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Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study

Open AccessPublished:June 17, 2022DOI:https://doi.org/10.1016/j.jtho.2022.06.002

      Abstract

      Introduction

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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).

      Keywords

      Introduction

      Lung cancer is the leading cause of cancer-related mortality worldwide and is responsible for more than 600,000 deaths per year in the People’s Republic of China.
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      Nevertheless, despite objective response rates (ORRs) of 61% to 71% in patients with the EGFR T790M mutation, treatment with osimertinib also has several limitations, such as substantial adverse events (AEs) and high medical costs.
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      Nevertheless, the treatment alternatives after resistance of first- or second-generation EGFR TKIs are still limited.
      Befotertinib (D-0316) is a novel, potent, highly selective, third-generation TKI, targeting both sensitizing EGFR (L858R at exon 21 [21L858R] or deletion of exon 19 [19Del]) and T790M mutations. The aim of this study was to evaluate the efficacy and safety of befotertinib in patients with locally advanced or metastatic NSCLC that had progressed after prior therapy with a first- or second-generation EGFR TKI. In our previous phase 1 study, the efficacy of befotertinib at 100 mg was substantially better than that at 50 mg; despite the slightly higher safety risk, no dose-limiting toxicity occurred.
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      Thus, 100 mg once daily was recommended in the phase 2 study. In addition, a liner correlation was observed between steady-state concentration/trough concentration and befotertinib dose in the dose range of 50 mg to 100 mg. As a result, it was predicted that 75 mg dose would have a better efficacy than 50 mg dose and a better safety profile than 100 mg dose, which was confirmed by the results of four patients treated with 75 mg befotertinib in the phase 1 study. To ensure the efficacy and safety, 100 mg with a 21-day lead-in at 75 mg was used in cohort B as the optimal dose.

      Materials and Methods

      Study Design and Participants

      This study was a single-arm, open-label, phase 2 study at 49 centers across mainland China between March 2019 and October 2019. The full protocol was in the Supplementary Appendix 1. Eligible patients were aged 18 years or older with histologically or cytologically confirmed locally advanced or metastatic NSCLC according to the eighth edition of the cancer staging manual of the American Joint Committee on Cancer
      that was not suitable for radical surgery or radiotherapy; had measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1; had Eastern Cooperative Oncology Group performance status of 0 to 1; had life expectancy of no less than 12 weeks; and had radiological progression during or after treatment with a first- or second-generation EGFR TKI, such as gefitinib and erlotinib. All patients were required to be centrally confirmed EGFR T790M positive by tumor tissue biopsy or blood samples.
      Key exclusion criteria included other malignant tumors except for clinically cured cervical carcinoma in situ, basal cell carcinoma, squamous cell carcinoma of the skin, or papillary thyroid carcinoma; treatment with a first- or second-generation EGFR TKI within 7 days of befotertinib initiation or previous treatment with a third-generation EGFR TKI, such as osimertinib, abivertinib, or efluentinib; treatment with chemotherapy or immunotherapy within 4 weeks before the first dose of the befotertinib, or treatment with radiotherapy within 2 weeks before the first dose of befotertinib, or previous treatment with two or more lines of systemic chemotherapy or immunotherapy; underwent surgery within 28 days before befotertinib initiation or major surgery was planned during the study period; failure to recover from the toxic effects of previous treatments and clinical evaluation before befotertinib initiation suggested AEs of grade greater than or equal to 2 (except for hair loss) according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03; spinal compression or symptomatic unstable brain metastases that required treatment with steroids within 4 weeks before inclusion; uncontrolled hypertension, active bleeding, or infection; any conditions that might impair the ability of the participant to take oral medication or influence drug absorption after oral intake, such as severe chronic gastrointestinal disease, previous gastrointestinal surgery, or refractory nausea/vomiting; inadequate hepatic, renal, or cardiac function; allergy to the study drug or components of the drug or suspected allergic symptoms; using or requiring potent inhibitors or inducers of CYP3A4, CYP3A5, CYP2D6, or CYP2C8 within the week before the first dose of the study drug; and recent participation in a clinical trial of another drug or medical device and the last intervention in the previous trial such as dosing of drug was given within 4 weeks before the first dose of befotertinib in this study; or planned to participate in any other clinical trial during the study period.
      This study was approved by the institutional review board or independent ethics committee of each study center, and written informed consent was obtained from each patient before enrolment in the study. This study was performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.

      Procedures

      For cohort A, befotertinib was administered orally before or with a meal at a dose of 50 mg once daily, with treatment for 21 days as one cycle. The dose was not adjusted during the study in this cohort. The treatment was stopped temporally if the patient developed grade 3 or higher AEs until the patient had recovered to the baseline clinical level. If the patient was believed to be able to benefit from the treatment according to the investigators’ judgments, the treatment was then continued at the original dose. If grade 3 or higher AEs reappeared after the resumption of drug therapy, the patient was withdrawn from the study.
      The patients in cohort B were treated with one cycle of befotertinib 75 mg daily (before or with the meal). If no grade 2 or higher thrombocytopenia or headache occurred within the first cycle, the dose was increased to 100 mg until disease progression occurred, withdrawal criteria were met, or the end of study; if grade 2 or higher thrombocytopenia or headache occurred in the first cycle, the dose of 75 mg daily was maintained.
      Tumor assessments with either computed tomography or magnetic resonance imaging scans of the chest, abdomen, pelvis, and any other suspected areas were performed at baseline, after administration of the first dose of befotertinib, and then every 6 weeks thereafter until disease progression, initiation of a new antitumor therapy, withdrawal of informed consent, or death. Tumor response was assessed by investigators and blinded independent review committee (IRC) according to the Response Evaluation Criteria in Solid Tumors version 1.1.
      AEs were monitored throughout the study and graded according to the Common Terminology Criteria for Adverse Events version 4.03.

      End Points and Assessments

      The primary end point was ORR assessed by an IRC, defined as the percentage of patients with confirmed complete response (CR) or partial response (PR). The secondary end points were investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), intracranial PFS (iPFS), and iORR. The population pharmacokinetics will be reported elsewhere. PFS was defined as the time from the first dosing to disease progression or death from any cause. OS was defined as the time from the first dosing to death from any cause. DOR was defined as the period from the first day of CR or PR to disease progression or death. Disease control was defined as CR, PR, or stable disease. For patients with intracranial metastasis at baseline, iPFS was defined as the time from the first dosing to intracranial progression or death from any cause, and iORR was defined as the percentage of patients with intracranial CR or intracranial PR.
      Changes in the Health-Related Quality of Life (HRQoL) score at protocol-specified time points in comparison with the baseline score were calculated using the Lung Cancer Subscale (LCS) and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire.
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      What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592.
      The percentages of patients with a HRQoL score that increased by more than or equal to 6 points (worsened), decreased by more than or equal to 6 points (improved), and increased or decreased by less than 6 points (stable) were calculated.

      Statistical Analysis

      For cohort A, assuming an ORR of 56%, with one-sided α of 0.025 and power of 80%, at least 166 patients were needed. Considering a drop-off rate of 20%, the study planned to enroll 208 patients.
      For cohort B, at least 271 patients were required assuming an ORR of 55%, with one-sided α of 0.025 and power of 90%. Considering a drop-off rate of 5%, the study planned to enroll 286 patients.
      The intention-to-treat population was used for the analysis of efficacy end points and included all patients that received randomization, did not violate key inclusion criteria, and received at least one dose of the study drug. The per-protocol set included patients who had no protocol violations that might influence efficacy assessment, did not use drugs that were forbidden by protocol, and with good compliance. Patients who received at least one dose of the study drug were included in the safety set.
      Continuous data are described as means ± SDs if normally distributed or as medians (ranges) if non-normally distributed. Categorical data are described as numbers (percentages). For time-to-event efficacy analyses, including PFS, OS, DOR, and iPFS, median values and 95% CIs with Kaplan-Meier methods were used. All statistical analyses were performed using SAS version 9.2 or higher (SAS Institute, Cary, NC). This study was registered with ClinicalTrials.gov, NCT03861156.

      Results

      Baseline Characteristic

      Among 503 patients screened between March 22, 2019, and October 31, 2019, in cohort A, 327 patients did not meet the eligibility criteria. Eventually, 176 patients were enrolled in cohort A (Fig. 1A). The baseline clinical characteristics of the patients in cohort A are found in Table 1.
      Figure thumbnail gr1
      Figure 1Enrolment of the study participants. (A) 50 mg cohort. (B) 75 to 100 mg cohort.
      Table 1Baseline Clinical Characteristics of the Study Participants
      Characteristics50 mg Cohort (n = 176)75–100 mg Cohort (n = 290)All (N = 466)
      Age (y)61.0 (32–81)62.5 (37–79)63.0 (32–81)
      Sex
       Male71 (40.3)100 (34.5)171 (36.7)
       Female105 (59.7)190 (65.5)295 (63.3)
      ECOG-PS score
       046 (26.1)62 (21.4)108 (23.2)
       1130 (73.9)228 (78.6)358 (76.8)
      Pathologic type
      Two patients were adenosquamous carcinoma and the other two included poorly differentiated non–small cell carcinoma and poorly differentiated carcinoma in fibrous tissue.
       Adenocarcinoma176 (100.0)286 (98.6)462 (99.1)
       Squamous carcinoma000
       Other04 (1.4)4 (0.9)
      Stage
       III4 (2.3)5 (1.7)9 (1.9)
       IV172 (97.7)285 (98.3)457 (98.1)
      Brain metastasis
      The brain metastasis in 50 mg cohort was not assessed by IRC, and thus the brain metastasis was assessed by investigator. Whereas 105 (36.2%) patients had brain metastasis assessed by IRC in 75–100 mg cohort.
      56 (31.8)84 (29.0)140 (30.0)
      Smoking history
       Yes62 (35.2)77 (26.6)139 (29.8)
       No114 (64.8)213 (73.4)327 (70.2)
      EGFR mutation status
      One patient in 75 to 100 mg cohort had both EGFR 19Del and 21L858R mutations and the other four patients were negative 19Del and negative 21L858R.
       19Del121 (68.8)191 (65.9)312 (67.0)
       21L858R54 (30.7)95 (32.8)149 (32.0)
       Other1 (0.6)4 (1.4)5 (1.1)
      Previous treatment lines
       1165 (93.8)254 (87.6)419 (89.9)
       211 (6.3)36 (12.4)47 (10.1)
      Note: Data are presented as n (%) or median (range). Percentages might not sum to 100 due to rounding.
      19Del, deletion of exon 19; 21L858R, L858R at exon 21; ECOG-PS, Eastern Cooperative Oncology Group performance status; IRC, independent review committee.
      a Two patients were adenosquamous carcinoma and the other two included poorly differentiated non–small cell carcinoma and poorly differentiated carcinoma in fibrous tissue.
      b The brain metastasis in 50 mg cohort was not assessed by IRC, and thus the brain metastasis was assessed by investigator. Whereas 105 (36.2%) patients had brain metastasis assessed by IRC in 75–100 mg cohort.
      c One patient in 75 to 100 mg cohort had both EGFR 19Del and 21L858R mutations and the other four patients were negative 19Del and negative 21L858R.
      Among 689 patients screened in cohort B between September 12, 2019, and October 18, 2020, 399 patients were excluded. Hence, 290 patients were enrolled in cohort B (Fig. 1B). The dose was not increased to 100 mg in 78 patients, with 57 patients (73.1%) maintaining at 75 mg (33 due to thrombocytopenia, 18 due to headache, one due to both thrombocytopenia and headache, and five due to investigator’s decision), 14 patients (17.9%) reducing to 50 mg (8 due to thrombocytopenia and six due to investigator’s decision), and seven patients (9.0%) discontinued treatment in the first cycle (3 due to patients’ decision, two due to death, one due to investigator’s decision, and one due to disease progression). Among these two dead patients, one was due to cerebral infarction and the other was due to unknown cause of sudden death, but both were not related to befotertinib. The baseline clinical characteristics of the patients in cohort B are found in Table 1. All patients received at least one dose of befotertinib, and no patients had inclusion criteria violations. Thus, all patients were included in analyses of efficacy and safety.

      Efficacy

      At data cutoff (August 15, 2021), 21 (11.9%) of 176 patients in cohort A and 86 (29.7%) of 290 patients in cohort B remained on treatment. The IRC-assessed ORR was 67.6% (95% CI: 61.9%–72.9%) in cohort B (Table 2). Tumor shrinkage was revealed in Figure 2.
      Table 2Response to Befotertinib Assessed by an Independent Review Committee in Intention-To-Treat Population
      Parameters75–100 mg Cohort (N = 290)
      Complete response0 (0)
      Partial response196 (67.6)
      Stable disease79 (27.2)
      Progressive disease6 (2.1)
      Not evaluable9 (3.1)
      Objective response rate67.6 (61.9–72.9)
      Disease control rate94.8 (91.6–97.1)
      Note: Data are presented as n (%) or % (95% confidence interval). Considering the 50 mg was not recommended dose, the response in 50 mg cohort was not assessed by independent central review.
      Figure thumbnail gr2
      Figure 2Waterfall plots in 75 to 100 mg cohort assessed by IRC. The dashed line at 20% represents the boundary for determination of progressive disease, and the dashed line at −30% represents the boundary for determination of partial response. Patients with shrinkage of target lesion size but enlargement of other lesions, resulting in disease progression. IRC, independent review committee.
      Subgroup analyses in cohort B revealed that the ORR was 68.6% (95% CI: 58.8%–77.5%) for patients with baseline brain metastasis and 67.0% (95% CI: 59.7%–73.7%) for those without baseline brain metastasis. In addition, ORR was 68.5% (95% CI: 62.4%–74.2%) for patients who had received one line of previous therapy and 61.1% (95% CI: 43.5%–76.9%) for those who had received two lines of prior therapy. Furthermore, ORR was 71.2% (95% CI: 64.2%–77.5%) for patients with 19Del mutation and 58.9% (95% CI: 48.4%–68.9%) for those with 21L858R mutation (Fig. 3). Among 78 patients whose dose was not escalated to 100 mg in cohort B, 45 achieved PR with an IRC-assessed ORR of 57.7% (95% CI: 46.0%–68.8%), and for patients increased dose to 100 mg, ORR was 71.2% (95% CI: 64.6%–77.2%). There is no difference in terms of patient characteristics between these 78 patients with escalating to 100 mg patients.
      Figure thumbnail gr3
      Figure 3Subgroup analyses of the ORR in 75 to 100 mg cohort based on the intention-to-treat population. 19Del, deletion of exon 19; 21L858R, L858R at exon 21; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate.
      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 DCR was 93.2% (95% CI: 88.4%–96.4%) and 94.8% (95% CI: 91.6%–97.1%) in cohorts A and B, respectively (Supplementary Table 1).
      There were 56 patients with intracranial metastases at baseline in cohort A and 84 patients in cohort B assessed by investigator (Supplementary Table 2). Among 15 of those with measurable target lesion in cohort A, one patient achieved CR and three achieved PR, yielding an iORR of 26.7% (95% CI: 7.8%–55.1%). In cohort B, among 21 of those with measurable target lesion, 12 patients achieved CR or PR, giving an iORR of 57.1% (95% CI: 34.0%–78.2%). In cohort B, the IRC-assessed iORR was 55.9% (95% CI: 37.9%–72.8%).
      Death or disease progression occurred in 133 patients (75.6%) in cohort A and 165 patients (56.9%) in cohort B. The median PFS assessed by investigator 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 (Fig. 4A and B). The median investigator-assessed DOR was 12.5 (95% CI: 11.1–15.2) months and 12.4 (95% CI: 11.0–14.6) months in cohorts A and B, respectively (Supplementary Fig. 1A and B). Furthermore, the IRC-assessed median PFS and DOR in cohort B were 16.6 (95% CI: 15.0–not evaluable [NE]) months and 18.0 (95% CI: 13.8–NE) months. For patients whose dose was not escalated to 100 mg in cohort B, the median DOR and median PFS assessed by IRC were 12.7 (95% CI: 8.3–18.0) months and 15.1 (95% CI: 9.8–19.4) months, respectively. Patients who increased their dose to 100 mg had a median DOR of NE (95% CI: 13.9–NE) months and a median PFS of 17.9 (95% CI: 15.0–NE) months based on IRC assessment.
      Figure thumbnail gr4
      Figure 4Kaplan-Meier analysis of progression-free survival. (A) 50 mg cohort. (B) 75 to 100 mg cohort. CI, confidence interval.
      Death or progression of the intracranial lesion occurred in 21 of 56 patients (37.5%) in cohort A and 24 of 84 patients (28.6%) in cohort B assessed by investigator. The median iPFS was 16.5 (95% CI: 8.6–NE) months in cohort A. In cohort B, median investigator-assessed iPFS for patients with and without brain metastasis was NE (95% CI: 13.8–NE) and NE (95% CI: NE–NE) (Supplementary Fig. 2A and B). In cohort B, IRC-assessed iPFS was NE (95% CI: 16.5–NE). In addition, the median IRC-assessed PFS for patients with and without brain metastasis was 12.5 (95% CI: 9.6–NE) months and 17.9 (95% CI: 15.2–NE) months, respectively.
      The OS was immature. The OS events occurred in 94 patients (53.4%) in cohort A, and the median OS was 23.9 (95% CI: 21.1–27.1) months. Nevertheless, in cohort B, 67 patients (23.1%) died during the study period.
      In cohort A, comparisons of HRQoL scores with baseline assessments indicated that the FACT-L TOI score, FACT-LCS score, and total FACT-L score were improved in 56.3%, 61.9%, and 61.9% of the patients, stable in 39.2%, 34.7%, and 32.4% of the patients, and worsened in 3.4%, 2.3%, and 4.5% of the patients, respectively. In cohort B, the FACT-L TOI, FACT-LCS, and total FACT-L scores were improved in 40.7%, 47.9%, and 46.2% of the patients, stable in 55.2%, 45.9%, and 49.0% of the patients, and worsened in 1.7%, 3.8%, and 2.4% of the patients, respectively.

      Safety

      At the cutoff date, the median duration of exposure to befotertinib was 42.4 (interquartile range: 23.9–74.1) weeks and 48.6 (interquartile range: 23.9–63.7) weeks in cohorts A and B, respectively. In cohort A, treatment-emergent AEs (TEAEs), grade 3 or higher TEAEs, treatment-related AEs (TRAEs), and grade 3 or higher TRAEs occurred in 169 patients (96.0%), 63 patients (35.8%), 150 patients (85.2%), and 36 patients (20.5%), respectively. The most common TRAEs were listed in Table 3. Furthermore, 48 patients (27.3%) experienced serious AEs (SAEs) and 20 patients (11.4%) had SAEs considered related to the treatment. Dose interruptions occurred in 40 patients (22.7%) due to AEs and 32 patients (18.2%) because of TRAEs. The dose discontinuation was observed in 12 patients (6.8%) due to AEs and nine patients (5.1%) due to TRAEs. A total of 11 patients (6.3%) died during the study period, and one (0.6%) was associated with the study drug (cerebral infarction).
      Table 3Treatment-Related Adverse Events in the 50 mg Cohort and 75 to 100 mg Cohort (Safety Set)
      Adverse Event, n (%)50 mg Cohort (n = 176)75–100 mg Cohort (n = 290)
      Any GradeGrade ≥3Any GradeGrade ≥3
      Thrombocytopenia93 (52.8)9 (5.1)183 (63.1)42 (14.5)
      Leukopenia34 (19.3)2 (1.1)74 (25.5)8 (2.8)
      Anemia33 (18.8)070 (24.1)2 (0.7)
      Pruritus26 (14.8)021 (7.2)0
      Rash26 (14.8)2 (1.1)63 (21.7)4 (1.4)
      Proteinuria22 (12.5)025 (8.6)0
      Lipid metabolism diseases21 (11.9)1 (0.6)44 (15.2)3 (1.0)
      Arrhythmia19 (10.8)027 (9.3)0
      Elevated ALT18 (10.2)1 (0.6)40 (13.8)3 (1.0)
      Elevated AST18 (10.2)1 (0.6)40 (13.8)3 (1.0)
      Decreased appetite16 (9.1)1 (0.6)20 (6.9)3 (1.0)
      Hyperuricemia16 (9.1)2 (1.1)14 (4.8)0
      Elevated serum creatinine15 (8.5)048 (16.6)0
      Headache15 (8.5)1 (0.6)83 (28.6)3 (1.0)
      Abdominal discomfort14 (8.0)027 (9.3)0
      Other venous embolism and thrombotic events14 (8.0)3 (1.7)23 (7.9)3 (1.0)
      Musculoskeletal pain13 (7.4)037 (12.8)1 (0.3)
      Electrolyte imbalance12 (6.8)3 (1.7)21 (7.2)6 (2.1)
      Nausea12 (6.8)023 (7.9)0
      Elevated bilirubin10 (5.7)013 (4.5)0
      Pulmonary embolism11 (6.3)9 (5.1)15 (5.2)14 (4.8)
      Urinary tract infection9 (5.1)1 (0.6)9 (3.1)1 (0.3)
      Fatigue8 (4.5)042 (14.5)0
      Hematuria8 (4.5)015 (5.2)0
      Weight loss7 (4.0)020 (6.9)1 (0.3)
      Dizziness7 (4.0)019 (6.6)1 (0.3)
      QT interval prolongation6 (3.4)2 (1.1)14 (4.8)2 (0.7)
      Diarrhea6 (3.4)016 (5.5)1 (0.3)
      Interstitial lung disease3 (1.7)07 (2.4)2 (0.7)
      Elevated fibrin D-dimer2 (1.1)017 (5.9)1 (0.3)
      Backache2 (1.1)015 (5.2)0
      Note: Data are illustrated as n (%). Any grade treatment-related adverse events with an incidence ≥5% and all grade ≥3 treatment-related adverse events are found.
      ALT, alanine transaminase; AST, aspartate transaminase.
      In cohort B, the incidence of TEAEs, TRAEs, grade 3 or higher AEs, grade 3 or higher TRAEs, SAEs, treatment-related SAEs, fatal AEs, and fatal TRAEs was 99.3%, 93.1%, 45.2%, 29.3%, 27.2%, 10.0%, 5.9%, and 0.3%, respectively. AEs and TRAEs led to permanent discontinuation of drug therapy in 10.0% and 6.9% of patients, respectively. A total of 17 patients (5.9%) died during the study period, and one (0.3%) was associated with the study drug (interstitial lung disease).

      Discussion

      This multicenter, single-arm, phase 2 study investigated the efficacy and safety of befotertinib for locally advanced or metastatic NSCLC in patients with disease progression and T790M mutation after prior treatment with a first- or second-generation EGFR TKI. High ORR and DCR were observed in the 75 to 100 mg cohort, especially in patients with intracranial metastases. The most common AE of befotertinib was thrombocytopenia and headache, and the safety profile with befotertinib in this study was acceptable and manageable. The results indicate that 75 to 100 mg befotertinib is recommended for the treatment of locally advanced or metastatic NSCLC in patients harboring the T790M mutation who develop resistance to first- or second-generation EGFR TKIs.
      In a phase 1 trial, befotertinib at both 50 mg and 100 mg had a favorable efficacy with ORR of 33.3% and 45.5%, DCR of 86.7% and 93.9%, and the median PFS of 8.3 and 9.6 months, respectively.
      • Jian H.
      • Wang K.
      • Cheng Y.
      • et al.
      Phase I trial of a third generation EGFR mutant-selective inhibitor (D-0316) in patients with advanced non-small cell lung cancer.
      Therefore, these two doses (50 mg and 100 mg) were selected to further evaluate the efficacy. Notable findings of our efficacy evaluation in the 290 patients administered 75 to 100 mg befotertinib were that the ORR was 64.8%, the DCR was 94.8%, and median PFS was 12.5 months. The investigator-assessed ORR was 54.0% (95% CI: 46.3%–61.5%) in 50 mg and 65.9% (95% CI: 60.1%–71.3%) in 75 to 100 mg. These efficacy results are comparable with those reported for other third-generation EGFR TKIs after the failure of first- or second-generation agents. A phase 1 study of osimertinib in 127 patients with EGFR T790M who had been treated previously with other EGFR TKIs found that the ORR was 61%, the DCR was 95%, and median PFS was 9.6 months.
      • Jänne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
      A phase 3 study of 279 patients with NSCLC harboring the T790M mutation who were treated with osimertinib after failure of prior therapy determined that the ORR was 71%, the DCR was 93%, and median PFS was 10.1 months.
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      A pooled analysis of two phase 2 studies revealed that the ORR, DCR, and median PFS in 411 patients treated with osimertinib was 66%, 91%, and 9.9 months, respectively.
      • 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 AURA17, another phase 2 study of osimertinib in an Asian population, the ORR, DCR, and median PFS were 62%, 88%, and 9.7 months, respectively.
      • Zhou C.
      • Wang M.
      • Cheng Y.
      • et al.
      AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
      A phase 1 study of aumolertinib for NSCLC that had progressed after prior treatment found that the ORR, DCR, and median PFS were 52%, 92%, and 11.0 months, respectively, in 94 patients with the EGFR T790M mutation.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      A multicenter, open-label, single-arm, phase II study: the third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO).
      Furthermore, the APOLLO study reported that the ORR, DCR, and median PFS in 244 patients treated with aumolertinib were 68.9%, 93.4%, and 12.4 months, respectively.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+NSCLC: updated post NMPA-approval results from the APOLLO registrational trial.
      The ORR, DCR, and median PFS of furmonertinib in patients with T790M-mutant NSCLC (n = 220) were 74%, 94%, and 9.6 months, respectively.
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      The ORR, DCR, and median PFS for lazertinib were 54%, 87%, and 9.5 months, respectively.
      • Ahn M.J.
      • Han J.Y.
      • Lee K.H.
      • et al.
      Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study.
      Therefore, befotertinib may be a new option with promising efficacy for patients harboring the T790M mutation who exhibit tumor progression after prior therapy with a first- or second-generation agent.
      Patients with cerebral metastases usually have short PFS compared with those without cerebral metastases. The proportion of patients with cerebral metastases was 36.2% at 75 to 100 mg in this study, which was comparable with that in AURA3 (33%),
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      APOLLO (36.1%),
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+NSCLC: updated post NMPA-approval results from the APOLLO registrational trial.
      AURA17 (37%),
      • Zhou C.
      • Wang M.
      • Cheng Y.
      • et al.
      AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
      and AURA pooled analysis (39%)
      • 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.
      but less than the phase 2 study of furmonertinib (48%).
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      Although befotertinib at 50 mg and 75 to 100 mg achieved favorable antitumor effect, the iORR had remarkable improvement from 20.0% (95% CI: 4.3%–48.1%) at 50 mg to 52.9% (95% CI: 35.1%–70.2%) at 75 to 100 mg. The iDCR was 100.0% (95% CI: 83.9%–100.0%) in 75 to 100 mg cohort. A pooled analysis of two phase 2 trials reported that the iORR and iDCR of osimertinib were 54% and 92%, respectively, in 50 patients with intracranial lesions.
      • Goss G.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.
      Furthermore, the iORR and iDCR were 60.9% and 91.3%, respectively, in patients treated with aumolertinib
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      A multicenter, open-label, single-arm, phase II study: the third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO).
      and 65.5% and 100%, respectively, in patients treated with furmonertinib.
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      Thus, similar to other third-generation EGFR TKIs, 75 to 100 mg befotertinib has clinically meaningful efficacy against brain metastases and was selected in an ongoing phase 3 study (NCT04206072).
      The 21L858R and 19Del mutations account for most mutations (85%–90%) in the EGFR kinase domain that respond to EGFR TKIs.
      • Gazdar A.F.
      Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.
      Subgroup analyses of patients with different EGFR mutations revealed that the ORR and DCR were 69.6% (95% CI: 62.6%–76.1%) and 94.8% (95% CI: 90.6%–97.5%), respectively, in patients with the 19Del mutation and 53.7% (95% CI: 43.2%–64.0%) and 95.8% (95% CI: 89.6%–98.8%), respectively, in patients with the 21L858R mutation. Previous research found that the ORR for osimertinib was 77% (95% CI: 69%–84%) in patients with the 19Del mutation and 59% (95% CI: 46%–71%) in patients with the 21L858R mutation.
      • Goss G.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.
      Furthermore, the ORR for aumolertinib in patients with the 19Del and 21L858R mutations was 72.3% (95% CI: 64.5%–79.1%) and 63.5% (95% CI: 52.4%–73.7%), respectively,
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+NSCLC: updated post NMPA-approval results from the APOLLO registrational trial.
      whereas corresponding values for furmonertinib were 76.5% (95% CI: 68.4%–83.3%) and 71.4% (95% CI: 60.5%–80.8%), respectively.
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      Thus, the efficacy of befotertinib in patients with the 19Del and 21L858R mutations of the EGFR was broadly comparable with that reported for other third-generation EGFR TKIs.
      The results of this phase 2 trial indicate that befotertinib has an acceptable safety profile, and no new safety signals were detected. The TRAEs observed in the present study were different with those reported previously for other third-generation EGFR TKIs. The side effects of EGFR TKIs often include rash, diarrhea, hepatic toxicity, interstitial lung disease, and stomatitis.
      • Shah R.R.
      • Shah D.R.
      Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology.
      Previous studies evaluating osimertinib have described diarrhea in 41% to 58%, rash in 34% to 58%, nausea in 14% to 22%, and reduced appetite in 18% to 21% of patients with NSCLC.
      • Jänne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
      ,
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      ,
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      Moreover, grade 3 or higher AEs were reported in 23% to 34% of patients taking osimertinib, and the incidence of TRSAEs was approximately 6%.
      • Jänne P.A.
      • Yang J.C.
      • Kim D.W.
      • et al.
      AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
      ,
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      ,
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      Compared with osimertinib, befotertinib had less treatment-related diarrhea (5.5%) and rash (21.7%). The incidence of treatment-related diarrhea was comparable with furmonertinib (5%) but more than aumolertinib (none). The incidence of treatment-related rash was more than furmonertinib (7%) and aumolertinib (13.9%). Notably, more thrombocytopenia (63.1%) was observed in 75 to 100 mg cohort and 42 of 290 patients (14.5%) had grade 3 or higher thrombocytopenia. It was also reported that thrombocytopenia is a common AE in other third-generation EGFR TKIs. Nevertheless, we must acknowledge that the incidence in this study was higher than that in the previous studies. The exact mechanism of thrombocytopenia caused by an EGFR TKI is unknown. Even so, this AE was manageable with a 21-day lead-in at 75 mg in our study. Only four of 290 patients (1.4%) discontinued befotertinib due to thrombocytopenia. The incidence of headache was high and unusual for a third-generation EGFR TKI. The mechanism of headache caused by befotertinib remains unknown. Nevertheless, the incidence of grade 3 to 4 headache was low, and the patients were able to tolerate it without affecting the efficacy. One of the important TRAEs for furmonertinib was prolonged QT interval, which was reported in 15% of the patients.
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      Nevertheless, in our study, grade 3 QT interval prolongation was observed in three of 290 patients (1.0%). More increased blood creatine phosphokinase was observed in 20.9% patients who received aumolertinib.
      • Lu S.
      • Wang Q.
      • Zhang G.
      • et al.
      Efficacy of aumolertinib (HS-10296) in patients with advanced EGFR T790M+NSCLC: updated post NMPA-approval results from the APOLLO registrational trial.
      In our study, two patients (0.7%) had interstitial lung disease of grade 3 after befotertinib treatment, which was not observed in the phase 1 study even at the dose of 150 mg (n = 3).
      • Jian H.
      • Wang K.
      • Cheng Y.
      • et al.
      Phase I trial of a third generation EGFR mutant-selective inhibitor (D-0316) in patients with advanced non-small cell lung cancer.
      The interstitial lung disease was reported in 1% to 3% patients who received osimertinib
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      ,
      • Zhou C.
      • Wang M.
      • Cheng Y.
      • et al.
      AURA17 study of osimertinib in Asia-Pacific patients (pts) with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC): updated phase II results including overall survival (OS).
      and in less than 1% patients receiving furmonertinib.
      • Shi Y.
      • Hu X.
      • Zhang S.
      • 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.
      There is currently no evidence of a higher risk of interstitial lung disease of befotertinib compared with other third-generation EGFR TKIs. Thus, the safety profile of befotertinib is acceptable in comparison with other available agents.
      Assessing HRQoL outcomes can reveal how positive PFS outcomes can translate into additional patient benefit. Advanced NSCLC has a negative impact not only on survival but also on quality of life. Previous studies have revealed that EGFR-targeting therapy was found to be associated with HRQoL benefits of different degrees.
      • Gelibter A.
      • Ceribelli A.
      • Pollera C.F.
      • et al.
      Impact of gefitinib (‘Iressa’) treatment on the quality of life of patients with advanced non-small-cell lung cancer.
      ,
      • Bezjak A.
      • Tu D.
      • Seymour L.
      • et al.
      Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.
      Nevertheless, these studies mostly focus on first-generation EGFR TKIs. Other third-generation EGFR TKIs seldom reported data on HRQoL outcomes. Osimertinib achieved improvement or stable in three-quarters of patients with 9% to 28% worsening assessed by symptom/functioning/global health status scales/items from the European Organization for Research and Treatment of Cancer. In this study, most patients (>95%) improved or maintained stable regarding FACT-L TOI, FACT-LCS, and total FACT-L scores in both cohorts. Befotertinib may improve quality of life in patients with treated NSCLC and has a particularly outstanding performance.
      Osimertinib has become a new standard of care for first-line treatment of NSCLC based on FLAURA study.
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      An ongoing phase 3 study (NCT04206072) will provide further information regarding the efficacy and safety of befotertinib. In addition, a phase 2 study (NCT05007938) to evaluate befotertinib combining with icotinib as first-line treatment in patients with locally advanced or metastatic NSCLC harboring sensitizing EGFR mutation is ongoing.
      This study has some limitations. First, most study participants had stage IV adenocarcinoma and relatively few patients were included with other disease stages or pathologic types. Second, immaturity of the data precluded the accurate calculation of PFS, DOR, and OS. Third, a comparator group was not included, and thus the subgroup results are descriptive without the comparator group. In addition, this study was done in one country, and further research will be warrant to explore the generalizability.
      In conclusion, 75 to 100 mg befotertinib is an effective and safe treatment for patients with locally advanced or metastatic NSCLC with EGFR T790M mutation who were previously treated with first- or second-generation EGFR TKIs. Befotertinib may represent an alternative option for patients with NSCLC harboring the T790M mutation and have resistance to first- or second-generation EGFR TKIs.

      CRediT Authorship Contribution Statement

      Shun Lu: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Data curation, Writing—original draft, Writing—review and editing, Visualization, Supervision, Project administration, Funding acquisition.
      Yiping Zhang, Guojun Zhang, Jianying Zhou, Shundong Cang, Ying Cheng, Gang Wu, Peiguo Cao, Dongqing Lv, Hong Jian, Chengshui Chen, Xiangming Jin, Panwen Tian, Kai Wang, Guanming Jiang, Gongyan Chen, Qun Chen, Hui Zhao, Cuimin Ding, Renhua Guo, Guoping Sun, Bin Wang, Liyan Jiang, Zhe Liu, Jian Fang, Junquan Yang, Wu Zhuang, Yunpeng Liu, Jian Zhang, Yueyin Pan, Jun Chen, 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: Investigation, Resources, Data curation, Writing—review and editing.
      Lieming Ding, Ling Zhang: Conceptualization, Methodology, Investigation, Data curation, Writing—review and editing, Supervision, Project administration.
      Xiaobin Yuan, Lin Yao, Zhilin Shen: Software, Investigation, Validation, Formal analysis, Data curation, Writing—original draft, Writing—review and editing, Visualization.

      Acknowledgments

      This study was funded by Betta Pharmaceuticals and was also supported by the National Key R&D Program of China (grant number 2016YFC1303300), the National Natural Science Foundation of China (82030045), and Shanghai Municipal Science & Technology Commission Research Project (17431906103 and 19411950500). The authors appreciate all the sites that contributed to recruitment, the patients, and their families who participated in this study.

      Supplementary Data

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