed of a sugar-modified trastuzumab, MMAE payload and a cleavable vc-linker. MRG002 was effective in HER2-low expressing breast cancer in preclinical studies. Hence, we conducted the phase II study to evaluate the safety and anti-tumor efficacy of MRG002 in HER-low breast cancer. Methods: HER2 low tumor expression was determined by a central lab and had to be immunohistochemistry (IHC)1+ or 2+/ISH-. Eligible patients had advanced/metastatic HER2-low expressing breast cancer that failed standard therapies. MRG002 was administered intravenously once every 3 weeks at the dose of 2.6 mg/kg, until disease progression or unacceptable toxicity which ever occurred first. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC). The secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and safety. Results: A total of 56 female patients with HER2-low advanced or metastatic breast cancer were enrolled at the time of data cut-off (Dec 31, 2021) and had received at least one cycle of MRG002. The median age was 55 (30-72) years. Most patients were HER2 IHC1+ (83.9%), hormone receptor positive (HR+) (85.7%), and with a ECOG PS of 1 (57.1%). Twenty-eight patients (50.0%) had received at least 2 lines of chemotherapy and the median treatment was 3. Forty-one patients (73.2%) had visceral metastasis and 31 patients (55.4%) had bone metastasis. The ORR and DCR in 49 evaluable patients were 34.7% and 75.5%, with 17 PR, 20 SD and 12 PD. Subgroup analysis indicated that the ORR was 39.5% (15/38) and DCR was 76.3% (29/38) among the evaluable patients with visceral metastasis. The tumor responses were similar in both the HER2 IHC 1+ and IHC 2+ subgroups, as is 34.1% and 37.5% respectively, which might be attributed to fewer IHC 2+ enrollment in this trial. Although only 8 HR- subjects enrolled in our study, the ORR (37.5%) and DCR (62.5%) is promising in these triple negative BC patients post to ≥2 line therapies. Most common treatment related adverse events (TRAEs) were grade 1 or 2. The most common TRAEs (≥20%) were neutrophil count decreased (53.6%), white blood cell count decreased (48.2%), AST increased (46.4%), alopecia and ALT increased (39.3%), blood lactate dehydrogenase increased(33.9%), GGT increased (32.1%), nausea (32.1%), vomiting (23.2%), constipation (23.2%), diarrhea(23.2%) and hyperglycemia (21.4%). Most common grade ≥3 TRAE(≥10%) was neutrophil count decreased(14.3%). No patients died due to MRG002. Conclusions: MRG002 shows promising efficacyand well tolerated in patients with HER2-low breast cancer. Further evaluation is underway. Clinical trial information: NCT04742153.

Background Entinostat is a novel, potent, once weekly, orally bioavailable, class I selective histone deacetylase (HDAC) inhibitor. In a previous Phase II study, the combination of entinostat with exemestane showed significant improvement of overall survival in patients with advanced hormone receptor (HR) positive breast cancer. To verify and further confirm the benefit of HDAC inhibitor in combination with exemestane we designed a randomized, controlled trial to assess the efficacy and safety in a larger population of Chinese patients with advanced, HR positive breast cancer. Methods We carried out the randomized, double-blind, placebo-controlled, Phase III trial at 35 sites in China. Eligible patients were women (aged ≥18 years) with HR positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, ECOG performance status of 0-1, and adequate haematological and biochemical parameters. Patients were randomly assigned (2:1) via an interactive web-response system to orally take 5 mg entinostat or placebo. Both groups received oral administration of 25 mg exemestane daily. Randomization was stratified according to previous usage of CDK4/6 (yes vs no), fulvestrant (yes vs no), chemotherapy (yes vs no), and the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was Independent Radiographic Committee (IRC)-assessed progression free survival (PFS). Efficacy and safety analyses were done in all patients who received at least one dose of any study treatment. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. This study was registered with ClinicalTrials.gov with the number of NCT03538171. Results From April 16th, 2019 to May 13th, 2020, 354 patients were enrolled and randomly assigned as 235 to the entinostat group and 119 to the placebo group. IRC-assessed median PFS was 6.32 months (95% CI 5.30-9.11) in the entinostat group and 3.72 months (95% CI 1.91-5.49) in the placebo group (HR 0.74 [95% CI 0.57-0.96]; p&lt;0.001). The most common Grade 3 or 4 adverse events in the entinostat group vs placebo group were neutropenia (103 [43.8%] vs 119 [0.8%] ), thrombocytopenia (20 [8.5%] vs 1 [0.8%]), and leucopenia (15 [6.4%] vs 0). Serious adverse events occurred in 28 out of 235 patients (11.9%) in the entinostat group and 11 out of 119 patients (9.2%) in the placebo group. Conclusions Entinostat and exemestane combination treatment significantly improved PFS compared with exemestane alone in patients with advanced, HR positive, HER2 negative breast cancer that progressed after previous endocrine therapy. Entinostat and exemestane combination was generally tolerated and can offer meaningful clinical benefit in these patients with unmet medical need. This phase III trial was sponsored by Taizhou EOC Pharma Co., Ltd. Citation Format: Binghe Xu, Qingyuan Zhang, Xichun Hu, Qing Li, Tao Sun, Wei Li, Quchang Ouyang, Jingfen Wang, Zhongsheng Tong, Min Yan, Huiping Li, Xiaohua Zeng, Changping Shan, Xian Wang, Xi Yan, Jian Zhang, Yue Zhang, Jiani Wang, Liang Zhang, Ying Lin, Jifeng Feng, Qianjun Chen, Jian Huang, Yongkui Lu, Hongsheng Li, Jinsheng Wu, Jing Cheng, Yanrong Hao, Cuizhi Geng, Min Lu, Yanping Li, Xi Chen, Lihua Song, Xueying Wu, Changlu Hu, Xinhong Wu, Xiaojia Wang, Yueyin Pan, Yuehong Cui, Guohua Yu, Sanyuan Sun. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-06.

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.

9001 Background: Patients (pts) with EGFRm+ NSCLC have high rates of CNS metastasis, few treatment options, and a poor prognosis. So far there are no solid evidence from head to head phase 3 trials in this setting. The potent EGFR TKI AZD3759 has high blood–brain barrier penetration, preliminary data has shown promising intracranial (IC) and systemic antitumor activity, and a tolerable safety profile. Methods: This was the first phase 3, open-label, multicenter, randomized controlled trial to compare the efficacy and safety of first-line AZD3759 with first generation EGFR TKIs specifically in pts with EGFRm+ (L858R and/or exon 19Del) NSCLC and CNS metastasis. Adult pts were randomized 1:1 to receive AZD3759 (200 mg twice daily) or first generation EGFR TKIs (the control group, gefitinib 250 mg or erlotinib 150 mg once daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Results: Between Feb 1, 2019, and Jan 12, 2021, 439 pts were randomized: 220 to AZD3759 and 219 to the control group. As of July 12, 2022, median follow-up was 20.4 months (mo) for both. Median PFS (95% CI) was significantly superior with AZD3759 vs the control group (9.6 [8.2–9.7] vs 6.9 [6.3–8.0] mo; HR 0.719, 95% CI 0.580–0.893; p=0.0024). The objective response rate (ORR; BICR/RECIST 1.1) was 68.6% for AZD3759 vs 58.4% for the control group ( p=0.027), with a trend toward longer median duration of response (DoR) with AZD3759 (8.2 vs 6.8 mo; p=0.0997). IC PFS, ORR, and DoR with AZD3759 were all superior vs the control group regardless of the assessor or evaluation criteria. The overall survival was immature. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs 94.0%). Grade ≥3 TRAEs occurred in 65.9% (AZD3759) and 18.3% (the control group) of pts. The main TRAEs were skin and subcutaneous tissue events, gastrointestinal system events and abnormal liver function. No new safety signals arose. Conclusions: First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm+ NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity. Clinical trial information: NCT03653546 . [Table: see text]