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Kaplan-Meier estimate of overall survival

Purpose:Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with non–small cell lung cancer (NSCLC) harboring 21-L858R mutation.Patients and Methods:Patients with treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee.Results:From May 2015 to November 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; and 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively) and was significantly longer than that in L858R-RD group [12.9 months vs. 9.2 months, hazard ratio (HR): 0.75; 95% confidence interval (CI), 0.53–1.05]. A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57–1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups.Conclusions:High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.

Differential binding of icotinib for L858R vs exon19del mutant EGFR. The green represents icotinib; the gray represents pocket residues; the blue represents αC-helix; the red represents delE746-A750; the yellow dotted line indicates hydrogen bond; the Dark green dotted line represents the cation-pi interaction; the GK means gatekeeper.

Purpose: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with non–small cell lung cancer (NSCLC) harboring 21-L858R mutation. Patients and Methods: Patients with treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee. Results: From May 2015 to November 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; and 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively) and was significantly longer than that in L858R-RD group [12.9 months vs. 9.2 months, hazard ratio (HR): 0.75; 95% confidence interval (CI), 0.53–1.05]. A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57–1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. Conclusions: High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.

Introduction: Extensive-stage small cell lung cancer (ES-SCLC) is associated with limited treatment options and poor prognosis. Immunotherapy has recently showed robust clinical activity in ES-SCLC. In this double-blind, phase 3 trial, we evaluated adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, in combination with standard chemotherapy (chemo) as first-line treatment for ES-SCLC. Methods: Patients naïve to systemic treatment for ES-SCLC were randomized 1:1 to receive 4-6 cycles of adebrelimab (20 mg/kg, iv, d1, q3w) or placebo with carboplatin (AUC 5, d1, q3w) plus etoposide (100 mg/m2, d1, d2, d3, q3w), followed by maintenance therapy with adebrelimab or placebo. The primary endpoint was overall survival (OS). Results: 462 patients were randomized and treated (adebrelimab+chemo, n=230; placebo+chemo, n=232). As of Oct 08, 2021, with an median follow-up of 13.5 mo (all patients; 22.5 mo for patients alive), OS was significantly prolonged with adebrelimab+chemo vs placebo+chemo (median, 15.3 mo [95% CI 13.2-17.5] vs 12.8 mo [95% CI 11.3-13.7]; hazard ratio [HR], 0.72 [95% CI 0.58-0.90], 1-sided p=0.0017); OS rate was 62.9% vs 52.0% at 12 mo and 31.3% vs 17.2% at 24 mo. Progression-free survival (PFS) per independent review committee (IRC) was 5.8 mo (95% CI 5.6-6.9) with adebrelimab+chemo vs 5.6 mo (95% CI 5.5-5.7) with placebo+chemo (HR 0.67, 95% CI 0.54-0.83); PFS rate was 49.4% vs 37.3% at 6 mo and 19.7% vs 5.9% at 12 mo. Objective response rate (ORR) and duration of response (DoR) also favored the adebrelimab+chemo group (Table 1). Grade ≥3 treatment-related adverse events occurred in 85.7% vs 84.9% of patients with adebrelimab+chemo vs placebo+chemo, with the most common (frequency ≥5%) being hematological toxicities in both groups. Conclusions: The addition of adebrelimab to chemotherapy significantly improved OS with an acceptable safety profile, supporting this combination as a new first-line treatment option for ES-SCLC. Efficacy outcomes Adebrelimab+Chemo (n=230) Placebo+Chemo (n=232) Median OS (95% CI), mo 15.3 (13.2-17.5) 12.8 (11.3-13.7) HR (95% CI)*, 1-sided log-rank p 0.72 (0.58-0.90); p=0.0017 12-mo OS rate (95% CI), % 62.9 (56.3-68.8) 52.0 (45.4-58.2) 24-mo OS rate (95% CI), % 31.3 (24.9-37.9) 17.2 (12.1-23.0) Median PFS (95% CI), mo 5.8 (5.6-6.9) 5.6 (5.5-5.7) HR (95% CI)*, 1-sided log-rank p 0.67 (0.54-0.83); p Citation Format: Ying Cheng, Jie Wang, Caicun Zhou, Wenxiu Yao, Qiming Wang, Xuhong Min, Gongyan Chen, Xingxiang Xu, Xingya Li, Fei Xu, Yong Fang, Runxiang Yang, Guohua Yu, Youling Gong, Jun Zhao, Yun Fan, Quan Liu, Lejie Cao, Yu Yao, Yunpeng Liu, Xiaoling Li, Jingxun Wu, Zhiyong He, Kaihua Lu, Liyan Jiang, Huiqing Yu, Chengping Hu, Wenhua Zhao, Jian Zhao, Gang Wu, Dingzhi Huang, Chengshui Chen, Cuimin Ding, Baihong Zhang, Xiuwen Wang, Hui Luo, Baolan Li, Ben Zhang, Haowen Li, Ke Ma. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage SCLC: A phase 3 trial [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 CT038.

D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) Background: Despite initial response to EGFR-TKI, most patients (pts) develop resistance with the EGFR T790M mutation detectable in ~50% of patients treated with first-/second-generation EGFR-TKIs. D-0316 is a third-generation EGFR-TKI that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in pts with non-small cell lung cancer (NSCLC). We report the results of a registered, single-arm, phase II study of D-0316 in NSCLC pts with EGFR T790M who progressed on previous treatment with first-line EGFR-TKIs. Methods: In this phase II, open-label, single-arm study, eligible pts were those who had confirmed locally advanced or metastatic NSCLC, and had disease progression after first-line EGFR-TKI and with T790M mutation. Pts were initially orally given D-0316 50 mg. However, considering the benefits and risks of the pts, the dose was modified to 100 mg once daily with a 21-day lead-in at 75 mg once daily. The primary endpoint was objective response rate (ORR) based on independent review committee (IRC) according to RECIST 1.1.Results: As of October 31, 2019, 176 pts were enrolled in the 50 mg phase, in which 90 pts had partial response, achieving an ORR of 51.1% (95%CI: 43.5-58.7). Despite the immature PFS, disease progression or death occurred in 60 pts (34.1%) and the median PFS was 8.4 months (95% CI: 8.0-NE). Between September 12, 2019 and July 29, 2020, 689 pts were screened and 290 pts (median age 62.5) were enrolled in China and received 100mg D-0316 with a 21-day lead-in at 75 mg. At data cutoff (October 18, 2020), the median duration of follow-up was 5.5 months. 188 of the 290 pts achieved confirmed partial responses by IRC. The ORR was 64.8% (95% CI: 59.0-70.3) and the disease control rate (DCR) was 95.2% (95% CI: 92.0-97.3). The ORR was consistent across in most subgroups. Among 34 pts with brain metastases at baseline, 18 pts achieved confirmed partial responses and the intracranial ORR was 52.9% (95% CI: 35.1-70.2). The PFS, DoR, and OS were premature. The most common treatment-related adverse events were thrombocytopenia (57.2%), headache (27.6%), leukopenia (23.4%), anemia (22.1%) and rash (20.7%). The most common grade 3 or higher treatment-related adverse events were thrombocytopenia (11.7%). One death was due to treatment-related adverse events (interstitial lung disease). Six interstitial lung diseases (2.1%) were observed during study treatment. Conclusion: D-0316 has showed strong anti-tumor activities and tolerable toxicity in pts with EGFR T790M-positive NSCLC who have progressed after EGFR-TKI treatment. Citation Format: Shun Lu, Yiping Zhang, Guojun Zhang, Jianying Zhou, Shundong Cang, Ying Cheng, Gang Wu, Peiguo Cao, Dongqing Lv, Xiangming Jin, Hong Jian, Chengshui Chen, Guanming Jiang, Panwen Tian, Kai Wang, Hui Zhao, Gongyan Chen, Qun Chen, Cuimin Ding, Junquan Yang, Renhua Guo, Guoping Sun, Bin Wang, Liyan Jiang, Wu Zhuang, Zhe Liu, Jian Fang, Yunpeng Liu, Jian Zhang, Jun Chen, Yueyin Pan, Qitao Yu, Min Zhao, Jiuwei Cui, Dianming Li, Tienan Yi, Zhuang Yu, Yan Yang, Yan Zhang, Xiuyi Zhi, Yunchao Huang, Rong Wu, Liangan Chen, Aimin Zang, Lejie Cao, Qingshan Li, Xiaoling Li, Yong Song, Donglin Wang, Shucai Zhang. D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT170.