Results of the phase IIa study to evaluate the efficacy and safety of rezivertinib (BPI-7711) for the first-line treatment of locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation from a phase I/IIa study

This was a multicenter, single-arm, open-label, phase IIa study, which was part of the phase I/IIa study (NCT03386955), conducted across 20 hospitals in the People’s Republic of China. Key inclusion criteria included patients aged 18–75 years; with a histologically or cytologically confirmed locally advanced or metastatic NSCLC harboring EGFR-sensitive mutations, including exon 19 deletion, L858R, G719X, and L861Q which were detected through tissue or/and plasma biopsies by central laboratory testing using the Cobas® EGFR Mutation Test, Version 2, Roche Diagnostics, South Branchburg, NJ, USA; who have at least one measurable lesion; with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1; who have no disease deterioration over the previous 2 weeks; and with at least a 12-week life expectancy who were not suitable for operation or radiotherapy. Patients with previous neoadjuvant or adjuvant therapies including chemotherapy, radiotherapy, and investigational drug were acceptable, except EGFR TKIs. Adequate organ function was required as defined by platelet (PLT) count ≥ 100 × 10⁹/L, absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, hemoglobin ≥ 90 g/L, total bilirubin ≤ 1.5 × the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (total bilirubin ≤ 3 × ULN, ALT ≤ 5 × ULN, and AST ≤ 5 × ULN were allowed if liver metastases existed), serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault equation, QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation ≤ 470 ms at rest, international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN without taking an anticoagulant. Before the first dose of rezivertinib, all prior treatment-related adverse events (TRAEs) had to be at grade ≤ 1 except for hair loss and peripheral nerve toxic reaction. The ability to swallow capsules was required.

Key exclusion criteria included patients who received previous anticancer treatment for advanced NSCLC including EGFR TKIs, cytotoxic chemotherapy, and investigational agent; any clinically significant electrocardiogram (ECG) abnormality (such as QTcF prolongation > 470 ms at rest, complete left bundle branch block); any factor that increased the risk of QTcF prolongation (such as New York Heart Association II-IV, hypokalemia, long QT syndrome); any condition that possibly affected drug absorption such as severe or uncontrolled inflammatory gastrointestinal disease, abdominal colostomy, gastrointestinal perforation within 6 months, extensive bowel resection, or tube feeding patients; medical history of interstitial lung disease (ILD), radiation pneumonitis that required steroid treatment, and acute or progressive lung disease that could lead to ILD; active infection disease such as hepatitis B, hepatitis C, and human immunodeficiency virus, inactive hepatitis B was acceptable; major surgery within 4 weeks, minor operation within 2 weeks; radiotherapy with a wide field within 4 weeks, or radiotherapy within a limited field within 1 week before the first dose of rezivertinib; patients with any other concomitant cancer or recurrent cancer within 5 years, except radical operation of carcinoma in situ of cervix, non-melanoma skin cancer, noninvasive superficial bladder cancer, or radical operation of carcinoma in situ with no recurrence within 3 years; patients with spinal cord compression or meningeal metastases, symptomatic brain metastases, except asymptomatic brain metastases not requiring steroids and/or local therapy before this study, asymptomatic brain metastases after local therapy such as radiotherapy and steroids and/or antiepileptic therapy at least 7 days before the first dose of rezivertinib.

Informed consent was obtained from every patient before enrollment. The study was done in accordance with the Declaration of Helsinki and approved by the institutional review board or independent ethics committee associated with each participating hospital.

Eligible patients received rezivertinib 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment beyond progression was permitted if clinical benefits could be obtained in the judgment of the investigators.

Dose adjustment was allowed according to such principles. If a patient had a grade ≥ 3 TRAE, the administration of rezivertinib should be suspended, and supportive care should be given accordingly. After the grade ≥ 3 TRAE was relieved or recovered to grade ≤ 1 within 2 weeks after dose interruption, the investigators would restart the treatment at the initial dose (180 mg) or a lower dose (120 mg → 60 mg) according to the patient’s condition, and close medical monitoring was necessary.

Efficacy was assessed by blinded independent central review (BICR) and by investigators with enhanced computed tomography scans for the chest and abdomen or magnetic resonance imaging scans for the brain at baseline and every 2 treatment cycles (6 weeks) from the first dose of rezivertinib. In the period between the time when the informed consent was signed and 30 days after the last dose of rezivertinib, adverse events (AEs) were monitored continuously. During the treatment period, physical examinations, vital signs, ECOG PS scores, hematology, serum chemistry, urinalysis, 12-lead ECGs, and echocardiography were documented and assessed at protocol-specified time points.

The primary endpoint was ORR in full analysis set (FAS) evaluated by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [19]. The efficacy for patients with central nervous system (CNS) metastases was measured by BICR according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria [20]. The secondary endpoints included DCR, duration of response (DoR), and PFS assessed by both BICR and investigators; overall survival (OS); safety assessed by investigators. Safety referred to treatment-emergent adverse events (TEAEs) and TRAEs which were assessed in the safety set (SS) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

FAS referred to all patients enrolled who received at least one dose of rezivertinib. SS included all patients who received at least one dose of rezivertinib and had safety data available. ORR was defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). DCR was defined as the proportion of patients who had confirmed CR, PR, or stable disease (SD). DoR was defined as the time from the first CR or PR to disease progression or death which applied only to patients with confirmed CR or PR. PFS was defined as the time from the first dose of rezivertinib until the earliest date of documented disease progression or death due to any cause. OS was defined as the time from the date of the first dose of rezivertinib until death due to any cause. CNS-ORR was defined as the proportion of confirmed CR or PR in brain metastatic lesions, as evaluated by BICR according to the RANO-BM criteria. CNS-DCR was defined as the proportion of confirmed CR, PR, or SD in brain metastatic lesions evaluated by BICR according to the RANO-BM criteria.

The 95% confidence interval (CI) for ORR and DCR was determined by the Clopper-Pearson method. The 95% CI for median values of PFS, DoR, and OS was calculated by the Kaplan–Meier method. All statistical analyses were performed using SAS® Version 9.3 or higher.

From Jun 12, 2019, to Oct 17, 2019, 68 patients were screened. Finally, a total of 43 eligible patients were enrolled, and all patients received rezivertinib treatment (Fig. 1). Patient baseline characteristics are presented in Table 1.

At the data cutoff date on Dec 23, 2021, all patients had terminated rezivertinib treatment, while 22 (51.2%) patients had progressive disease (PD), 15 (34.9%) patients terminated the study by sponsor due to the data cutoff, 4 (9.3%) patients discontinued due to TEAEs, 1 patient terminated due to investigator decision, and 1 patient withdrew of consent (Fig. 1). The median duration of follow-up was 25.3 (95% CI: 25.0–26.2) months.

All 43 patients were included in FAS. The BICR-assessed and investigator-assessed ORRs were 83.7% (95% CI: 69.3–93.2%) and 69.8% (95% CI: 53.8–83.0%), respectively. The BICR-assessed and investigator-assessed DCRs were 97.7% (95% CI: 87.7–99.9%) and 95.3% (95% CI: 84.2–99.4%), respectively. The tumor shrinkage was observed in 95.3% (41/43) of patients (Fig. 2A). The forest plot for subgroups of patients having objective responses assessed by BICR in FAS was presented in Fig. 2B. The BICR-assessed and investigator-assessed median DoR were 19.3 (95% CI: 15.8–25.0) months and 19.3 (95% CI: 8.3–25.0) months, respectively. The median duration of rezivertinib exposure was 20.6 (range: 1.1–27.5) months (Fig. 3A), and the BICR-assessed percentage change of tumor size from baseline at different time points was presented in Fig. 3B. At the data cutoff date on Dec 23, 2021, 26 (60.5%) of 43 patients were with PFS events, while 22 (51.2%) had developed PD and 4 (9.3%) patients died before PD. The BICR-assessed and investigator-assessed median PFS were 20.7 (95% CI: 13.8–24.8) months and 22.0 (95% CI: 16.8–26.3) months, respectively (Fig. 4A). Among the 43 patients, 2 patients harbored uncommon EGFR mutations. For these 2 patients, one patient was with G719X and S768I mutations, and the BICR-assessed PFS was 5.6 months with the best objective response (BOR) of PR (the Cobas® EGFR Mutation Test, Version 2, Roche Diagnostics, South Branchburg, NJ, USA, was used for EGFR mutations detection, which was not able to further confirm this patient’s specific G719X type); the other patient was with only L861Q mutation, and the BICR-assessed PFS was 3.6 months with the BOR of SD. Additionally, there were 2 patients accompanied with T790M mutation mistakenly enrolled in this study, one patient was a 67-year-old male with T790M positive and exon 19 deletion mutation who had SD and a PFS of 19.0 months and the other patient was a 65-year-old male with T790M positive and L858R mutation who had PR and a PFS of 21.0 months. At the data cutoff date on Dec 23, 2021, the OS was immature, and 14 (37.2%) patients died, while 27 (62.8%) patients were still alive, one patient was lost to follow-up, and one withdrew of consent. Among 12 (27.9%) of 43 patients with CNS metastases at baseline, the CNS-ORR and CNS-DCR were 50.0% (95%CI: 21.1–78.9%) and 58.3% (95%CI: 27.7–84.8%), respectively. The probability of CNS progression at 12 months was 33.3%. Efficacy results are listed in Table 2. The BICR-assessed median PFS for the patients without and with CNS metastases at baseline were 22.0 (95% CI: 13.8–not calculable [NC]) months and 15.2 (95% CI: 6.4–NC) months, respectively (p = 0.3991, Fig. 4B); while the BICR-assessed median PFS for patients with EGFR exon 19 deletion mutation and EGFR L858R mutation were 20.7 (95% CI: 13.8–NC) and 17.7 (95% CI: 6.4–NC) months, respectively (p = 0.1835, Fig. 4C).

All 43 patients were included in SS. TEAEs occurred in 42 patients (97.7%), while TRAEs occurred in 40 patients (93.0%) (Additional file 1: Table S1). The most common TRAEs were white blood cell (WBC) decreased (19 of 43, 44.2%), PLT decreased (17 of 43, 39.5%), ANC decreased (13 of 43, 30.2%), anemia (11 of 43, 25.6%), ALT increased (8 of 43, 18.6%), lymphocyte count decreased (6 of 43, 14.0%), AST increased (5 of 43, 11.6%), etc. (Table 3). No ILD was reported. Dose interruption occurred in 2 (4.7%) patients due to TRAEs, and no dose reduction or discontinuation due to TRAEs was recorded.