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Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial

      Abstract

      Introduction

      As a novel third-generation EGFR tyrosine kinase inhibitor (TKI), SH-1028 (formerly oritinib) is developed to inhibit both sensitizing EGFR mutations and EGFR T790M mutation.

      Methods

      This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807). Eligible patients were those with advanced NSCLC with centrally confirmed EGFR T790M mutation who progressed after first- or second-generation EGFR TKIs or with primary EGFR T790M mutations. Each patient received SH-1028 tablets orally at 200 mg/d until disease progression or intolerable toxicity. Tumor response was evaluated every 6 weeks per the Response Evaluation Criteria in Solid Tumors, version 1.1. The primary end point was objective response rate by an independent review committee. The secondary end points were progression-free survival, overall survival (OS), disease control rate, safety, and so on.

      Results

      A total of 286 patients with EGFR T790M-positive advanced NSCLC were enrolled in this study, including 59 patients in part A (dose-verification study) and 227 patients in part B (second-line registration study). By data cutoff on September 17, 2021, the independent review committee–assessed objective response rate was 55.9% (95% confidence interval [CI]: 42.4–68.8) in part A and 60.4% (95% CI: 53.7–66.8) in part B. The median progression-free survival was 12.4 months (95% CI: 8.3–20.8) in part A and 12.6 months (95% CI: 9.7–15.3) in part B. The median OS was 26.0 months (95% CI: 23.3–not reached) in part A, and OS was immature in part B. Among the 286 patients, 44 of them experienced at least one grade 3 or higher treatment-related adverse event, with the most common ones as increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (three [1.0%]). Treatment-related skin rash was reported in 26 patients (9.1%), all grade 1 or 2. There was no interstitial lung disease reported in this study.

      Conclusions

      SH-1028 is efficacious and tolerable in second-line treatment of patients with advanced NSCLC with positive EGFR T790M.

      Keywords

      Introduction

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      SH-1028 is a novel, irreversible, third-generation EGFR TKI developed by Nanjing Sanhome Pharmaceutical Co., Ltd. The inhibitory activities of osimertinib and its active metabolites against wild-type EGFR resulted in diarrhea and rash.
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      Previous phase 1 trial (NCT03603262) revealed the preliminary clinical efficacy and tolerable toxicity of SH-1028 on patients with locally advanced or metastatic NSCLC with EGFR T790M mutation and identified the recommended phase 2 dose as 200 mg once daily (data unpublished).
      This phase 2 trial (NCT03823807) was divided into the following two parts: part A (dose-verification study) and part B (second-line registration study). By data cutoff on September 17, 2021, independent review committee (IRC)–assessed ORR was 55.9% (95% confidence interval [CI]: 42.4–68.8) in part A and 60.4% (95% CI: 53.7–66.8) in part B. The median PFS was 12.4 months (95% CI: 8.3–20.8) in part A and 12.6 months (95% CI: 9.7–15.3) in part B. This study is ongoing for survival follow-up.

      Materials and Methods

      Patient

      This was a multicenter, single-arm, open-label, phase 2 trial (NCT03823807), including the following two parts: part A (dose-verification study) and part B (second-line registration study). Eligible patients were screened at 12 centers in part A and 47 centers in part B.
      Patients were eligible if they were aged 18 years or above; had histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v.1.1); Eastern Cooperative Oncology Group performance status score of 0 to 2 with a life expectancy of more than 3 months; had PD after first- or second-generation EGFR TKI therapy; and had signed written informed consents. All the patients must confirm from tumor tissue or pleural effusion cells to harbor an acquired or primary EGFR T790M mutation by the central laboratory using ADx-ARMS EGFR Detection Method (Amoy Diagnostics Co., Ltd., Xiamen, People’s Republic of China). Patients with asymptomatic stable central nervous system metastases not requiring steroids for at least 4 weeks before the first dose of SH-1028 were permitted into the trial.
      Key exclusion criteria included previous treatment with third-generation EGFR TKIs; treatment with any cytotoxic chemotherapy or any other anticancer drugs within 14 days of the first dose of SH-1028; treatment with any investigational drugs within 5 half-lives or 14 days of the first dose of SH-1028; inadequate bone marrow and organ function; and history of hypersensitivity to any ingredients of SH-1028. Detailed inclusion and exclusion criteria are presented in Supplementary Table 1.

      Treatment and Assessments

      All the patients were administered SH-1028 orally at 200 mg/d in 21-day cycles until PD, intolerable toxicity, withdrawal of consent, or when other discontinuation criteria were met. Subsequent SH-1028 therapy was allowed if the investigator determined that the patients with PD could still achieve clinical benefits.
      Systemic and intracranial tumor responses were evaluated by both the IRC and investigators every 6 weeks as per RECIST v.1.1. The primary end point was ORR, which was defined as the percentage of patients who had confirmed as complete response (CR) or partial response (PR). The secondary end points included the following: DCR, which was defined as the percentage of patients who had confirmed as CR, PR, or stable disease (SD); duration of response (DOR), which was defined as the time since first recorded nonprogression response until the time of recorded progression or death; PFS, which was defined as time since first dose to PD or death; OS, which was defined as time since the first dose to death for any reason; intracranial ORR (iORR), which was defined as the percentage of patients with brain metastases who had confirmed as intracranial CR or PR; intracranial DCR (iDCR), which was defined as the percentage of patients with brain metastases who had confirmed as intracranial CR, PR, or SD; and intracranial PFS, which was defined as the time since the first dose to intracranial lesions progression or death.
      The severity of adverse events (AEs) was evaluated by investigators according to Common Terminology Criteria for Adverse Events, version 5.0. From the time when patients signed the informed consents to 30 days after the last administration, all AEs occurring throughout the study should be recorded, including AEs, serious AEs, deaths, discontinuation for any reason, abnormal laboratory test results, and changes in vital signs or physical examination findings. The investigators carried out follow-up visit regularly for safety assessment and determined the relationship between AEs and the treatment.

      Statistical and Regulatory Considerations

      Part A of the study was aimed to verify the preliminary efficacy and safety of SH-1028 as second-line treatment. When at least 30 patients underwent tumor evaluation by the investigators and ORR exceeded 45% in part A, part B would be started. Meanwhile, according to the requirements of the Center for Drug Evaluation, enrollment in part A would continue until 60 patients were enrolled. It was assumed that the ORR of SH-1028 was 55% and ORR threshold was set at 45%, α = 0.05, with 80% test power, and sample size would be 200 patients. Considering a certain dropout rate of 10%, approximately 220 patients would be enrolled in part B of the study.
      All data for this analysis were cut off on September 17, 2021. The numbers of patients with CR, PR, SD, PD, and unevaluable disease were recorded, and then ORR and DCR were calculated according to the IRC-assessed best overall response during the study. The two-sided 95% CIs were estimated by using the Clopper-Pearson exact method. Kaplan-Meier method was used for time-to-event efficacy analyses, such as PFS, DOR, and OS. Chi-square test was used to compare intragroup differences in each subgroup. The AEs were coded according to MedDRA (Chinese 24.0 or latest version) and graded using the Common Terminology Criteria for Adverse Events, version 5.0. SAS software version 9.2 or above (SAS Institute, Cary, NC) was used to perform all the calculations. The Janus Clinical Research Institute was responsible for the statistical analysis of efficacy and safety data. This study was registered with clinical trials.gov, NCT03823807.
      This trial was conducted in accordance with the Declaration of Helsinki, the Good Clinical Practice issued by the China National Medical Products Administration, and the Good Clinical Practice principles of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, including the Drug Administration Law of the People's Republic of China. This study also complied with local laws and regulations and was approved by the ethics committee of each center.

      Results

      Patient

      Between April 4, 2019, and September 17, 2021, a total of 532 EGFR T790M-positive patients were screened, with 288 patients were eligible and enrolled in this study, of whom 286 patients received at least one dose of SH-1028 (200 mg, once daily) and were included in the full analysis set and safety analysis set (Fig. 1).
      A total of 59 EGFR T790M-positive patients with measurable baseline lesions were enrolled into part A at 12 centers in the People’s Republic of China from April 4, 2019, to February 5, 2020. All these patients received at least one dose of SH-1028 orally at 200 mg/d and were included in full analysis set of efficacy. In part A, all the patients had adenocarcinoma. Before participating in this study, 31 patients (52.5%) received one line of therapy, among whom, one was treated with chemotherapy and 30 were treated with EGFR TKI; 26 patients (44.1%) received at least two lines of therapy, in whom all received one line of EGFR TKI therapy and at least one line of chemotherapy. There were 56 patients (94.9%) with an acquired EGFR T790M mutation after previous first- or second-generation TKI therapy and three having primary EGFR T790M mutation. Among them, 37 patients (62.7%) had EGFR exon 19 deletion mutation, 21 (35.6%) EGFR exon 21 L858R mutation, and one (1.7%) EGFR G719X mutation. At the data cutoff on September 17, 2021, as confirmed by the investigators, 46 patients (78.0%) discontinued SH-1028, among whom 23 (39.0%) withdrew from the study, including 21 deaths, and the other 23 (39.0%) patients were still ongoing for survival follow-up. There were 13 patients (22.0%) remaining on SH-1208 therapy.
      From December 19, 2019, to March 17, 2021, a total of 227 patients with EGFR T790M-positive advanced NSCLC were enrolled into part B at 47 centers in the People’s Republic of China. All the 227 patients had measurable lesions at baseline and had orally administered SH-1028 200 mg/d for at least once. Thus, all the patients were included in the analyses of efficacy. In part B, 223 (98.2%) patients had adenocarcinomas. Before participating in this study, 161 patients (70.9%) received one line of therapy, among whom, 160 were treated with EGFR TKI and one was treated with chemotherapy; 57 patients (25.1%) received at least two lines of therapy, 55 of them received one line of EGFR TKI therapy and at least one line of chemotherapy, and two patients only received two lines of EGFR TKI therapy. There were 217 cases with confirmed EGFR T790M mutation after previous treatment with first- or second-generation EGFR TKI and 10 patients with primary EGFR T790M mutation. There were 144 patients (63.4%) who had EGFR exon 19 deletion mutation and 69 (30.4%) who had EGFR exon 21 L858R mutation. At the data cutoff on September 17, 2021, 136 patients (59.9%) discontinued SH-1028, among whom 54 (23.8%) withdrew from the study, including 39 deaths, and the other 82 (36.1%) were still ongoing for survival follow-up. In part B, 91 patients (40.1%) remained on SH-1208. Detailed demographic and baseline tumor information of all the patients are found in Table 1.
      Table 1Baseline Demographic and Characteristics of Patients
      CharacteristicsPart A (n = 59)Part B (n = 227)
      Age, y, median (range)62.0 (35–78)62.0 (35–87)
       <65, n (%)35 (59.3)133 (58.6)
       ≥65, n (%)24 (40.7)94 (41.4)
      Sex, n (%)
       Male21 (35.6)97 (42.7)
       Female38 (64.4)130 (57.3)
      ECOG performance status, n (%)
       09 (15.3)20 (8.8)
       149 (83.1)198 (87.2)
       21 (1.7)9 (4.0)
      Smoking status, n (%)
       Never45 (76.3)169 (74.4)
       Ever14 (23.7)58 (25.6)
      Pathological types, n (%)
       Adenocarcinoma59 (100.0)223 (98.2)
       Squamous cell carcinoma01 (0.4)
       Others03 (1.3)
      EGFR sensitizing mutation type, n (%)
       None (T790M mutation only)02 (0.9)
       Exon 19 deletion37 (62.7)144 (63.4)
       L858R21 (35.6)69 (30.4)
       Others
      Other mutations: comutations of L858R and exon 19 deletion, no sensitizing EGFR mutations (EGFR Thr790Met resistance mutation only), or only rare sensitizing EGFR mutations or comutations (G719X, S768I, L861Q mutation, or comutation, etc.).
      1 (1.7)12 (5.3)
      EGFR TKI treatment, n (%)
       Gefitinib37 (62.7)152 (67.0)
       Icotinib16 (27.1)56 (24.7)
       Erlotinib3 (5.1)12 (5.3)
       Afatinib05 (2.2)
       Others03 (1.3)
      Disease stage, n (%)
       IV57 (96.6)226 (99.6)
       IIIB2 (3.4)1 (0.4)
      Brain metastases, n (%)
       Yes21 (35.6)80 (35.2)
       No38 (64.4)147 (64.8)
      ECOG, Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor.
      a Other mutations: comutations of L858R and exon 19 deletion, no sensitizing EGFR mutations (EGFR Thr790Met resistance mutation only), or only rare sensitizing EGFR mutations or comutations (G719X, S768I, L861Q mutation, or comutation, etc.).

      Efficacy

      Efficacy in EGFR T790M-Positive Patients

      In part A, one patient achieved CR, 32 achieved PR, and 24 had SD as confirmed by IRC, with an ORR of 55.9% (95% CI: 42.4–68.8) (Fig. 2A) and a DCR of 98.3% (95% CI: 90.9–>99.9). Of the 33 patients confirmed to have an objective response, 17 (51.5%) had progressed or died subsequently by the data cutoff on September 17, 2021, whereas data of the other 16 patients (48.5%) were censored. The median DOR was 15.2 months (95% CI: 8.3–not reached). On the basis of the IRC assessment, there were 29 patients (49.2%) who had progressed or died at the cutoff date, whereas the other 30 (50.8%) were censored. The median PFS was 12.4 months (95% CI: 8.3–20.8) (Fig. 3A). The PFS rates at 6 months and 12 months were 73.2% (95% CI: 59.0–83.2) and 51.3% (95% CI: 35.8–64.8), respectively. At the cutoff date, 21 patients (35.6%) had died, with a median follow-up of 18.2 months (interquartile range: 9.7–23.5), and the median OS was 26.0 months (95% CI: 23.3–not reached) (Fig. 3A). On December 3, 2019, a total of 33 patients in part A were assessed by investigators, with an ORR of 54.5%; thus, part B started the enrollment on December 19, 2019.
      Figure thumbnail gr2
      Figure 2Waterfall plot for best percentage change from baseline in target lesion size by IRC: (A) patients in part A (n = 59); (B) patients in part B (n = 227); and (C) patients with assessable intracranial metastases (n = 31). CI, confidence interval; CR, complete response; DCR, disease control rate; IRC, independent review committee; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier plots for mPFS and mOS of (A) patients in part A (n = 59) and (B) patients in part B (n = 227). (C) Subgroup analyses of patients with exon 19 deletion mutation (n = 144) or exon 21 L858R mutation (n = 69). (D) Subgroup analyses of patients with brain metastases (n = 80) or without brain metastases (n = 147). (E) Forest plot for subgroup analyses of the ORR of patients in part B (n = 227). mOS, median OS; mPFS, median PFS; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
      In part B, 137 patients achieved PR and 68 achieved SD, with an IRC-assessed ORR of 60.4% (95% CI: 53.7–66.8) and an IRC-assessed DCR of 92.5% (95% CI: 88.3–95.6) (Fig. 2B). Of the 137 patients with confirmed objective response, 42 (30.7%) had progressed or died subsequently by the data cutoff on September 17, 2021, whereas the other 95 patients (69.3%) were censored. The median DOR was 12.5 months (95% CI: 11.2–NR). According to the IRC assessment, 91 patients (40.1%) had experienced PFS events at the cutoff date, whereas the other 136 (59.9%) were censored, and the mPFS was 12.6 months (95% CI: 9.7–15.3) (Fig. 3B). The PFS rates at 6 months and 12 months were 70.7% (95% CI: 63.8–76.5) and 52.9% (95% CI: 44.8–60.3), respectively. At the cutoff date, 39 patients (17.2%) had died, with a median follow-up time of 9.7 months (interquartile range: 5.8–12.5), but OS data were immature (Fig. 3B). The detailed evaluation results are found in Figure 3 and Table 2.
      Table 2Summary of Efficacy Assessed by IRC
      ParametersPart A (n = 59)Part B (n = 227)
      ORRn (%)33 (55.9)137 (60.4)
      95% CI42.4, 68.853.7, 66.8
      DCRn (%)58 (98.3)210 (92.5)
      95% CI90.9, >99.988.3, 95.6
      Overall optimal response
       CRn (%)1 (1.7)0
       PRn (%)32 (54.2)137 (60.4)
       SDn (%)24 (40.7)68 (30.0)
       NNn (%)1 (1.7)5 (2.2)
       PDn (%)1 (1.7)8 (3.5)
       NEn (%)09 (4.0)
       PFSMedian (mo)12.412.6
      95% CI8.3, 20.89.7, 15.3
      OSMedian (mo)26.0NR
      95% CI23.3, NRNR, NR
      CI, confidence interval; CR, complete response; DCR, disease control rate; IRC, independent review committee; NE, not evaluable; NN, not CR/not PD; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

      Intracranial Efficacy

      Patients with measurable brain metastasis lesions at baseline in part B were included in the intracranial efficacy analysis to evaluate the intracranial efficacy of SH-1028 as per RECIST v.1.1. A total of 80 patients (35.2%) had brain metastases at baseline, 31 of whom had measurable intracranial lesions. Among these 31 assessable patients, 11 were confirmed by IRC to be PR, 18 were SD, with an iORR at 35.5% (95% CI: 19.2–54.6) (Fig. 2C) and the iDCR at 93.5% (95% CI: 78.6–99.2). A total of 23 patients (74.2%) had progressed or died at the cutoff date, whereas the other eight (25.8%) were censored, as assessed by the IRC. The intracranial PFS was 4.3 months (95% CI: 4.1–6.9). The detailed results are found in Supplementary Table 2.

      Subgroup Analysis

      Subgroup analysis of the primary efficacy end point (ORR) was conducted in the 227 EGFR T790M-positive patients from part B study. The factors of stratified analysis include sex, age, Eastern Cooperative Oncology Group performance status, smoking history, brain metastases, liver metastases, EGFR L858R mutation or exon 19 deletion, duration of previous EGFR TKI treatment, and lines of previous antitumor treatment.
      The ORR of patients with EGFR exon 19 deletion (71.5%) was significantly higher than that of the ones with EGFR L858R mutation (36.2%) (p ≤ 0.001); the mPFS of patients with EGFR exon 19 deletion was 13.8 months, longer than 9.7 months of patients with EGFR L858R mutation (Fig. 3C). The ORR of patients with brain metastases (53.8%) was lower than that of patients without brain metastases (63.9%) (p = 0.134). The mPFS of patients with brain metastases was 8.3 months, and that of patients without brain metastases was 13.8 months (Fig. 3D). A total of 29 patients (12.8%) had assessable liver metastasis lesions, and ORR of those with liver metastases (69.0%) was slightly higher than that of those without liver metastases (59.1%), but the difference was not statistically significant (p = 0.310). The forest plot for subgroup analyses of ORR is found in Figure 3D.

      Safety

      By the data cutoff on September 17, 2021, the median duration of treatment was 293 days in part A and 252.5 days in part B, with 13.95 and 12.02 cycles, respectively. The median daily dose intensity was 200.00 mg, with a relative dose intensity of 1.00 mg. The patients in the two cohorts had good compliance. The safety profile is found in Supplementary Table 3.
      Between April 4, 2019, and September 17, 2021, a total of 286 EGFR T790M-positive patients from part A and B studies had at least one safety follow-up. So, all patients were included in the safety analysis for second-line therapy. A total of 271 patients (94.8%) reported at least one treatment-emergent AE, including 244 (85.3%) cases considered to be treatment related. A total of 81 patients (28.3%) reported grade 3 or higher treatment-emergent AE, including 44 (15.4%) treatment-related events. At least one serious AE occurred in 53 patients (18.5%), including 10 (3.5%) treatment-related events. Owing to TRAEs, 29 patients (10.1%) interrupted the treatment, six patients (2.1%) reduced the dose, and five patients (1.7%) discontinued the treatment.
      The most common (≥10%) TRAEs included diarrhea (111 [38.8%]), increased serum creatinine phosphokinase level (75 [26.2%]), decreased leukocyte count (40 [14.0%]), increased serum creatinine phosphokinase MB level (38 [13.3%]), increased aspartate aminotransferase level (33 [11.5%]), increased serum creatinine level (32 [11.2%]), and nausea (30 [10.5%]). TRAEs of grade 3 or higher mainly included increased serum creatinine phosphokinase level (13 [4.5%]), diarrhea (six [2.1%]), and prolonged QT interval (3 [1.0%]). The incidence of treatment-related rash was 9.1% (26 of 286), all grades 1 to 2. There was no interstitial lung disease that occurred. Detailed common AEs that occurred during treatment are presented in Table 3.
      Table 3Summary of Common (≥10%) TEAEs or (≥5%) TRAEs in EGFR T790M-Positive Patients (n = 286)
      AETreatment-Emergent, n (%)Treatment-Related AE, n (%)
      Any gradeGrade ≥3Any gradeGrade ≥3
      Diarrhea119 (41.6)6 (2.1)111 (38.8)6 (2.1)
      Increased serum creatinine phosphokinase80 (28.0)13 (4.5)75 (26.2)13 (4.5)
      Anemia53 (18.5)2 (0.7)26 (9.1)2 (0.7)
      Decreased white blood cell count45 (15.7)2 (0.7)40 (14.0)0
      Nausea42 (14.7)030 (10.5)0
      Upper respiratory tract infection40 (14.0)3 (1.0)8 (2.8)0
      Increased serum creatinine phosphokinase MB40 (14.0)038 (13.3)0
      Decreased appetite39 (13.6)023 (8.0)0
      Cough39 (13.6)04 (1.4)0
      Increased serum creatinine38 (13.3)1 (0.3)32 (11.2)1 (0.3)
      Vomiting38 (13.3)1 (0.3)27 (9.4)0
      Increased aspartate aminotransferase36 (12.6)033 (11.5)0
      Decreased platelet count33 (11.5)2 (0.7)28 (9.8)1 (0.3)
      Rash28 (9.8)026 (9.1)0
      Increased blood lactate dehydrogenase28 (9.8)022 (7.7)0
      Positive in occult blood26 (9.1)015 (5.2)0
      Increased alanine aminotransferase25 (8.7)024 (8.4)0
      Hyperuricemia24 (8.4)1 (0.3)19 (6.6)1 (0.3)
      Prolonged electrocardiogram QT interval23 (8.0)3 (1.0)21 (7.3)3 (1.0)
      Increased α-hydroxybutyrate dehydrogenase23 (8.0)021 (7.3)0
      Decreased neutrophil counts21 (7.3)2 (0.7)18 (6.3)0
      Increased blood bilirubin18 (6.3)017 (5.9)0
      AE, adverse event; TEAE, treatment-emergent AE; TRAE, treatment-related AE.

      Discussion

      In this study, SH-1028, a newly developed third-generation EGFR TKI, was found to have significant antitumor efficacy in patients with advanced NSCLC with positive EGFR T790M mutation, with an overall ORR of 60.4% and PFS of 12.6 months in part B study. The lower limit of the 95% CI for ORR was above the null hypothesis of 45%, reaching the primary end point of the study. The safety profile with SH-1028 in this study was acceptable and manageable.
      Comparison of efficacy of third-generation EGFR TKIs: As found in AURA2 extension component study in patients with advanced NSCLC, osimertinib achieved an ORR of 62% (95% CI: 54–68), a DCR of 90% (95% CI: 85–94), and a median PFS of 12.3 months (95% CI: 9.5–13.8).
      • Yang J.C.
      • Ahn M.J.
      • Kim D.W.
      • et al.
      Osimertinib in pretreated T790M-positive advanced non–small-cell lung cancer: AURA study phase 2 extension component.
      Aumolertinib had similar efficacy to that of osimertinib, with an ORR of 68.9% (95% CI: 62.6–74.6), a DCR of 93.4% (95% CI: 89.6–96.2), and a median PFS of 12.4 months (95% CI: 9.7–15.0).
      • Lu S.
      • Wang Q.M.
      • Zhang G.J.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial.
      Furmonertinib, a drug approved for patients with EGFR T790M-positive NSCLC in the People’s Republic of China, achieved an ORR of 74% (95% CI: 68–80) and a median PFS of 9.6 months (95% CI: 8.2–9.7).
      • Shi Y.K.
      • Hu X.S.
      • Zhang S.C.
      • et al.
      Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
      As for the subgroups, osimertinib achieved an ORR of 67% (95% CI: 58–76) in Asian population and an ORR of 74% (95% CI: 61.5–84.5) in Korean population.
      • Ahn M.J.
      • Han J.Y.
      • Kim D.W.
      • et al.
      Osimertinib in patients with T790M-positive advanced non-small cell lung cancer: Korean subgroup analysis from phase 2 studies.
      In a dose-escalation and dose-expansion study, rezivertinib achieved an overall ORR of 59.3% (95% CI: 51.6–66.7), a DCR of 91.3% (95% CI: 86.0–95.0), and a mPFS of 9.7 months (95% CI: 8.3–11.1); notably, the ORR of the 180 mg (RP2D) dose group was 60.5%.
      • Shi Y.K.
      • Zhao Y.Q.
      • Yang S.
      • et al.
      Safety, efficacy, and pharmacokinetics of rezivertinib (BPI-7711) in patients with advanced NSCLC with EGFR T790M mutation: a phase 1 dose-escalation and dose-expansion study.
      The efficacy of SH-1028 was comparable with that of these other third-generation EGFR TKIs, having an ORR of 60.4%, a DCR of 92.5%, a DOR of 12.5 months, and a PFS of 12.6 months in this study.
      In the subgroup analysis of this trial, the ORR of patients with brain metastases (53.8%) was lower than that of patients without brain metastases (63.9%). The intracranial efficacy of SH-1028 was not as good as the other third-generation TKIs, with an iORR of 35.5% (95% CI: 19.2–54.6) and an iDCR of 93.5% (95% CI: 78.6–99.2). This result might associate with the small sample size (only 31 patients with assessable intracranial lesions were enrolled), and many of the patients with brain metastases were treated with whole-brain radiation. The efficacy of SH-1208 in patients with brain metastases will be further analyzed in the ongoing phase 3 trial. Besides, the ORR of those with liver metastases (69.0%) was slightly higher than that of those without liver metastases (59.1%); the mPFS of patients with liver metastases was 6.8 months; and the mDOR was 8.1 months (Supplementary Table 4). Approximately 13% of patients with metastatic NSCLC had liver metastases. A study in Cox proportional hazards model revealed that liver metastasis was an unfavorable prognostic factor for the survival in patients with advanced NSCLC, resulting in a median OS of only 3.8 months, whereas brain and bone metastases were not statistically significant prognostic factors.
      • Tamura T.
      • Kurishima K.
      • Nakazawa K.
      • et al.
      Specific organ metastases and survival in metastatic non-small-cell lung cancer.
      At present, our sample size of the liver metastasis subgroup is small, the representativeness for efficacy is limited, and further analysis will be done in our phase 3 trial (NCT04239833). Considering the short survival of patients with advanced NSCLC with liver metastases, SH-1028 may have the potential to benefit these patients. In addition, through the subgroup analysis, the ORR of patients with EGFR exon 19 deletion (71.5%) was significantly higher than that of patients with EGFR L858R mutation (36.2%); similar trend was also observed in the mPFS. These results suggest that SH-1028 can bring more benefits to patients with EGFR exon 19 deletion.
      The safety data in this study revealed that SH-1028 was well tolerated in T790M-positive patients. TRAEs of grade 3 or higher mainly included increased serum creatinine phosphokinase level (4.5%), diarrhea (2.1%), and prolonged QT interval (1.0%). Especially, the incidence of treatment-related rash was only 9.1%, all grades 1 to 2. This suggests that SH-1028 has much less skin toxicity compared with osimertinib. Reviewing the recent safety results in the Asian subgroup, most common TRAEs of osimertinib in Chinese were decreased white blood cell count (41%), anemia (38%), rash or acne (37%), thrombocytopenia (28%), diarrhea (24%), and decreased neutrophil count (24%)21; however, those in Korean were rash (53%), cough (33%), paronychia, diarrhea, and decreased appetite (each 32%).
      • Ahn M.J.
      • Han J.Y.
      • Kim D.W.
      • et al.
      Osimertinib in patients with T790M-positive advanced non-small cell lung cancer: Korean subgroup analysis from phase 2 studies.
      Various study results of osimertinib revealed that rash was still the most significant AE, with the incidence ranging from 37% to 46.2%. It was followed by diarrhea, with the incidence ranging from 24% to 47%, significantly higher than other adverse reactions in some trials.
      • Yang J.C.
      • Ahn M.J.
      • Kim D.W.
      • et al.
      Osimertinib in pretreated T790M-positive advanced non–small-cell lung cancer: AURA study phase 2 extension component.
      ,
      • Jänne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
      ,
      • Ahn M.J.
      • Han J.Y.
      • Kim D.W.
      • et al.
      Osimertinib in patients with T790M-positive advanced non-small cell lung cancer: Korean subgroup analysis from phase 2 studies.
      ,
      • Cheng Y.
      • He Y.
      • Li W.
      • et al.
      Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China, a randomized study.
      • Ohe Y.
      • Imamura F.
      • Nogami N.
      • et al.
      Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset.
      • Ahn M.J.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies.
      In fact, the molecular structure of SH-1028 was optimized in the early stage of research and development to reduce the inhibition of wild-type EGFR, with the purpose to reduce skin and gastrointestinal toxicity clinically.
      • Han L.W.
      • Zhang X.M.
      • Wang Z.Q.
      • et al.
      SH-1028, an irreversible third-generation EGFR TKI, overcomes T790M-mediated resistance in non-small cell lung cancer.
      Although the incidence of diarrhea with severity greater than or equal to grade 3 was very low and most cases resolved spontaneously, the occurrence of diarrhea in patients after medication remained high in this study. Furthermore, as one of the two main active metabolites of osimertinib, AZ5104 displayed a greater potency than osimertinib in vitro, but a far poor selectivity for wild-type and mutant EGFR in vitro, whereas AZ7550 had a decreased potency against the mutant and wild-type EGFR in vitro but offered a similar selectivity profile to osimertinib.
      • Zhou P.
      • Chen G.
      • Gao M.Q.
      • Wu J.
      Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC.
      So, the typical EGFR toxicities of osimertinib probably attribute to these metabolites, especially to AZ5104. Nevertheless, Imp3, the main active metabolite of SH-1028, exhibited good inhibition efficiency against EGFR-mutated kinases and cells in vitro but a weaker inhibitory effect on wild-type EGFR, indicating it can maintain a good selectivity.
      • Han L.W.
      • Zhang X.M.
      • Wang Z.Q.
      • et al.
      SH-1028, an irreversible third-generation EGFR TKI, overcomes T790M-mediated resistance in non-small cell lung cancer.
      Through a unique metabolic pathway, SH-1028 may confer fewer adverse reactions compared with osimertinib.
      Potential cardiotoxicity is one of the most important safety events that should be paid attention. Referring to the results of phase 2 trial of furmonertinib, prolonged QT interval related to treatment occurred at an elevated level (15%).
      • Shi Y.K.
      • Hu X.S.
      • Zhang S.C.
      • et al.
      Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
      In contrast, 7.3% of patients reported prolonged QT interval in this study, and the severity mostly ranged from grade 1 to 2. Another notable possible safety event is pulmonary toxicity. In FLAURA Japanese subset, the incidence of interstitial lung disease (ILD) and pneumonitis was high (12.3%).
      • Ohe Y.
      • Imamura F.
      • Nogami N.
      • et al.
      Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset.
      ILD trends to cause pulmonary fibrosis, which can lead to dyspnea or respiratory failure. To date, ILD has not occurred in any patient during the phase 1 and 2 trials of SH-1028.
      This study has several limitations. First, it is a single-arm trial, and the subgroup analysis has no comparator group. Second, the study was done in one country, lacking analysis of efficacy in different ethnicities. In addition, at the time of data cutoff, the PFS and OS data were not mature enough to comprehensively evaluate the survival benefit of SH-1028 in patients with advanced EGFR-mutated NSCLC.
      A randomized, controlled, double-blind, multicenter, phase 3 trial (NCT04239833) is ongoing, aiming to evaluate SH-1028 versus gefitinib as first-line therapy for patients with advanced EGFR-mutated NSCLC. Currently, this phase 3 trial has completed the enrollment of patients.
      In conclusion, SH-1028 has good efficacy and safety in patients with locally advanced or metastatic NSCLC with EGFR T790M mutation. Therefore, SH-1028 is expected to become a new treatment option for second-line therapy of patients with advanced NSCLC.

      CRediT Authorship Contribution Statement

      Anwen Xiong, Shengxiang Ren: Conceptualization, Methodology, Investigation, Data curation, Writing—original draft, Writing—review and editing.
      Huaimin Liu, Liyun Miao, Lei Wang, Jianhua Chen, Wei Li, Runpu Li, Xiang Wang, Zhiwei Lu, Donglin Wang, Xiaohong Wu, Zhihua Liu, Ligang Xing, Yimin Mao, Chunling Liu, Aiping Zeng, Hongrui Niu, Yingying Du, Yuping Sun, Yueyin Pan, Yanping Hu, Xiaodong Zhang, Xueqin Chen, Zhiyong Ma, Na Li, Jianyong Zhang,
      Min Zhao, Xiaoling Li, Feng Ye, Mingjun Li, Guohua Yu: Investigation, Resources, Data curation, Writing—review and editing.
      Xiaomeng Zhang: Methodology, Software, Validation, Formal analysis, Writing—review and editing.
      Jie Min, Dong Han: Software, Validation, Formal analysis, Writing—review and editing.
      Jin Li: Conceptualization, Methodology, Writing—review and editing.
      Caicun Zhou: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing—original draft, Writing—review and editing, Visualization, Supervision, Project administration, Funding acquisition.

      Acknowledgments

      This study was funded by Sanhome Pharmaceutical Co., Ltd., which participated in study design, data collection, data analysis, and data interpretation. All authors had full access to all the data in the study, and the corresponding authors had final responsibility for the decision to submit for publication. This study was also supported, in part, by grants from the Backbone Program of Shanghai Pulmonary Hospital (number [No.] FKGG1802), Shanghai Pujiang Talent Plan (No. 2019PJD048), Shanghai Science and Technology Committee Foundation (No. 19411950300), Program of Shanghai Academic Research Leader (No. 21XD1423200), and Shanghai Key Disciplines of Respiratory (No. 2017ZZ02012). The authors thank all patients and their families and all the staff at the study centers.

      Supplementary Data

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