Rezivertinib versus Gefitinib as First-line Therapy for EGFR-mutated Locally Advanced or Metastatic NSCLC Patients (REZOR): A Multicenter, Double-blinded, Randomized Phase 3 Study

doi:10.21203/rs.3.rs-4616293/v1

REZOR is a multicenter, double-blinded, randomized phase 3 study aimed to compare the efficacy and safety of rezivertinib (BPI-7711) and gefitinib as first-line therapies in patients with EGFR mutated locally advanced or metastatic non-small-cell lung cancer (NSCLC). The study included eligible patients from 50 hospitals across China. Those who had been histologically or cytologically confirmed NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation by central laboratory were randomly assigned (1:1) to receive once daily either rezivertinib 180 mg or gefitinib 250 mg. The primary endpoint was progression-free survival (PFS) evaluated by blinded independent central review (BICR), which was significantly superior in the rezivertinib group than the gefitinib group (19.3 versus 9.6 months, HR = 0.48, P < 0.0001) and the prespecified subgroup efficacy analysis showed consistency. Rezivertinib is a potential choice due to the superior efficacy compared with gefitinib in targeted patients without new safety signals identified. ClinicalTrials.gov identifier: NCT03866499.

Health sciences/Diseases/Cancer/Lung cancer/Non-small-cell lung cancer

Health sciences/Medical research/Drug development

rezivertinib

gefitinib

NSCLC

EGFR TKI

According to the 2022 global and China cancer statistics, lung cancer has been reported with highest incidence and mortality (12.4% of the total diagnosed cases and 18.7% of the total cancer deaths worldwide; 1,060,600 cases and 733,300 deaths in China) ^1,2 Among patients with lung cancer, up to 80-85% was with non-small-cell lung cancer (NSCLC), over 40% of lung adenocarcinoma patients were detected with epidermal growth factor receptor (EGFR) mutations in East Asian ^3–7. In China, the enormous medical demands and high safety requirements are still needed to be satisfied. Nowadays, EGFR tyrosine kinase inhibitors (TKIs), especially the third-generation EGFR TKIs are the standard of first-line therapy for EGFR mutated NSCLC ^8–10. Over the past 20 years, small-molecule tyrosine kinase inhibitors have changed the treatment landscape of advanced solid tumors ^11,12. For the first-line therapy of NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation, the first- or second-generation EGFR TKIs such as gefitinib, erlotinib, icotinib, afatinib, dacomitinib ^13–17, and the third-generation EGFR TKIs osimertinib, aumolertinib, furmonertinib and befotertinib had been approved in China ¹⁰. Clinical trials had revealed that the single use of third-generation EGFR TKIs can significantly optimize the clinical efficacy while compared with the first-generation EGFR TKIs in the first-line therapy ^18–24.

Rezivertinib (BPI-7711) is a novel third-generation EGFR TKI jointly developed by Beta Pharma (Shanghai) Co., Ltd., Shanghai, China and Beta Pharma Inc., Princeton, NJ, USA. Phase I and phase IIb study had showed promising efficacy and preferable safety profile for NSCLC patients, with central nervous system (CNS) metastasis and EGFR T790M mutation after the treatment of first- or second-generation EGFR TKIs ^25–27. According to these results, rezivertinib was approved for the treatment of adult patients with locally advanced or metastatic NSCLC who have experienced disease progression during or after previous treatment with EGFR TKIs and have been confirmed to have positive EGFR T790M mutation by the China National Medical Products Administration (NMPA) at May 15, 2024. The phase IIa study further demonstrated promising efficacy and safety for the first-line treatment of NSCLC patients with EGFR exon 19 deletion or exon 21 L858R mutation ²⁸. In this article, the details of the multicenter, double-blinded, randomized phase 3 study (REZOR), in which rezivertinib versus gefitinib were as first line therapies for EGFR-mutated locally advanced or metastatic NSCLC patients, will be elucidated and discussed.

Patient disposition

From 15 July 2019 to 14 February 2022, a total of 695 patients were screened across 50 hospitals in China. Among them, 369 eligible patients were double blindly randomized to receive either rezivertinib 180 mg/day plus placebo (n = 184) or gefitinib 250 mg/day plus placebo (n = 185) in a 1:1 ratio and all of them were included into the intention-to-treat (ITT) set. Patient baseline characteristics are presented in Table 1. At the data cutoff date on 30 November 2023, 53 (28.8%) and 22 (11.9%) patients in the rezivertinib and gefitinib groups remained on the main study treatment, respectively, while 10 (5.4%) patients from the gefitinib group were still on cross-over treatment (Fig. 1).

Primary outcome

The study met the primary endpoint of blinded independent central review (BICR)-assessed progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ²⁹. The median follow-up duration was 24.9 (95% confidence interval [CI]: 24.4-25.8) and 24.4 (95% CI: 23.1-25.1) months for the rezivertinib and gefitinib groups, respectively. 94 (51.1%) and 127 (68.6%) BICR-assessed PFS events occurred in the rezivertinib and gefitinib groups, respectively. The BICR-assessed median PFS was 19.3 (95% CI: 13.8-22.1) and 9.6 (95% CI: 8.4-11.3) months in the rezivertinib and gefitinib groups, respectively, hazard ratio (HR) = 0.48 (95% CI: 0.36-0.63; P < 0.0001; Fig. 2).

A consistent efficacy for BICR-assessed PFS was observed across prespecified subgroups (Fig. 3, 4a-f). For patients with EGFR exon 19 deletion, 43 (46.2%) and 65 (67.0%) BICR-assessed events occurred in the rezivertinib and gefitinib groups (Fig. 3), while the BICR-assessed median PFS was 22.1 (95% CI: 13.8-NC) and 9.7 (95% CI: 8.4-13.8) months (HR = 0.38; 95% CI: 0.26-0.57; P < 0.0001; Fig. 4a). For those with L858R mutation, 51 (56.0%) and 62 (70.5%) BICR-assessed events occurred (Fig. 3), and the BICR-assessed median PFS was 13.9 (95% CI: 9.7-17.9) and 9.6 (95% CI: 6.9-12.4) months (HR = 0.59; 95% CI: 0.40-0.85; P = 0.0053; Fig. 4b). For patients without CNS metastases at baseline, 53 (48.6%) and 79 (69.9%) BICR-assessed events occurred in the rezivertinib and gefitinib groups (Fig. 3), and the BICR-assessed median PFS was 22.0 (95% CI: 13.8-25.2) and 9.6 (95% CI: 7.0-12.4) months, respectively (HR = 0.46; 95% CI: 0.32-0.65; P < 0.0001; Fig. 4c). For those with CNS metastases at baseline, 41 (54.7%) and 48 (66.7%) BICR-assessed events occurred in the rezivertinib and gefitinib groups (Fig. 3), and the BICR-assessed median PFS was 16.0 (95% CI: 12.5-22.2) and 9.7 (95% CI: 8.5-13.8) months, respectively (HR = 0.52; 95% CI: 0.34-0.80; P = 0.003; Fig. 4d). For patients harboring EGFR mutations detected with tissue samples, 64 (49.2%) and 96 (68.6%) BICR-assessed events occurred in the rezivertinib and gefitinib groups (Fig. 3), and the BICR-assessed median PFS was 20.7 (95% CI: 13.9-24.9) months and 9.7 (95% CI: 8.3-12.4) months (HR = 0.47; 95% CI: 0.34-0.66; P＜0.0001; Fig. 4e). For those detected with plasma samples, 38 (50.0%) and 43 (69.4%) BICR-assessed events occurred in the rezivertinib and gefitinib groups (Fig. 3), and the BICR-assessed median PFS was 16.0 (95% CI: 9.7-24.9) months and 9.6 (95% CI: 6.9-11.0) months (HR = 0.48; 95% CI: 0.30-0.75; P = 0.0014; Fig. 4f).

Secondary outcomes

120 (65.2 %) and 151 (81.6 %) investigator-assessed PFS events occurred in the rezivertinib and gefitinib groups, respectively. The investigator-assessed median PFS was 16.6 (95% CI: 13.6-19.3) and 10.5 (95% CI: 8.4-12.4) months in the rezivertinib and gefitinib groups, respectively (HR = 0.56; 95% CI: 0.44-0.72; P < 0.0001; Extended Data Fig. S1), demonstrating consistency with the BICR-assessed PFS for the ITT set. The results of other secondary endpoints including BICR-assessed objective response rate (ORR), disease control rate (DCR), time to response (TTR) and duration of response (DoR) were shown in Extended Data Table S1. Overall survival (OS) remained immature and there were still 97 (52.7%) and 95 (51.4%) patients under OS follow-up in the rezivertinib and gefitinib groups, respectively. The ITT set tumor shrinkage was shown in Extended Data Fig. S2. The CNS efficacy was assessed by BICR per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) ³⁰. For 75 (40.8%) patients with CNS metastases at baseline in the rezivertinib group and 72 (38.9%) patients in the gefitinib group, the CNS PFS was 22.5 (95% CI: 16.6-NC) and 15.2 (95% CI: 11.0-NC) months, respectively (HR = 0.61; 95% CI: 0.36-1.05; P = 0.0737). 95 (51.4%) of 185 patients in gefitinib group received EGFR T790M detection after disease progression, and 37 (39.4%) of 95 patients detected with secondary EGFR T790M mutation entered the cross-over rezivertinib treatment phase, 19 (51.4%) events occurred in 37 patients and the BICR-assessed median PFS2 was 19.8 (95% CI: 16.9-23.6) months (Extended Data Fig. S3-4). The BICR-assessed objective response and DoR for cross-over rezivertinib treatment were displayed in Extended Data Table S2.

Safety

All 369 patients randomized and received treatment were included in the safety set (SS, Table 2). The median duration of exposure was 16.0 (range: 0.0-29.7) and 11.0 (range: 0.0-28.9) months for the rezivertinib and gefitinib groups, respectively. Treatment-emergent adverse events (TEAEs) were reported in 182 (98.9%) patients of rezivertinib group and 181 (97.8%) patients of gefitinib group, respectively. The top five treatment-related adverse events (TRAEs) were white blood cell (WBC) count decreased (39.7%), platelet (PLT) count decreased (33.2%), alanine aminotransferase (ALT) increased (28.3%), anaemia (26.1%), aspartate aminotransferase (AST) increased (25.5%) and absolute neutrophil count (ANC) decreased (25.5%) in the rezivertinib group, while that in the gefitinib group were ALT increased (38.4%), AST increased (35.7%), diarrhoea (27.0%), rash (25.9%) and blood bilirubin increased (18.4%). Grade 3 or higher TEAEs (44.6% in the rezivertinib group; 43.2% in the gefitinib group) and TRAEs (23.4% in the rezivertinib group; 23.2% in the gefitinib group) were similar in both groups, and the number of patients suffered TEAEs (27.7% in the rezivertinib group; 26.5% in the gefitinib group) and TRAEs (19.6% in the rezivertinib group; 22.2% in the gefitinib group) leading to dose adjustment was similar as well. One patient died from TRAE in the rezivertinib group, due to pneumonia and interstitial lung disease. The patients suffered less serious TRAEs in the rezivertinib group (n=13, 7.1%) while compared with the gefitinib group (n=21, 11.4%). The summary of adverse events (AEs) of rezivertinib cross-over treatment was shown in extended Data Table S3.

In the REZOR study, rezivertinib showed superior overall and CNS efficacy and a manageable safety profile in the first-line therapy for locally advanced or metastatic NSCLC patients with EGFR mutations.

The REZOR study’s primary endpoint showed BICR-assessed median PFS of 19.3 (95% CI: 13.8-22.1) and 9.6 (95% CI: 8.4-11.3) months in the rezivertinib and gefitinib groups with statistical significance (HR = 0.48; 95% CI: 0.36-0.63; P < 0.0001). The median PFS of the other four third-generation EGFR TKIs approved by China NMPA was also significantly prolonged over gefitinib/erlotinib/icotinib. For osimertinib in the FLAURA study, the median PFS of osimertinib group and gefitinib/erlotinib groups was 18.9 months and 10.2 months (HR = 0.46; 95% CI: 0.37-0.57; P < 0.001), respectively^18,19,31. For almonertinib in the AENEAS study, the median PFS of almonertinib and gefitinib groups was 19.3 months and 9.9 months (HR = 0.46; 95% CI: 0.36-0.60; P < 0.0001), respectively ²⁰. For furmonertinib in the FURLONG study, the median PFS of furmonertinib group and gefitinib groups was 20.8 months and 11.1 months (HR = 0.44; 95% CI: 0.34-0.58; P < 0.0001), respectively ²¹. In the phase 3 study of befotertinib versus icotinib, the median PFS was 22.1 (95% CI: 17.9-not estimable) and 13.8 (95% CI: 12.4-15.2) months for befotertinib and icotinib groups (HR = 0.49; 95% CI: 0.36-0.68; P < 0.0001), respectively ²⁴.

The rezivertinib group showed significantly prolonged PFS over gefitinib group among patients with different EGFR mutations, including EGFR exon 19 deletion subgroup (22.1 [95% CI: 13.8-NC] versus 9.7 [95% CI: 8.4-13.8] months; HR = 0.38; 95% CI: 0.26-0.57; P < 0.0001) and L858R mutation (13.9 [95% CI: 9.7-17.9] versus 9.6 [95% CI: 6.9-12.4] months; HR = 0.59; 95% CI: 0.40-0.85; P = 0.0053). Similar results were found in other third-generation EGFR TKIs. In the FLAURA study, the median PFS in the osimertinib group was 21.4 (95% CI: 16.5-24.3) and 11.0 (95% CI: 9.7–12.6) months in the gefitinib/erlotinib group for patients with EGFR exon 19 deletion (HR = 0.43; 95% CI: 0.32-0.56; P < 0.001); and 14.4 (95% CI: 11.1-18.9) months in the osimertinib group versus 9.5 (95% CI: 8.1-11.0) months in the gefitinib group for patients with EGFR L858R mutation (HR = 0.51; 95% CI: 0.36-0.71; P < 0.001) ¹⁸. In the AENEAS study, it was 20.8 (95% CI: 18.1-20.9) months for the aumolertinib group and 12.3 (95% CI: 9.6-13.8) months for the gefitinib group with EGFR exon 19 deletion (HR = 0.39; 95% CI: 0.28-0.54; P < 0.0001), and 13.4 (95% CI: 7.3-18.0) versus 8.3 (95% CI: 6.8-9.9) months for those with L858R mutation (HR = 0.60; 95% CI: 0.40-0.89; P = 0.0102) ²⁰. In the FURLONG study, furmonertinib significantly reduced the risk of progression or death over gefitinib among patient with EGFR exon 19 deletion (HR = 0.35; 95% CI: 0.23-0.53; P < 0.0001) and L858R mutation (HR = 0.54; 95% CI: 0.37-0.77; P = 0.0006) ²¹. Befotertinib also showed significantly longer PFS than icotinib among patients with exon 19 deletion (HR = 0.42; 95% CI: 0.29-0.62; P < 0.0001), while no significantly longer PFS was observed among patients with L858R mutation ²⁴. In the FLAURA study, the patients with EGFR exon 19 deletion and EGFR L858R mutation were 175 (62.7%) and 104 (37.3%) in the osimertinib group ¹⁸. In the AENEAS study, it was 140 (65.4%) and 74 (34.6%) in the aumolertinib group ²⁰. In the FURLONG study, it was 91 (51.1%) and 87 (48.9%) in the furmonertinib group ²¹. In the befotertinib phase 3 study, it was 117 (64.3%) and 65 (35.7%) in the befotertinib group ²⁴. These indicated that the EGFR exon 19 deletion was associated with longer median PFS compares to EGFR L858R mutation, this might contribute to a better overall efficacy if the proportion of patients enrolled with EGFR exon 19 deletion was higher. The percentage of patients with EGFR exon 19 deletions in the REZOR study was numerically lowest among these studies.

For patients with CNS metastases at baseline, the median PFS was 16.0 versus 9.7 months (HR = 0.52; 95% CI: 0.34-0.80; P = 0.003) in the rezivertinib and gefitinib groups, respectively. The median PFS of the study treatment group and control group was 15.2 versus 9.6 months (HR = 0.47; 95% CI: 0.30-0.74; P < 0.001) in the FLAURA study ¹⁸, 15.3 versus 8.2 months (HR = 0.38; 95% CI: 0.24-0.60; P < 0.001) in the AENEAS study ²⁰, 18.0 versus 12.4 months (HR = 0.50; 95% CI: 0.32-0.80; P = 0.0028) in the FURLONG study ²¹, and 19.4 versus 13.7 months (HR = 0.48; 95% CI: 0.28-0.84; P = 0.0086) in the phase 3 study of befotertinib versus icotinib ²⁴. These results indicated the superior efficacy of the third-generation over first-generation EGFR TKIs in patient with CNS metastases at baseline with longer median PFS and lower risk of progression or death.

For 147 patients (rezivertinib group: n=75; gefitinib group: n=72) with CNS metastases at baseline, the CNS PFS (22.5 [95% CI: 16.6-NC] versus 15.2 [95% CI: 11.0-NC] months; HR = 0.61; 95% CI: 0.36-1.05; P = 0.0737) was similar with other third-generation EGFR TKIs when compared with the first-generation. In the FLAURA study, osimertinib reduced the risk of CNS progression or death over gefitinib/erlotinib (HR = 0.48; 95% CI: 0.26-0.86; P = 0.014) ³². In the AENEAS study, almonertinib achieved significantly longer median CNS-PFS over gefitinib (29.0 vs 8.3 months; HR = 0.323; 95% CI: 0.18-0.58; P < 0.0001) ³³. In the FURLONG study, furmonertinib significantly prolonged the median CNS-PFS over gefitinib (20.8 versus 9.8 months; HR = 0.40; 95% CI: 0.23-0.71; P = 0.0011) ²². The median investigator-assessed intracranial PFS was not estimable (95% CI: 9.7-not estimable) in the befotertinib group versus 15.2 months (10.4-22.1; HR = 0.69 [95% CI: 0.36-1.33]; P = 0.26) in the icotinib group ²⁴.

In the rezivertinib group, 130 (70.7%) and 76 (41.3%) patients detected the EGFR mutations with tissue and plasma samples at baseline, while in the gefitinib group it was 140 (75.7%) and 62 (33.5%), respectively. For patients harboring EGFR mutations detected with tissue samples, 64 (49.2%) and 96 (68.6%) BICR-assessed events occurred in the rezivertinib and gefitinib groups, and the BICR-assessed median PFS was significantly extended in the rezivertinib group (20.7 [95% CI: 13.9-24.9] versus 9.7 [95% CI: 8.3-12.4] months; HR = 0.47 [95% CI: 0.34-0.66; P＜0.0001] ). The result was consistent among those with plasma samples (38 [50.0%] events in the rezivertinib; 43 [69.4%] in the gefitinib groups), and the BICR-assessed median PFS was 16.0 (95% CI: 9.7-24.9) versus 9.6 (95% CI: 6.9-11.0) months (HR = 0.48; 95% CI: 0.30-0.75; P = 0.0014). Meanwhile, for patients detected with tissue samples, the BICR-assessed median PFS was longer than those detected with plasma samples, which was consistent with the previous studies of rezivertinib^25,26,28. Among the third-generation EGFR TKIs, plasma EGFR mutations were merely detected in the first-line treatment studies. However, patients harboring EGFR mutations were detected with plasma sample in the REZOR and the AENEAS studies. In the AENEAS study ²⁰, among 280 patients detected with tissue sample, 176 events occurred with the HR of 0.44 (95% CI: 0.32-0.60) in the aumolertinib group over gefitinib group, and among 149 patients detected with plasma sample, 87 events occurred with the HR of 0.53 (95% CI: 0.34-0.82) in the aumolertinib group over gefitinib group. Results from this study and the AENEAS study indicated that the efficacy of patients with EGFR mutation detected by plasma sample was worse than that by tissue sample.

The safety profile of rezivertinib was manageable without new safety signals, and the main AEs were hematological and hepatological toxicities. The top five TRAEs were WBC count decreased (39.7%), PLT count decreased (33.2%), ALT increased (28.3%), anaemia (26.1%), AST increased (25.5%) and ANC decreased (25.5%). The main AEs in the gefitinib group were gastro-intestinal toxicities, hepatological and dermatological toxicities, with ALT increased (38.4%), AST increased (35.7%), diarrhoea (27.0%), rash (25.9%) and blood bilirubin increased (18.4%). In the FLAURA study, especially hematological toxicity of osimertinib was more obvious among Chinese patients ^31,34. The frequency of ≥ grade 3 hematological TRAEs of rezivertinib was low, such as ANC decreased (4.9%), WBC count decreased (2.7%), lymphocyte count decreased (2.7%) and PLT count decreased (2.2%) and anaemia (0.5%). The hematological AEs was clinically well-manageable, that among 184 patients in the rezivertinib group, no patient experienced serious hematological TEAEs or TEAEs leading to death; 9 (4.9%) patients experienced dose adjustment due to ANC decreased, 5 (2.7%) due to PLT count decreased, 4 (2.2%) due to WBC count decreased respectively, and 2 (1.1%) due to lymphocyte count decreased; 1 (0.5%) patient in the rezivertinib group experienced treatment termination due to anaemia. For the hepatological TRAEs, the ALT and AST increased related to rezivertinib was observed in 52 (28.3%) and 47 (25.5%) patients, and 4 (2.2%) and 3 (1.6%) of them was ≥ grade 3, while in gefitinib group totally 71 (38.4%) and 66 (35.7%) experienced related ALT and AST increased, of which 15 (8.1%) and 12 (6.5%) was ≥ grade 3. 2 (1.1%) and 1 (0.5%) patients in the rezivertinib group experienced serious TRAEs of ALT and AST increased respectively, while 3 (1.6%) and 1 (0.5%) patients experienced dose adjustment. No patient experienced TEAEs leading to treatment termination or death.

There are limitations of this study. Firstly, all patients were enrolled from China, there might be a potential bias while comparing with other ethnic patients. Meanwhile, the mechanism of rezivertinib after disease progression needed further exploration.

In conclusion, this study met the primary endpoint, rezivertinib (BPI-7711) showed superior overall and subgroups efficacy and a manageable safety profile for the treatment among the locally advanced or metastatic NSCLC patients with EGFR mutations in the first-line setting, when compared with gefitinib.

Study design

This was a multicenter, double-blinded, randomized phase 3 study (NCT03866499), conducted across 50 hospitals in China. Informed consent form (ICF) 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 were stratified by EGFR exon 19 deletion or L858R mutation and presence of brain metastases at baseline, then randomly assigned (1:1) to two treatment groups with either oral rezivertinib (BPI-7711) 180 mg/day plus placebo, or oral gefitinib 250 mg/day plus placebo, until unacceptable toxicity occurred, disease progression, or other treatment discontinuation criteria were met. Each cycle lasts for 21 days. Treatment beyond progression was permitted if the investigators determined that clinical benefits could be obtained. Eligible patients confirmed of disease progression by investigator from the gefitinib group with secondary T790M mutation detected may enter the cross-over treatment phase, to receive open-label rezivertinib treatment until unacceptable toxicity occurred, re-evaluation showed disease progression, or other treatment discontinuation criteria were met.

Inclusion criteria

Patients must meet all the following inclusion criteria to be eligible for this study:

1. Written ICF signed and dated by the patient prior to any study-related treatments, sampling, or analysis.

2. Male or female, aged ≥18 years at the time of signing the ICF.

3. Histologically or cytologically confirmed NSCLC (adenocarcinoma or adenocarcinoma-dominant).

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, with no deterioration within the two weeks prior to enrollment, and an expected survival of at least 12 weeks.

5. No prior systemic therapy for locally advanced or metastatic NSCLC that is unsuitable for radical surgery or radiotherapy. Prior neoadjuvant or adjuvant therapy (chemotherapy/radiotherapy/research drugs, excluding EGFR TKIs) is permissible, provided there has been ≥ 6 months since the end of such treatment and tumor progression.

6. At least one measurable lesion per RECIST version 1.1 that has not been previously irradiated. If the patient has only one measurable lesion and it has been biopsied, the baseline computed tomography (CT) scan must be conducted either before the biopsy or at least 14 days post-biopsy. Previously irradiated lesions can only be considered if there is unequivocal progression, and they should not be chosen as target lesions.

7. Confirmation from the central laboratory that the tumor harbors one of the two common EGFR gene mutations (Exon 19 deletion, L858R) that are sensitive to EGFR-TKI treatment, with or without other EGFR mutations, but excluding Exon 20 insertions. Testing samples for EGFR mutations included tissue and/or plasma. If a tissue sample is unavailable, plasma testing results should be used.

8. Clinical laboratory test results meeting the following criteria:

a) PLT ≥100×10^9/L

b) ANC ≥1.5×10^9/L

c) Hemoglobin ≥ 90 g/L

d) Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (up to 3 times ULN if liver metastases are present)

e) ALT and AST ≤3 times ULN (up to 5 times ULN if liver metastases are present)

f) Creatinine ≤1.5 times ULN or creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula)

g) Resting electrocardiogram (ECG) showing corrected QT interval (QTcF) ≤470 msec

h) For patients not on anticoagulants, international normalized ratio (INR) ≤1.5 times ULN and activated partial thromboplastin time (APTT) ≤1.5 times ULN. Patients on heparin anticoagulation therapy may be included if these parameters are within normal limits. Patients on warfarin anticoagulation therapy must have been on a stable dose of warfarin with an INR within therapeutic range for at least 28 days prior to enrollment.

9. Ability to swallow oral medication.

10. Women of childbearing potential must use effective contraception, not be breastfeeding, and have a negative pregnancy test prior to the start of study treatment. Alternatively, they must be proven to be incapable of becoming pregnant.

11. Male patients must agree to use barrier contraception.

12. Any previous treatment-related clinical toxicities must have resolved to baseline or grade 1, except for alopecia and stable grade 2 or lower peripheral neuropathy.

Exclusion criteria

Subjects will be excluded from the study if they meet any of the following criteria:

1. Prior systemic treatment for locally advanced or recurrent metastatic disease, including chemotherapy or targeted therapy.

2. Positive for primary T790M mutation.

3. Treatment with any of the following within 14 days prior to the first dose of the study drug: investigational drugs, strong CYP3A4 inhibitors or inducers, herbal medications for antitumor purposes, or the antihypertensive drug labetalol.

4. Any of the following cardiac criteria: QTcF >470 msec at rest; clinically significant arrhythmias, conduction abnormalities, or resting ECG abnormalities, such as complete left bundle branch block, third-degree conduction block, second-degree conduction block, PR interval >250 msec; factors that increase the risk of QTc prolongation or arrhythmic events, such as symptomatic heart failure (New York Heart Association [NYHA] Class II-IV), hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death before age 40, or concomitant medication known to prolong QT interval.

5. History of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any clinically active interstitial lung disease.

6. Known active infections, such as hepatitis B, hepatitis C, or human Immunodeficiency Virus (HIV). Well-controlled hepatitis B, etc., may be considered for inclusion in the study with concurrent antiviral treatment.

7. Concurrent malignancies or other malignancies within the last 5 years that are still being treated. Patients with cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder tumors (non-invasive), or in situ cancers treated curatively and without recurrence for at least 3 years may be considered for inclusion.

8. Significant gastrointestinal disorders that may interfere with the absorption of the study drugs, as determined by the investigator (e.g., uncontrolled inflammatory gastrointestinal disease, history of abdominal fistula or gastrointestinal perforation within 6 months, extensive small intestine resection requiring tube feeding or parenteral hydration/nutrition).

9. Spinal cord compression, leptomeningeal metastasis, or symptomatic brain metastasis. Asymptomatic brain metastasis may be allowed if: the brain metastasis is discovered at screening, judged not to require steroids and/or local treatment by the investigator; or if previously treated with local therapy (e.g., radiotherapy) and asymptomatic, the patient has discontinued steroids and/or antiepileptic treatment at least 7 days prior to the first dose of the study drugs.

10. Local radiotherapy within 1 week prior to the first dose of study treatment for symptom relief, or radiotherapy involving more than 30% of bone marrow or large field radiotherapy within 4 weeks prior to the first dose of the study drugs.

11. Major surgery ≤ 4 weeks or minor surgery ≤ 2 weeks before the first dose of the study drugs.

12. Any unstable condition or factors that may endanger the patient's safety or affect compliance with study requirements.

13. Pregnant or breastfeeding women.

14. Inadequate mental or behavioral capacity to understand the nature, significance, and risks of the study.

15. Substance abuse, alcoholism, medical or psychological conditions, or social barriers that may interfere with participation or evaluation of the study results, as judged by the investigator. Any factor that, in the opinion of the investigator, makes the candidate unsuitable for the study drugs. Candidates unwilling or unable to comply with the study protocol requirements.

Outcomes

The primary endpoint was PFS evaluated by BICR per the RECIST version 1.1, which was defined as the time from randomization to disease progression or death. The secondary endpoints included PFS evaluated by the investigator, best overall response (BOR), ORR, DCR, DoR, and TTR evaluated by both the BICR and investigator, OS, and quality of life using EORTC QLQ-C30 and QLQ-LC13. For patients in the gefitinib group who progressed and received cross-over treatment with rezivertinib, PFS2, ORR, DCR and DoR were evaluated by both BICR and the investigator, quality of life was assessed by patients as well. BOR was defined as the best response recorded during the study. ORR was defined as the proportion of patients with CR or PR. DCR was defined as the proportion of patients with CR, PR, or SD. DoR was defined as the time from achieving CR or PR to disease progression or death. TTR was defined as the time from randomization to the first occurrence of CR or PR. OS was defined as the time from randomization to death. PFS2 was defined as the time from randomization to the second occurrence of disease progression or death from any cause after initiating cross-over treatment with rezivertinib treatment, whichever occurred first. The efficacy for patients with CNS metastases was measured by BICR according to the RANO-BM. For patients with baseline brain metastases assessed by the investigator, CNS ORR, CNS DCR, CNS DoR, CNS TTP, and CNS PFS for brain metastases evaluated by BICR would be conducted independently. CNS ORR was defined as the proportion of patients with brain metastases at baseline who achieved a CR or PR. CNS DCR was defined as the proportion of patients with brain metastases at baseline who achieved CR, PR, or SD (lasting ≥ 39 days after the start of study treatment). For patients reporting CNS response (CR or PR), CNS DoR was defined as the time from the first CNS CR or PR to the first reported CNS disease progression or death due to any cause, whichever occurred first. CNS TTP was defined as the time from randomization to CNS disease progression, while CNS PFS was defined as the time from randomization to CNS disease progression or death.

Safety was assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Statistical analysis

To determine the sample size, based on historical data, the median PFS of first-line EGFR mutation-positive NSCLC patients was estimated to be around 15.0 months in the rezivertinib group and 10.5 months in the gefitinib group. Assuming a randomization ratio of 1:1, considering a 10% dropout rate for PFS, Type I error α = 0.05, a total of 367 patients (approximately 275 events) were needed to achieve an 84% power to detect HR = 0.7. A pre-planned interim analysis would be conducted when approximately 193 (70%) PFS events evaluated by the BICR have been collected. The corresponding one-sided α value was 0.0074 based on the Lan-DeMets approximation to the O’Brien-Fleming boundary. On Jun 16, 2023, the independent Data Monitoring Committee (DMC) determined that based on the interim analysis results, the primary endpoint (PFS evaluated by BICR) has met the presupposed α level at the interim analysis, this updated analysis was descriptive in nature and not subject to multiplicity control. All data reported here was based on the updated analysis (Data cut-off date: Nov 30, 2023).

Statistical analysis in this study included ITT set and SS. ITT set involved all randomized patients. The efficacy analysis would be based on the ITT set. Patients who have received at least one non-zero dose of the study drugs would be included in the SS. Safety analysis will be based on the SS according to the actual treatment group. Summary of time-to-event variables would be based on the Kaplan-Meier method. The primary efficacy analysis for PFS was based on stratified log-rank test with stratification factors used for randomization (baseline exon 19 deletion vs. L858R mutation and presence of brain metastases). The HR and its corresponding 95% CI were calculated based on the stratified Cox proportional hazards model.

For the primary efficacy endpoint, additional subgroup analysis included age (<65 years, ≥65 years), gender (male, female), baseline ECOG PS score (0, 1), types of EGFR testing samples (tissue, plasma). Subgroup analysis focused on HR. For each subgroup, the HR (rezivertinib compared to gefitinib) and corresponding 95% CI would be estimated using a stratified Cox proportional hazards model.

Statistical analyses were performed with SAS version 9.4.

Data availability

The data and materials that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgements

This study (NCT03866499) was funded by Beta Pharma (Shanghai) Co., Ltd, Shanghai, China, partly supported by the New National Natural Science Foundation of China (82172856, 81972805) and the China National Major Project for New Drug Innovation (2017ZX09304015). The authors thank all the participating patients, their families, and the participating study teams. The authors thank Prof. Xiaoqing Liu, Prof. Ligong Nie, and Prof. Xiaolei Lin for participating the independent data monitoring committee interim analysis meeting. The authors would also like to thank Dr. Haohua Zhu and Dr. Tongji Xie (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China) for providing medical editing assistance with this article.

Author contributions

Y.S. was the leading principal investigator and designed the trial with the sponsor. Y.S. and T.W. were responsible for the administrative support. All authors contributed to patient recruitment and data acquisition, accessed and verified the data. Y.S., T.W. and A.Z. involved in data analysis and data interpretation. Y.S., T.W. and A.Z. did the manuscript writing. All authors reviewed and approved the final version of the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Competing interests

D.Z., J.P., H.S., F.G., T.W. and A.Z. are employees of Beta Pharma (Shanghai) Co., Ltd. All other authors declare no competing interests.

Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74, 229–263 (2024).
Han, B. et al. Cancer incidence and mortality in China, 2022. Journal of the National Cancer Center 4, 47–53 (2024).
Miller, K. D. et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 69, 363–385 (2019).
Shi, J.-F. et al. Clinical characteristics and medical service utilization of lung cancer in China, 2005-2014: Overall design and results from a multicenter retrospective epidemiologic survey. Lung Cancer 128, 91–100 (2019).
Yamaoka, T., Ohba, M. & Ohmori, T. Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms. Int J Mol Sci 18, 2420 (2017).
Shi, Y. et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 9, 154–62 (2014).
Shi, Y. et al. Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology - Mainland China Subset Analysis of the PIONEER study. PLoS One 10, e0143515 (2015).
Hendriks, L. E. et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34, 339–357 (2023).
Owen, D. H. et al. Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1. J Clin Oncol JCO2400762 (2024) doi:10.1200/JCO.24.00762.
Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care, C. A. for C. O. China clinical practice guideline for epidermal growth factor receptor tyrosine kinase inhibitors in stage IV non‑small cell lung cancer (version 2023). Zhonghua Yi Xue Za Zhi 103, 3160–3173 (2023).
Wu, Q., Qian, W., Sun, X. & Jiang, S. Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. J Hematol Oncol 15, 143 (2022).
Huang, L., Jiang, S. & Shi, Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020). J Hematol Oncol 13, 143 (2020).
Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361, 947–57 (2009).
Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12, 735–42 (2011).
Shi, Y. K. et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advancedEGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Annals of Oncology 28, 2443–2450 (2017).
Wu, Y.-L. et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15, 213–222 (2014).
Wu, Y.-L. et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18, 1454–1466 (2017).
Soria, J.-C. et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 378, 113–125 (2018).
Ramalingam, S. S. et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 382, 41–50 (2020).
Lu, S. et al. AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations. J Clin Oncol 40, 3162–3171 (2022).
Shi, Y. et al. Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study. Lancet Respir Med 10, 1019–1028 (2022).
Shi, Y. et al. Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study. Journal of Thoracic Oncology (2022) doi:10.1016/j.jtho.2022.07.1143.
Shi, Y. et al. Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer. Lancet Reg Health West Pac 48, 101122 (2024).
Lu, S. et al. Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study. Lancet Respir Med 11, 905–915 (2023).
Shi, Y. 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. J Thorac Oncol 17, 708–717 (2022).
Shi, Y. et al. Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study. J Thorac Oncol 17, 1306–1317 (2022).
Yang, S. et al. Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies. Lung Cancer 180, 107194 (2023).
Shi, Y. et al. 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. BMC Med 21, 11 (2023).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45, 228–247 (2009).
Lin, N. U. et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16, e270-8 (2015).
Cheng, Y. et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol 16, 165–176 (2021).
Reungwetwattana, T. et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 36, 3290–3297 (2018).
Lu, S. et al. Aumolertinib activity in patients with CNS metastases and EGFR-mutated NSCLC treated in the randomized double-blind phase III trial (AENEAS). Journal of Clinical Oncology 40, 9096–9096 (2022).
Lucchini, E. et al. Targeting the epidermal growth factor receptor in solid tumors: focus on safety. Expert Opin Drug Saf 13, 535–549 (2014).

Table 1. Demographic and clinical characteristics of patients (ITT set)

Patients	Rezivertinib, n (%) (n=184)	Gefitinib, n (%) (n=185)
Age, y, n (%)
Median (Range)	61.0 (32.0-86.0)	62.0 (30.0-81.0)
＜50	26 (14.1)	22 (11.9)
50 -＜65	87 (47.3)	82 (44.3)
≥ 65	71 (38.6)	81 (43.8)
Sex, n (%)
Male	72 (39.1)	80 (43.2)
Female	112 (60.9)	105 (56.8)
Race, n (%)
Asian	184 (100.0)	185 (100.0)
ECOG PS, n (%)
0	41 (22.3)	32 (17.3)
1	143 (77.7)	153 (82.7)
Histology type, n (%)
Adenocarcinoma Nos	179 (97.3)	177 (95.7)
Acinar Adenocarcinoma	2 (1.1)	2 (1.1)
Solid Adenocarcinoma	1 (0.5)	1 (0.5)
Invasive Mucinous Adenocarcinoma	1 (0.5)	4 (2.2)
Minimally Invasive Adenocarcinoma	1 (0.5)	0
Adenosquamous Carcinoma	0	1 (0.5)
EGFR-sensitive mutation type, n (%)
Exon 19 deletion	93 (50.5)	97 (52.4)
L858R	91 (49.5)	88 (47.6)
CNS metastases, n (%)
Yes	75 (40.8)	72 (38.9)
No	109 (59.2)	113 (61.1)
Disease Status, n (%)
Locally Advanced	1 (0.5)	1 (0.5)
Metastatic	183 (99.5)	184 (99.5)
Metastatic Site, n (%)
Lung	183 (99.5)	183 (98.9)
Lymph Node	146 (79.3)	144 (77.8)
Bone	108 (58.7)	105 (56.8)
Brain	75 (40.8)	72 (38.9)
Pleural Effusion	74 (40.2)	72 (38.9)
Pleura	61 (33.2)	54 (29.2)
Liver	29 (15.8)	35 (18.9)
Adrenal Gland	23 (12.5)	24 (13.0)
Mediastinum	1 (0.5)	6 (3.2)
Retroperitoneum	0	4 (2.2)
Others	23 (12.5)	37 (20.0)

Note: ITT, intention-to-treat; ECOG, Eastern Cooperative Oncology Group; PS, performance score; EGFR, Epidermal Growth Factor Receptor; CNS, central nervous system; Nos, not otherwise specified.

Table 2. Summary of AEs in SS

AEs	Rezivertinib, n (%) (n=184)		Gefitinib, n (%) (n=185)
	Any grade	≥ grade 3	Any grade	≥ grade 3
TEAE	182 (98.9)	82 (44.6)	181 (97.8)	80 (43.2)
TEAE Leading to Death	9 (4.9)		7 (3.8)
TEAE Leading to Treatment Termination	14 (7.6)		7 (3.8)
TEAE Leading to Dose Adjustment	51 (27.7)		49 (26.5)
TEAE Leading to Dose Interruption	38 (20.7)		27 (14.6)
TEAE Leading to Dose Reduction	29 (15.8)		30 (16.2)
TRAE	176 (95.7)	43 (23.4)	168 (90.8)	43 (23.2)
TRAE Leading to Death	1 (0.5)		0
TRAE Leading to Treatment Termination	9 (4.9)		7 (3.8)
TRAE Leading to Dose Adjustment	36 (19.6)		41 (22.2)
TRAE Leading to Dose Interruption	19 (10.3)		17 (9.2)
TRAE Leading to Dose Reduction	29 (15.8)		30 (16.2)
Serious TEAE	45 (24.5)		54 (29.2)
Serious TRAE	13 (7.1)		21 (11.4)
Serious TEAE Leading to Discontinuation of study drug	9 (4.9)		3 (1.6)
TRAE (incidence ≥10%) ^a	176 (95.7)	43 (23.4)	168 (90.8)	43 (23.2)
WBC count decreased	73 (39.7)	5 (2.7)	15 (8.1)	1 (0.5)
PLT count decreased	61 (33.2)	4 (2.2)	10 (5.4)	0
ALT increased	52 (28.3)	4 (2.2)	71 (38.4)	15 (8.1)
Anaemia	48 (26.1)	1 (0.5)	21 (11.4)	0
ANC decreased	47 (25.5)	9 (4.9)	17 (9.2)	3 (1.6)
AST increased	47 (25.5)	3 (1.6)	66 (35.7)	12 (6.5)
Diarrhoea	35 (19.0)	1 (0.5)	50 (27.0)	0
Decreased appetite	32 (17.4)	3 (1.6)	26 (14.1)	1 (0.5)
Lymphocyte count decreased	27 (14.7)	5 (2.7)	12 (6.5)	0
Drug eruption	24 (13.0)	4 (2.2)	28 (15.1)	1 (0.5)
Rash	20 (10.9)	1 (0.5)	48 (25.9)	1 (0.5)
Weight decreased	19 (10.3)	0	12 (6.5)	0
Alopecia	18 (9.8)	0	23 (12.4)	0
Vomiting	16 (8.7)	0	21 (11.4)	1 (0.5)
Hepatic function abnormal	11 (6.0)	1 (0.5)	19 (10.3)	5 (2.7)
Blood bilirubin increased	5 (2.7)	0	34 (18.4)	0

Note: Safety was determined by investigator as per CTCAE Version 4.03. ^a TRAE (incidence ≥10%) included TRAEs with an incidence ≥10% either in the rezivertinib or the gefitinib at any grade, and the order was arranged from highest to lowest according to the TRAE (incidence ≥10%) incidence rate of rezivertinib at any grade. AE, adverse event; SS, safety set; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; WBC, white blood cell; PLT, platelet; CTCAE, Common Terminology Criteria for Adverse Events.

Yes there is potential Competing Interest. D.Z., J.P., H.S., F.G., T.W. and A.Z. are employees of Beta Pharma (Shanghai) Co., Ltd. All other authors declare no competing interests.

Rezivertinib versus Gefitinib as First-line Therapy for EGFR-mutated Locally Advanced or Metastatic NSCLC Patients (REZOR): A Multicenter, Double-blinded, Randomized Phase 3 Study

Status:

Version 1

Abstract

Figures

Introduction

Results

Discussion

Online Methods

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1