Mefatinib versus gefitinib as a first-line treatment for EGFR-mutated non-small cell lung cancer: a randomized, double-blind, multicenter phase III study

Abstract

Mefatinib, a novel second-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor that has shown promising antitumor activity in targeting non-small cell lung cancer (NSCLC) with common and uncommon EGFR-activating mutations. In this phase III, randomized, double-blind trial in China, 336 eligible patients with advanced nonsquamous NSCLC harboring EGFR L858R or exon 19 deletion (ex19del) were assigned (2:1) to receive either mefatinib (60 mg daily, n = 223) or gefitinib (250 mg daily, n = 113). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee (IRC). The trial is registered with chinadrugtrials.org.cn (CTR20192297). After a median follow-up of 15.9 months for mefatinib and 18.5 months for gefitinib, mefatinib demonstrated a significantly longer median IRC-assessed PFS compared to gefitinib (13.7 vs. 9.7 months; hazard ratio [HR] = 0.68; 95% confidence intervals [CI]: 0.53–0.87; p = 0.002). The 30-month overall survival rate was 60.2% for mefatinib and 54.3% for gefitinib. Patients with EGFR ex19del had comparable PFS for both treatment arms (p > 0.100), whereas patients with EGFR L858R had significantly longer median PFS when treated with mefatinib than gefitinib (13.7 vs 8.3 months HR = 0.55 [95% CI: 0.38–0.78]; p = 0.001). Patients with EGFR L858R had a 30-month overall survival rate of 56.6% with mefatinib and 43.7% with gefitinib. Treatment-related adverse events ≥grade 3 were reported in 45.7% of the mefatinib group and 24.8% of the gefitinib group. No new safety signals were observed for mefatinib. Mefatinib demonstrated superior efficacy to gefitinib with a similar tolerability profile in the first-line treatment of EGFR-mutated advanced NSCLC.

Introduction

Lung cancer continues to be the most prevalent malignancy and is becoming a growing public health concern worldwide.^1–4 Owing to advancements in screening and detection techniques, there has been an increase in the number of new lung cancer diagnoses in China, with 1,060,600 newly diagnosed cases in 2022.³ Despite the availability of various therapeutic modalities, lung cancer mortality remains high, claiming approximately 733,300 lives in 2022.³

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Among Chinese patients diagnosed with NSCLC, over 50% were observed to harbor common somatic genetic alterations in the epidermal growth factor receptor (EGFR), specifically the missense mutation L858R and short deletion mutations in exon 19 (ex19del).^5–7 Since the approval of first- and second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, icotinib, and afatinib, nearly a decade ago, remarkable improvement in progression-free survival (PFS) has been seen among patients with EGFR-positive advanced NSCLC who have received treatment with these agents. The regulatory approval of these agents was granted following pivotal randomized clinical trials that showcased their favorable safety profile and longer PFS compared to standard platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC.^8–12 Several second- and third-generation EGFR-TKIs were subsequently introduced, including dacomitinib, osimertinib, osimertinib, befotertinib and furmonertinib, supported by key clinical trials demonstrating their superior PFS compared to standard first-generation EGFR-TKIs such as gefitinib.^13–20 Although the current standard of care EGFR-TKIs has resulted in a more favorable prognosis for patients with EGFR-positive NSCLC, there remains a discrepancy in certain populations. Specifically, patients with EGFR L858R treated with standard EGFR-TKI continue to have a subpar PFS rate, with minimal to no overall survival advantage, compared to patients with EGFR ex19del.^14,21–23

The importance of optimizing first-line therapy, therefore, cannot be overstated, as the initial treatment choice significantly influences the entire disease trajectory. An effective first-line agent that provides a durable response is critical for extending PFS, which not only delays the clinical deterioration associated with disease progression but also preserves the patient’s quality of life. Furthermore, postponing the emergence of drug resistance is a primary goal, as it delays the need to switch to subsequent lines of therapy, which may be more toxic or less effective.^24–26 Given that a substantial portion of patients with NSCLC in China harbor EGFR mutations, establishing a superior first-line treatment option has immense clinical and public health implications for this large patient population.^5–7

Mefatinib is a novel, orally active, highly selective second-generation EGFR-TKI, with the chemical structure shown in Supplementary Fig. 1. Preliminary clinical studies on mefatinib (MET306) demonstrated encouraging efficacy against both common and uncommon EGFR mutations.^27,28 In this study, we present the results of our multicenter phase III randomized controlled clinical trial investigating the efficacy and safety of mefatinib compared with gefitinib as a first-line therapy for patients diagnosed with locally advanced to advanced nonsquamous NSCLC harboring either the L858R or ex19del mutation.

Results

Patient disposition and baseline characteristics

Between September 2019 and June 2022, a total of 717 Chinese patients were enrolled and screened for eligibility. Of them, 318 were excluded for reasons listed in Supplementary Table 1. The remaining 336 patients met the inclusion and exclusion criteria and were randomized in a 2:1 ratio to receive mefatinib or gefitinib. A total of 223 patients received mefatinib, and 113 patients received gefitinib (Fig. 1). As shown in Table 1, the two groups had well-balanced and comparable demographics and baseline clinicopathological features. The mefatinib group had a median age of 63.0 years (range: 55.0–69.0), with 57.8% females. The gefitinib group had a median age of 60.0 years (range: 55.0–66.0), and 57.5% were females. Given that the EGFR genotype was a stratification factor, almost half of the cohort in each treatment arm harbored L858R (51.2%), and the other half had ex19del (48.8%), with their baseline characteristics summarized in Supplementary Table 2.

Fig. 1.

Study participant flow diagram

Table 1.

Patient demographics and baseline characteristics in the full analysis set

Characteristics	All (N = 334)	Mefatinib arm (n = 223)	Gefitinib arm (n = 113)
Age, median [range]	63.0 [55.0–68.0]	63.0 [55.0–69.0]	60.0 [55.0–66.0]
<65 years, n (%)	199 (59.2)	122 (54.7)	77 (68.1)
≥65 years, n (%)	137 (40.8)	101 (45.3)	36 (31.9)
Sex, n (%)
Male	142 (42.3)	94 (42.2)	48 (42.5)
Female	194 (57.7)	129 (57.8)	65 (57.5)
Smoking history
Previous or current smoker	97 (28.9)	63 (28.3)	34 (30.1)
Never smoked	239 (71.1)	160 (71.7)	79 (69.9)
ECOG PS, n (%)
0	74 (22.0)	46 (20.6)	28 (24.8)
1	262 (78.0)	177 (79.4)	85 (75.2)
Clinical stage, n (%)
IIIb	16 (4.8)	7 (3.1)	9 (8.0)
IIIc	7 (2.1)	7 (3.1)	0 (0.0)
IVa	140 (41.7)	90 (40.4)	50 (44.2)
IVb	173 (51.5)	119(53.4)	54 (47.8)
Histologic diagnosis, n (%)
Adenocarcinoma	334 (100)	223 (100)	113 (100)
Metastatic sites, n (%)
Lymph node	263 (78.3)	176 (78.9)	87 (77.0)
Lung	247 (73.5)	158 (70.9)	89 (78.8)
Liver	41 (12.2)	27 (12.1)	14 (12.4)
Thoracic cavity	129 (38.4)	81 (36.3)	48 (42.5)
Abdominal cavity	2 (0.6)	1 (0.4)	1 (0.9)
Adrenal gland	27 (8.0)	22 (9.9)	5 (4.4)
Bone	167 (49.7)	117 (52.5)	50 (44.2)
Pericardium	40 (11.9)	28 (12.6)	12 (10.6)
Others	20 (6.0)	15 (6.7)	5 (4.4)
EGFR mutation type, n (%)
exon 19 deletion	164 (48.8)	109 (48.9)	55(48.7)
L858R	172 (51.2)	114 (51.1)	58 (51.3)

ECOG PS Eastern cooperative oncology group performance status

Primary efficacy endpoint

At the data cutoff date (June 30, 2023), the median follow-up was 15.9 months (range: 1.1–36.3) for the mefatinib group and 18.5 months (range: 1.1–36.4) for the gefitinib group. Mefatinib had a significantly longer PFS than gefitinib (13.7 months [95% CI: 11.0–15.2] vs 9.7 months [95% CI: 8.3–12.4 months]; HR = 0.68 [95% CI: 0.53–0.87]; p = 0.002; Fig. 2a). The independent review committee (IRC)-assessed PFS was consistent with the investigator-assessed PFS (Supplementary Fig. 2; Appendix p 9). Moreover, as shown in Fig. 2b, the subgroup analysis demonstrates the PFS advantage with mefatinib over gefitinib regardless of clinical factors, such as sex, age, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and EGFR genotype.

Fig. 2.

Progression-free survival of the cohort. a Kaplan‒Meier curve comparing progression-free survival based on the independent review committee of the mefatinib and gefitinib groups of the full analysis cohort. The risk table below shows the number of cases included and censored per time point. b Forest plot showing the subgroup analysis of the impact of various clinical factors on progression-free survival

PFS by EGFR mutation subtype

Subgroup analyses of PFS outcomes based on EGFR genotypes were also performed. Patients with EGFR ex19del had a comparable median IRC-assessed PFS with mefatinib and gefitinib (12.6 months [95% confidence intervals (CI): 11.0–15.2] vs 12.5 months [95% CI: 9.6–15.1]) (hazard ratio [HR] = 0.83, 95% CI: 0.58–1.19; p = 0.307; Fig. 3a). IRC- and investigator-assessed clinical outcomes were broadly comparable between treatment arms among patients with EGFR ex19del (p > 0.100; Supplementary Table 2). Furthermore, patients with EGFR L858R had a significantly longer median IRC-assessed PFS when treated with mefatinib than gefitinib (13.7 months [95% CI: 9.7–15.3] vs 8.3 months [95% CI: 7.0–9.7]; HR = 0.55 [95% CI: 0.38–0.78]; p = 0.001; Fig. 3b). Consistently, the median investigator-assessed PFS was significantly longer with mefatinib than with gefitinib among patients with EGFR L858R (13.1 months [95% CI: 10.9–13.9] vs 9.6 months [95% CI: 6.9–11.0]; HR = 0.60 [95% CI: 0.43–0.85]; p = 0.003; Supplementary Table 3).

Fig. 3.

Progression-free survival based on EGFR genotype. Kaplan‒Meier curves comparing progression-free survival based on the independent review committee between patients with EGFR exon 19 deletion (ex19del) (a) and patients with EGFR L858R (b) treated with mefatinib and gefitinib. The risk table below shows the number of cases included and censored per time point

Secondary efficacy endpoints

IRC-assessed and investigator-assessed treatment outcomes are summarized in Table 2 and Supplementary Table 3, respectively. No significant difference was observed between the two groups in terms of IRC-assessed objective response rate (ORR; 81.2% vs 77.9%; odds ratio: 1.23 [95% CI: 0.70–2.14]; p = 0.477) and disease control rate (DCR; 89.7% vs 90.3%; p = 0.868) or investigator-assessed ORR and DCR. Among the treatment responders, those treated with mefatinib had a significantly longer median IRC-assessed duration of response (DoR; 12.5 months [95% CI: 11.0–14.0] vs 9.7 months [95% CI: 7.0–11.1]; HR = 0.68 [95% CI: 0.52–0.91]; p = 0.008; Table 2; Supplementary Fig. 3A). Patients with EGFR ex19del similarly benefited from treatment with mefatinib and gefitinib (12.6 months vs 11.1 months; HR = 0.83 [95% CI: 0.58–1.19]; p = 0.284; Table 2). Notably, patients with EGFR L858R benefited more from mefatinib than gefitinib, as shown by the significantly longer IRC-assessed DoR (12.5 months [95% CI: 9.7–15.2] vs 8.2 months [95% CI: 6.7–9.7]; HR = 0.54 [95% CI: 0.36–0.81]; p = 0.003; Table 2).

Table 2.

Clinical outcomes of the full analysis set assessed by the independent review committee

Clinical outcome	All		EGFR ex19del		EGFR L858R
	Mefatinib arm (n = 223)	Gefitinib arm (n = 113)	Mefatinib arm (n = 109)	Gefitinib arm (n = 55)	Mefatinib arm (n = 114)	Gefitinib arm (n = 58)
Complete response, n (%)	1 (0.4)	1 (0.9)	1 (0.9)	1 (1.8)	0 (0.0)	0 (0.0)
Partial response, n (%)	180 (80.7)	87 (77.0)	90 (82.6)	46 (83.6)	90 (78.9)	41 (70.7)
Stable disease, n (%)	19 (8.5)	14 (12.4)	5 (4.6)	5 (9.1)	14 (12.3)	9 (15.5)
Progressive disease, n (%)	12 (5.4)	2 (1.8)	8 (7.3)	1 (1.8)	4 (3.5)	1 (1.7)
Not evaluable, n (%)	11 (4.9)a	9 (8.0)b	5 (4.6)	2 (3.6)	6 (5.3)	7 (12.1)
Objective response rate, % (95% CI)	81.2 (75.4–86.1)	77.9 (69.1–85.1)	83.5 (75.2–89.9)	85.5 (73.3–93.5)	78.9 (70.3–86.0)	70.7 (57.3–81.9)
Odds ratio (95% CI)	1.23 (0.70–2.14)		0.86 (0.35–2.13)		1.55 (0.75–3.20)
P-value	0.477		0.745		0.231
Disease control rate, % (95% CI)	89.7 (84.9–93.3)	90.3 (83.2–95.0)	88.1 (80.5–93.5)	94.5 (84.9–98.9)	91.2 (84.5–95.7)	86.2 (74.6–93.9)
Odds ratio (95% CI)	0.94 (0.44–1.99)		0.43 (0.12–1.56)		1.66 (0.62–4.47)
P-value	0.868		0.189		0.310
Median progression-free survival, months; median (95% CI)	13.7 (11.0–15.2)	9.7 (8.3–12.4)	12.6 (11.0–15.2)	12.5 (9.6–15.1)	13.7 (9.7–15.3)	8.3 (7.0–9.7)
Hazard ratio (95% CI)	0.68 (0.53–0.87)		0.83 (0.58–1.19)		0.55 (0.38–0.78)
P-value	0.002		0.307		0.001
Duration of response, weeks; median (95% CI)	12.5 (11.0–14.0)	9.7 (7.0–11.1)	12.6 (9.7–15.2)	11.1 (8.3–13.8)	12.5 (9.7–15.2)	8.2 (6.8–9.7)
Hazard ratio (95% CI)	0.68 (0.52–0.91)		0.81 (0.55–1.20)		0.54 (0.36–0.81)
P-value	0.008		0.284		0.003
Median time to progression, months; median (95% CI)	13.8 (11.2–15.2)	9.7 (9.5–12.4)	13.9 (11.0–16.5)	12.5 (9.7–15.1)	13.8 (10.9–16.4)	8.3 (8.2–9.8)
Hazard ratio (95% CI)	0.70 (0.54–0.90)		0.81 (0.56–1.17)		0.56 (0.39–0.81)
P-value	0.005		0.263		0.002

CI confidence intervals, NE non-evaluable, SD standard deviation

^aThree patients in the Mefatinib arm deviated from the study protocol and are not evaluable for clinical outcomes

^bTwo patients in the Gefitinib arm deviated from the study protocol and are not evaluable for clinical outcomes

IRC-assessed time to progression (TTP) was also significantly longer for mefatinib than for gefitinib (13.8 months [95% CI: 11.2–15.2] vs 9.7 months [95% CI: 9.5–12.4]; HR = 0.70 [95% CI: 0.54–0.90]; p = 0.005; Supplementary Fig. 3C). Specifically, patients with EGFR L858R had a significantly longer IRC-assessed TTP with mefatinib than gefitinib (13.8 months [95% CI: 10.9–16.4] vs 8.3 months [95% CI: 8.2–9.8]; HR = 0.56 [95% CI: 0.39–0.81]; p = 0.002; Table 2). The median time to treatment failure (TTF) was significantly longer for mefatinib than gefitinib in the overall cohort (12.9 months vs 11.5 months; HR = 0.76 [95% CI: 0.60–0.97]; p = 0.026) and in patients with EGFR L858R (12.6 months vs 9.8 months; HR = 0.64 [95% CI: 0.46–0.89]; p = 0.008) (Supplementary Table 3).

Overall survival

The overall survival (OS) data for both groups remain immature. As of the data cutoff date, OS events occurred in 37.2% (83/223) of the mefatinib group and 39.8% (45/113) of the gefitinib group. There was no significant difference in OS between the two treatment groups (35.4 months vs 33.3 months; HR for death: 0.90 [95% CI: 0.63–1.30]; p = 0.577; Supplementary Fig. 4). The 30-month OS rate was 60.2% for mefatinib and 54.3% for gefitinib. Among the patients with EGFR L858R, OS events occurred in 41.2% (47/114) of those who received mefatinib and 50.0% (29/58) of those who received gefitinib. Patients with EGFR L858R had a trend of longer median OS, albeit with no significant difference (35.9 months [95% CI: 29.1–not evaluable (NE)] vs 29.1 months [95% CI: 22.1, NE]; HR = 0.76 [95% CI: 0.48–1.20]; p = 0.236 Supplementary Fig. 5). The 30-month OS rates in patients with EGFR L858R were 56.6% [95% CI: 45.6%, 66.2%] for those treated with mefatinib and 43.7% [95% CI: 26.9%, 59.3%] with gefitinib (Supplementary Table 3). Supplementary Table 4 summarizes the second-line therapy among patients who had experienced disease progression as of the data cutoff. Third-generation EGFR-TKI alone or in combination with either an antiangiogenic inhibitor or MET inhibitor was the most frequently administered agent, received by over half of the patients in both the mefatinib arm (56.0%, 79/141) and gefitinib arm (60.7%, 51/84).

Health-related quality of life

The mefatinib and gefitinib groups had generally comparable health-related quality of life (HRQoL) in terms of functional status, global health status, and symptoms, including fatigue, nausea and vomiting, pain, shortness of breath, insomnia, and loss of appetite. The HRQoL assessments for both groups from baseline and at different time points are summarized in Supplementary Tables 5 and 6. Based on the EORTC QLQ-C30 assessment, treatment with either mefatinib or gefitinib did not result in significant changes in functional scales, symptom scales, or overall health status, except for the significantly higher rates of diarrhea reported in the mefatinib group after receiving 24 weeks of treatment relative to baseline than in the gefitinib group (p < 0.001; Supplementary Table 5). Based on the EORTC QLQ-LC13 assessment, the mefatinib group had significantly higher rates of mouth pain (p = 0.002) and tingling hands or feet/peripheral neuropathy (p = 0.004) after receiving 24 weeks of treatment relative to baseline than the gefitinib group (Supplementary Table 6).

Safety

The mefatinib group had a mean treatment duration of 16.2±8.5 months (95% CI: 1.2–36.4), while the gefitinib group had a mean treatment duration of 17.6±10.1 months (95% CI: 1.1–36.5). AEs were observed in almost all participants, with adverse events (AEs) of any grade reported in 99.6% of the mefatinib group and 100.0% of the gefitinib group (Supplementary Table 7). In the mefatinib group, the most frequently reported treatment-related AEs (TRAEs) were diarrhea (96.0%), rash (83.9%), and stomatitis (62.8%). On the other hand, the most frequently reported TRAEs in the gefitinib group were rash (62.8%), diarrhea (61.9%), and alanine aminotransferase (ALT) increase (57.5%) (Table 3). The incidence rates of TRAEs of special interest are summarized in Supplementary Table 8.

Table 3.

Treatment-related adverse events (TRAE) observed in ≥10% of the safety population

Adverse event category (system organ class/Preferred term)	Mefatinib arm (n = 223)		Gefitinib arm (n = 113)
	Any grade, n (%)	≥Grade 3, n (%)	Any grade, n (%)	≥Grade 3, n (%)
Any treatment-related adverse event	222 (99.6)	102 (45.7)	108 (95.6)	28 (24.8)
Gastrointestinal disorders	219 (98.2)	60 (26.9)	91 (80.5)	3 (2.7)
Diarrhea	214 (96.0)	45 (20.2)	70 (61.9)	1 (0.9)
Stomatitisa	140 (62.8)	14 (6.3)	40 (35.4)	1 (0.9)
Nausea	45 (20.2)	1 (0.4)	15 (13.3)	0 (0.0)
Skin and subcutaneous tissue disorders	200 (89.7)	26 (11.7)	78 (69.0)	3 (2.7)
Rashb	187 (83.9)	26 (11.7)	71 (62.8)	2 (1.8)
Alopecia	40 (17.9)	0 (0.0)	8 (7.1)	0 (0.0)
Dry skin	28 (12.6)	0 (0.0)	7 (6.2)	1 (0.9)
Investigations	172 (77.1)	18 (8.1)	87 (77.0)	17 (15.0)
Alanine aminotransferase increased	97 (43.5)	7 (3.1)	65 (57.5)	8 (7.1)
Aspartate aminotransferase increased	90 (40.4)	5 (2.2)	65 (57.5)	7 (6.2)
Weight loss	63 (28.3)	7 (3.1)	11 (9.7)	2 (1.8)
Blood bilirubin increased	33 (14.8)	2 (0.9)	16 (14.2)	0 (0.0)
Blood creatinine increased	30 (13.5)	0 (0.0)	10 (8.8)	1 (0.9)
Gamma-glutamyltransferase increased	26 (11.7)	3 (1.3)	12 (10.6)	2 (1.8)
Blood creatine phosphokinase increased	24 (10.8)	0 (0.0)	13 (11.5)	0 (0.0)
Infections and infestations	127 (57.0)	10 (4.5)	35 (31.0)	2 (1.8)
Paronychiac	102 (45.7)	6 (2.7)	27 (23.9)	1 (0.9)
Urinary tract infection	24 (10.8)	0 (0.0)	8 (7.1)	1 (0.9)
Metabolic and nutrition disorders	121 (54.3)	11 (4.9)	52 (46.0)	4 (3.5)
Decreased appetite	68 (30.5)	2 (0.9)	21 (18.6)	2 (1.8)
Hypokalemia	30 (13.5)	9 (4.0)	6 (5.3)	0 (0.0)
Hypertriglyceridemia	26 (11.7)	0 (0.0)	15 (13.3)	2 (1.8)
Respiratory, thoracic and mediastinal disorders	68 (30.5)	3 (1.3)	13 (11.5)	1 (0.9)
Nasal mucosal hyperemiad	31 (13.9)	1 (0.4)	2 (1.8)	0 (0.0)
Cardiac disorders	44 (19.7)	0 (0.0)	20 (17.7)	0 (0.0)
Premature ventricular contractions	12 (5.4)	0 (0.0)	3 (2.7)	0 (0.0)
Blood and lymphatic system disorders	44 (19.7)	3 (1.3)	13 (11.5)	1 (0.9)
Anemia	43 (19.3)	3 (1.3)	12 (10.6)	1 (0.9)
General disorders and administration site conditions	42 (18.8)	6 (2.7)	18 (15.9)	1 (0.9)
Muscular weakness	15 (6.7)	3 (1.3)	3 (2.7)	1 (0.9)
Renal and urinary system disorders	39 (17.5)	0 (0.0)	14 (12.4)	0 (0.0)
Proteinuria	26 (11.7)	0 (0.0)	9 (8.0)	0 (0.0)
Nervous system disorders	23 (10.3)	0 (0.0)	9 (8.0)	0 (0.0)
Dizziness	8 (3.6)	0 (0.0)	2 (1.8)	0 (0.0)
Headache	8 (3.6)	0 (0.0)	2 (1.8)	0 (0.0)

The table shows adverse events that were reported in ≥10% of patients in either treatment group. Adverse events included adverse events observed after the first dose

^aStomatitis: preferred term (PT) includes oral mucositis and oral ulcers

^bRash events: PT includes infections and other diseases of the skin and subcutaneous tissue and other inflammatory conditions of the skin and subcutaneous tissue, including atopic dermatitis and related conditions, bullous dermatoses, contact dermatitis and other eczema, dermatitis due to substances taken internally, exfoliative dermatitis, erythematous conditions, lichen, pruritus and related conditions, psoriasis, and similar disorder, herpes zoster

^cParonychia: PT includes nail discoloration, nail peeling, nail disease, and paronychia

^dNasal mucosal abnormalities: PT includes epistaxis, rhinitis, nasal vestibulitis, nasal mucosal erosion, sinus disease, nasal mucosal disease, nasal ulcer, nasal congestion, nasal inflammation, and nasal mucosal ulcer

The mefatinib group experienced a higher incidence of Grade 3 and higher AEs than the gefitinib group (61.0% vs 45.1%), with Grade 3 and higher TRAEs of 45.7% and 24.8%, respectively. Compared with the gefitinib group, the mefatinib group had higher rates of treatment-related grade 3 or higher diarrhea (20.0% vs 0.9%), stomatitis (6.3% vs 0.9%), rash (11.7% vs 1.8%), weight loss (3.1% vs 1.8%), hypokalemia (4.0% vs 0.0%), and paronychia (2.7% vs 0.9%) (Table 3). The gefitinib group showed higher rates of treatment-related grade 3 or higher ALT increase (7.1% vs 3.1%) and elevated aspartate aminotransferase (AST) (6.2% vs 2.2%) than the mefatinib group (Table 3).

Notably, the mefatinib and gefitinib groups had a comparable rate of serious AEs (31.8% vs 31.0%), with the mefatinib group having a numerically lower rate of serious TRAEs than the gefitinib group (8.5% vs 10.6%). Among the serious TRAEs, the mefatinib group had a higher incidence of gastrointestinal AEs than the gefitinib group. However, the gefitinib group had a higher incidence of AEs classified under investigation, mainly reflected by the increased incidence of ALT and AST elevation, than the mefatinib group. The mefatinib group had ten cases (4.5%) resulting in death due to AEs, with TRAEs observed in a case who died of unknown etiology. In contrast, the gefitinib group had seven (6.2%) deaths due to AEs, with a case that succumbed to treatment-related grade 5 interstitial lung disease.

The mefatinib group had a higher incidence of AEs and TRAEs leading to permanent discontinuation than the gefitinib group (AEs, 5.4% vs 2.7%; TRAEs, 4.0% vs 1.8%). AEs that led to permanent discontinuation summarized according to system organ class were respiratory, thoracic and mediastinal disorders (1.8% vs 1.8%) and skin and subcutaneous tissue disorders (1.3% vs 0%). There was a low incidence of TRAEs that led to permanent discontinuation in both the mefatinib and mefitinib groups, with treatment-related rash observed at an incidence of 1.3% in the mefatinib group and not reported in the gefitinib group.

Compared with the gefitinib group, the mefatinib group had a higher incidence of AEs, leading to dose reduction (5.8% vs 2.7%). AEs that led to dose reduction were categorized under skin and subcutaneous tissue disorders (3.1% vs 0.9%), gastrointestinal disorders (1.3% vs 0%), and infection and infestations (1.3% vs 0%). Rash (3.1% vs 0.9%) and paronychia (1.3% vs 0%) were the most frequent TRAEs that led to dose reduction.

The incidence of AEs and TRAEs leading to treatment interruption was numerically higher in the mefatinib group than in the gefitinib group (AEs, 35.9% vs 27.4%; TRAEs, 30.9% vs 23.0%). The most frequent TRAEs that led to treatment interruption were diarrhea (9.0% vs 0%), stomatitis (4.9% vs 1.8%), rash (13.0% vs 3.5%), increased ALT (3.1% vs 8.8%), increased AST (3.1% vs 11.5%), increased gamma-glutamyl transferase (0.9% vs 1.8%), neutropenia (0% vs 1.8%), and paronychia (2.7% vs 0.9%). The incidence of diarrhea and rash leading to treatment interruption was higher with mefatinib than with gefitinib. In contrast, the incidence of an ALT/AST increase leading to treatment interruption was higher with gefitinib than with mefatinib.

Discussion

This report provides clinical evidence supporting the use of mefatinib as an efficacious and well-tolerated first-line therapy for Chinese patients with advanced NSCLC harboring EGFR mutations. This clinical trial was a double-blind, double-dummy parallel group randomized clinical study that successfully achieved its primary endpoint, as shown by the superior PFS benefit of mefatinib in the first-line treatment of EGFR-mutated advanced NSCLC compared with gefitinib (13.7 months vs 9.7 months; HR = 0.68 [95% CI: 0.53–0.87]; p = 0.002). Compared to gefitinib, first-line afatinib demonstrated a higher ORR (72.5% vs 56.0%) and longer median time to treatment failure (13.7 vs 11.5 months) but no difference in OS.^29,30 The ARCHER-1050 study demonstrated an improved median PFS (14.7 vs 9.2 months; HR = 0.59) and OS (34.1 vs 27.0 months; HR = 0.75) with first-line dacomitinib compared with gefitinib.^13,20 The FLAURA study established osimertinib as a third-generation standard of care, demonstrating a median PFS of 18.9 months (vs 10.2 months with gefitinib or erlotinib) and a median OS of 38.6 months (vs 31.8 months with gefitinib or erlotinib) in the overall population.^14,15 Beyond osimertinib, the AENEAS trial evaluating aumolertinib demonstrated a median PFS of 19.3 months compared to gefitinib’s 9.9 months, with an HR of 0.47.¹⁸ The FURLONG trial investigating furmonertinib showed a median PFS of 20.8 months versus 11.1 months with gefitinib (HR = 0.44).¹⁷ The recent MARIPOSA trial compared first-line lazertinib monotherapy with osimertinib monotherapy, demonstrating comparable efficacy with a median PFS of 18.5 months for lazertinib versus 16.6 months for osimertinib, making this the first head-to-head comparison of two third-generation EGFR-TKIs.³¹

Subgroup analysis showed the PFS advantage of mefatinib among patients with EGFR L858R-positive NSCLC over gefitinib (13.7 months vs 8.3 months; HR = 0.55 [95% CI: 0.38–0.78]; p = 0.001). Several clinical studies have reported the EGFR genotype-dependent variability in survival outcomes offered by various EGFR-TKIs, including third-generation EGFR-TKIs, with EGFR L858R associated with a poorer prognosis than EGFR ex19del.^15,21–23 For instance, the subgroup analysis from the FLAURA global study revealed a shorter median PFS among patients with EGFR L858R treated with osimertinib compared to patients with EGFR ex19del (14.4 months vs 21.4 months), and no OS benefit was observed compared to gefitinib.^14,32,33 Prospective clinical studies investigating other third-generation EGFR-TKIs yielded similar findings, demonstrating unfavorable survival outcomes in patients with EGFR L858R.^17–19 This selective efficacy of EGFR-TKIs remains a significant challenge in treating NSCLC with common EGFR mutations and improving the survival outcomes of patients with this specific molecular subset of NSCLC. Our previous study reported comparable survival outcomes for patients with EGFR L858R and ex19del mutations treated with first-line mefatinib²⁷ Consistent with these findings, patients harboring EGFR L858R exhibited a more favorable PFS outcome with first-line mefatinib than gefitinib (HR = 0.55). In patients with EGFR L858R mutations, the FLAURA study showed that first-line osimertinib significantly reduced the risk of death or progression compared to first-generation EGFR-TKIs (HR = 0.51).³⁴ Other third-generation EGFR-TKIs approved in China, including aumolertinib, furmonertinib, and rezivertinib, demonstrated HRs of 0.60, 0.54, and 0.64, respectively, in comparison with comparator first-generation EGFR-TKIs.^17,18,35 By demonstrating comparable outcomes with mefatinib in patients harboring EGFR ex19del and L858R mutations, our study suggests that mefatinib may serve as an alternative therapeutic option with distinct advantages for patients with EGFR L858R. This observation may inform treatment sequencing strategies, particularly in Asian populations where this mutation is more prevalent. Moreover, our recent phase II study reported the promising antitumor activity of mefatinib in targeting uncommon EGFR G719X, L861Q, and/or S768I mutations.²⁸ Collectively, this clinical evidence supports the therapeutic potential of mefatinib, positioning it as a possible best-in-class second-generation EGFR-TKI for the treatment of patients with NSCLC harboring common and uncommon EGFR mutations.

The differential efficacy of mefatinib in patients with EGFR L858R mutations may be attributable to fundamental structural and biochemical differences among common EGFR mutations. Specifically, the L858R point mutation resides within the helical turn of the activation loop and stabilizes the kinase domain in a constitutively active conformation, thereby conferring distinct conformational plasticity and pharmacological properties compared to ex19del mutations.²⁶ Notably, EGFR L858R-driven tumors demonstrate preferential activation of extracellular signal-regulated kinase (ERK)-dependent signaling pathways. While first-generation agents such as gefitinib selectively inhibit EGFR, mefatinib exerts a potent and irreversible pan-EGFR inhibitory effect, enabling comprehensive blockade of the erythroblastic oncogene B (ErbB) signaling axis. This broad-spectrum inhibition effectively targets ERK-mediated signaling vulnerabilities in L858R-driven tumors, potentially accounting for the substantial therapeutic benefit observed in this subgroup. Consequently, mefatinib may offer a distinct advantage for this historically challenging patient population. Nonetheless, this hypothesis remains speculative, and further investigations are warranted to elucidate the molecular mechanisms underlying the observed differential response.

The ongoing challenge of acquired resistance remains a significant hurdle in the treatment of NSCLC with targeted therapy.²⁴ The resistance mechanisms for commercially available EGFR-TKIs are well understood. These mechanisms involve the emergence of secondary EGFR mutations and EGFR-independent mutations that activate alternative signaling pathways.^24,25 The emergence of EGFR secondary mutations, particularly T790M, commonly occurs during treatment with first- and second-generation EGFR-TKIs, which can be effectively targeted by third-generation EGFR-TKIs such as osimertinib.²⁵ In our previous report, we identified EGFR T790M acquisition as the predominant resistance mechanism associated with mefatinib, occurring in approximately 42% of patients,²⁷ a pattern consistent with other first- and second-generation EGFR-TKIs. With the high prevalence of EGFR T790M acquisition during mefatinib treatment, osimertinib can be the treatment of choice following disease progression with mefatinib^.27 Following the approval of osimertinib as a first-line treatment, patients now have the option to receive osimertinib either as first-line treatment or after developing resistance to first- or second-generation EGFR-TKIs due to the EGFR T790M mutation.²⁵ The impressive extended PFS achieved with first-line osimertinib is noteworthy.³³ However, it is important to consider that using osimertinib as a first-line treatment presents a unique resistance mechanism profile compared to its use in later treatment settings.²⁵ The limited number of actionable mutations after first-line osimertinib resistance decreases the available targeted therapeutic options and increases the likelihood of resorting to chemotherapy following disease progression. This highlights the significance of using effective second-generation EGFR-TKIs, such as mefatinib, in the initial treatment settings of EGFR-mutated NSCLC. Compared with first-line gefitinib, the extent of PFS benefit observed among patients with EGFR L858R treated with first-line mefatinib (HR = 0.55) had a similar trend with the benefit reported for third-generation inhibitors. As such, the treatment sequencing approach that uses a second-generation EGFR-TKI in the first-line setting followed by a third-generation EGFR-TKI as a subsequent-line treatment may delay the use of chemotherapy and enhance the survival outcomes of patients with EGFR-mutated advanced NSCLC.

Despite the limitations of an immature OS, patients with EGFR L858R who received mefatinib treatment showed a potential for longer OS, as suggested by the numerically higher 30-month OS rate compared to those treated with gefitinib. This finding implies that the PFS advantage of mefatinib observed among patients with EGFR L858R may result in an OS extension. Mefatinib has the potential to be the treatment of choice that could address the unmet medical needs of patients with EGFR L858R due to its promising survival outcomes in this patient subset. Additional follow-up is necessary to provide conclusive evidence on the OS benefit of mefatinib.

Compared with gefitinib treatment, mefatinib treatment resulted in a higher incidence of gastrointestinal and dermatological AEs and a lower incidence of liver enzyme elevation. The safety profile of mefatinib as a first-line treatment was consistent with expectations, as no new safety signals were observed. The tolerability of mefatinib was generally good, as only a small percentage of patients required dose reduction (5.8% vs 2.7%) and treatment discontinuation (5.4% vs 2.7%), similar to gefitinib. Compared with studies that reported the safety profile for other second-generation EGFR-TKIs as first-line treatment, mefatinib treatment resulted in fewer dose reductions.^13,29

This study has several limitations that should be considered when interpreting the findings. First, this study employed gefitinib as the control comparator rather than osimertinib, which has emerged as the standard of care in many Western healthcare systems. However, gefitinib remained a widely used first-line agent in healthcare settings in China at the time of study initiation in September 2019. Second, patients with brain metastases were excluded from this trial, limiting the generalizability of the findings to this high-risk subgroup. Given the established central nervous system (CNS) penetration and efficacy of third-generation EGFR-TKIs in treating CNS metastases, this study prioritized the enrollment of patients without brain metastases to optimize therapeutic benefit. Nonetheless, our previous phase Ib/II study demonstrated that mefatinib retains meaningful efficacy in patients with brain metastases. In that study, 29% of participants had brain metastases and achieved an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months.²⁷ While these outcomes were somewhat shorter than those observed in patients without brain metastases, they remain clinically relevant and support the potential utility of mefatinib in selected cases. Consistently, the second-generation EGFR-TKI dacomitinib has shown robust systemic and intracranial activity in patients with EGFR-mutated NSCLC and severe brain metastases, with an overall ORR of 93.3%, intracranial ORR of 66.7%, median PFS of 16.8 months, and intracranial PFS of 16.6 months.³⁶ Third, this study was not designed to include a comprehensive biomarker analysis of cooccurring mutations and resistance mechanisms; however, these important analyses are being conducted as part of a separate, dedicated biomarker study with findings to be reported in subsequent publications. Notably, preliminary data from our phase Ib/II study demonstrated comparable PFS outcomes irrespective of concurrent TP53 mutation status (PFS: 14.0 months for patients with TP53 comutation vs 15.4 months for wild-type TP53; p = 0.315).²⁷ Fourth, biomarker analyses, including liquid biopsy, plasma circulating tumor DNA monitoring, and comprehensive DNA next-generation sequencing, were not systematically performed as part of this trial protocol, precluding detailed investigation of molecular mechanisms underlying treatment response and acquired resistance. Despite these limitations, the study was conducted according to a prespecified protocol with adequate statistical power to detect the primary endpoint, enrolled a substantial multicenter patient population, and achieved adequate event maturity for PFS analysis. Future studies incorporating biomarker profiling, comprehensive postprogression treatment documentation, and evaluation of the efficacy of mefatinib in broader patient populations, including those with symptomatic CNS metastases, would further strengthen the understanding of the clinical utility of mefatinib and optimal positioning within the EGFR-TKI treatment landscape. Mefatinib was granted regulatory approval in China in October 2025 for the treatment of patients with EGFR L858R-mutated NSCLC.

In conclusion, our study reports the superior efficacy of mefatinib compared with gefitinib as first-line therapy for Chinese patients with advanced NSCLC harboring EGFR L858R and ex19del. Mefatinib exhibited a favorable tolerability profile that was similar to that of gefitinib. Mefatinib may serve as a treatment option for the first-line treatment of EGFR-mutated advanced NSCLC and potentially improve survival outcomes, particularly in patients with EGFR L858R.

Methods

Study design

This study is a phase III, randomized, double-blind, double-dummy, parallel-group clinical trial conducted at 45 clinical sites in China (Appendix 1). The study aimed to compare the efficacy and safety of mefatinib compared with gefitinib as first-line therapy of patients diagnosed with unresectable, locally advanced to advanced nonsquamous NSCLC harboring EGFR L858R and ex19del mutations.

This study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice E6 (R2), the principles of the Declaration of Helsinki, and applicable regulations in China. The study was approved by the institutional review board/independent ethics committee of the participating centers, which are detailed in Appendix 1 (Supplementary Materials). All study participants provided written informed consent.

The trial is registered with chinadrugtrials.org.cn (CTR20192297).

Participants

Male and female patients aged 18 to 75 diagnosed with stage IIIb–IVb nonsquamous NSCLC (confirmed by histology or cytology and staged according to the 8th edition of the American Joint Committee on Cancer Tumor Node Metastasis classification) were eligible for inclusion in the study. Eligible participants were required to have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–1, no prior systemic therapy for advanced disease, and a tumor harboring a single EGFR L858R or ex19del mutation. Additional inclusion and exclusion criteria are summarized in Appendix 2.

Randomization and masking

Eligible patients were randomly assigned to the experimental and control arms in a 2:1 ratio using an eRand central randomization system (Nanjing Ode Data Technology, China), with stratification based on EGFR mutation types (ex19del vs L858R). Investigational drugs (mefatinib) and control drugs (gefitinib) were packaged according to the randomization schedule and blinded from all study personnel and participants. The experimental group received 60 mg mefatinib tablets and 250 mg gefitinib dummy tablets, while the comparator group received 60 mg mefatinib simulation tablets and 250 mg gefitinib tablets.

Procedures

The study medications were administered orally once daily. Study participants were allowed to receive study drug treatment until disease progression, death, loss to follow-up, or intolerable toxicity. Participants underwent radiological imaging using enhanced computed tomography (CT) scanning of the chest and whole abdomen (and based on clinical indications for brain or bone) at baseline and every six weeks until progressive disease (PD) was confirmed or new antitumor treatment was started, including patients who withdrew from the study due to reasons other than disease progression, death, or loss to follow-up. Treatment responses were evaluated by an independent review committee (IRC) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Outcomes

The primary efficacy endpoint was to investigate IRC-assessed PFS (defined as the time from randomization to disease progression or death from any cause, whichever occurred first). The secondary efficacy endpoints included (1) investigator-assessed PFS, (2) investigator-assessed OS (defined as the time from randomization to death from any cause) and 30-month OS rate, (3) IRC-assessed and investigator-assessed overall response rate (ORR, the proportion of patients with a complete or partial response), (4) IRC-assessed and investigator-assessed disease control rate (DCR, the proportion of patients with a complete response, partial response, or stable disease), (5) IRC-assessed and investigator-assessed duration of response (DoR, the date when objective response was confirmed until the first assessment of disease progression or death among patients who experienced objective response), (6) IRC-assessed and investigator-assessed time to progression (TTP, calculated from the date the treatment was initiated until disease progression, excluding data from deceased patients), (7) IRC-assessed and investigator-assessed time to treatment failure (TTF, from the date of randomization until treatment termination for any reason, including disease progression, toxicity, and death), and (8) other efficacy measures such as health-related quality of life (HRQoL, patient-reported outcomes on two European Organization for Research and Treatment of Cancer [EORTC].

Statistical analysis

The assumptions made in this superiority trial were as follows: a hazard ratio (HR) of progression of 0.69 for mefatinib compared with gefitinib, with a median PFS of 10.0 months for gefitinib³⁷ and 14.5 months for mefatinib.²⁷ For a statistically significant difference in PFS between the two groups, a minimum of 256 events is needed, with a one-sided α of 0.025 and a statistical power of 80%. The enrollment ratio of 2:1 resulted in a required sample size of 336 patients based on a 10% loss to follow-up rate. Unblinding was prespecified to occur upon reaching 70% of the target event count, as defined under preblinding conditions. Statistical analyses were performed using SAS statistical software version 9.4. Demographics and clinicopathological data were described using descriptive statistics. The quantitative variables are presented as the number and percentage of cases (n, %). Continuous variables are presented as medians with ranges (minimum and maximum values). The ORR and DCR are presented as percentages, with the corresponding 95% confidence intervals (CIs) calculated using the exact probability method based on the F distribution. The stratified Cochran‒Mantel‒Haenszel method was used to compare the difference in ORR or DCR between the two groups and calculate the odds ratio and 95% CI. The stratification factor used was EGFR genotype: ex19del vs L858R. PFS, OS, DoR, TTP, and TTF were analyzed using the Kaplan‒Meier method and are presented as the median and corresponding 95% CI. The log-rank test was used to compare survival outcomes between groups. Hazard ratios (HRs) and corresponding 95% CIs were calculated using Cox regression analysis. The median follow-up time was estimated using the reverse Kaplan‒Meier method, which calculates the median observation time for censored patients. Relatively aligned values for median follow-up and median PFS suggest a high event rate in both treatment arms, supporting the maturity of PFS data during the study follow-up period. HRQoL was compared using analysis of variance (ANOVA). Adverse events were presented using descriptive statistics without statistical testing.

Author contributions

J.Y., J.X., W.K. and C.C.Z. conceived and designed the study. C.N.Z. and J.Y. performed the formal analyses, developed the software, and prepared the visualizations. J.X., W.K. and C.C.Z. acquired funding, established methodology, provided resources, and supervised the project. J.Y., A.W.X., Q.M.W., J.H.C., W.K., and C.C.Z. administered the project and prepared the original draft of the manuscript. All authors contributed to data curation, reviewed, and edited the manuscript. All authors have read and approved the article.

Funding

Hangzhou Zhongmei Huadong Pharmaceutical Company.

Data availability

The authors declare that the data supporting the findings of this study are available within the main manuscript or the supplementary materials. Correspondence and requests for materials should be addressed to C.Z. at caicunzhoudr@163.com. Deidentified participant data and other materials can be provided by Hangzhou Zhongmei Huadong Pharmaceutical upon review of requests.

Competing interests

X.S., B.Y., C.Z., J.C. and J.X. are employees of Hangzhou Zhongmei Huadong Pharmaceutical Company. The other authors have no conflicts of interest to declare.

Ethical approval and consent to particpate

This study collected blood samples from the human subjects. This study was approved by the institutional review board/independent ethics committee of the participating centers, which are detailed in Appendix 1 (Supplementary Materials). Written informed consent were obtained from all participants before enrollment in the study.

Supplementary information

The online version contains supplementary material available at 10.1038/s41392-026-02904-0.