Gefitnib Delays Early Relapse, Fails to Improve DFS or OS Compared to Chemotherapy in EGFR-mutant NSCLC

Early relapse in patients with completely resected EGFR-mutant non–small cell lung cancer (NSCLC) was delayed with the adjuvant treatment of gefitinib (Iressa). Despite this outcome, the EGFR inhibitor did not significantly improve disease-free survival (DFS) or overall survival (OS) compared with cisplatin/vinorelbine, according to data from the phase 3 Japanese IMPACT trial (UMIN000006252) presented at the 2021 virtual ASCO Annual Meeting.¹

The median DFS patients treated with gefitinib was 35.9 months (95% CI, 30.0-47.7) compared with 25.0 months (95% CI, 17.7-41.8) in those who received cisplatin/vinorelbine (HR, 0.92; 95% CI, 0.67-1.28; P = .63). At a median follow-up of 70.1 months, the 5-year OS rate was 78.0% for 116 patients treated with gefitinib and 74.6% for 116 patients treated with cisplatin/vinorelbine (HR, 1.03; 95% CI, 0.65-1.65; P = .89).

“The IMPACT trial failed to demonstrate the superiority of DFS [with] gefitinib compared with cisplatin/vinorelbine for completely unresected NSCLC harboring EGFR mutations,” said Hirohito Tada, MD, principal investigator of the trial and member of the Suita Tokushukai Hospital Cancer Center in Japan.

Similar to the OS rates, no significant difference in DFS was seen for patients treated with gefitinib at 2 and 5 years. Specifically, the 2-year DFS rate with gefitinib was 63.7% compared with 52.3% with cisplatin/vinorelbine; 5-year DFS rates were 31.8% vs 34.1%, respectively.

Results of an exploratory subgroup analysis of DFS demonstrated a slight division in elderly patients (age ≥ 70 years) with an HR of 0.589 favoring gefitinib (95% CI, 0.284-1.222). Similarly, in the exploratory analysis of OS, patients age 70 years or more demonstrated better survival with gefitinib compared with cisplatin/vinorelbine (HR, 0.314; 95% CI, 0.101-0.981).

“The apparent noninferiority of DFS and OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for adjuvant chemotherapy with cisplatin/vinorelbine,” Tada said.

Investigators enrolled patients with completely resected EGFR mutation–positive (exon 19 deletion or L858R) stage II-III NSCLC. Patients were randomized 1:1 to receive gefitinib 250 mg once daily for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) every 3 weeks for 4 cycles. Patients who went on to receive gefitinib remained on treatment for the full 24 months or until disease progression or unacceptable toxicity.

The primary end point was DFS in the intention-to-treat population. Secondary end points included OS, safety, and relapse pattern. Efficacy was assessed every 6 months via contrast chest/abdominal CT and every 12 months via brain MRI, PET/CT, or bone scan.

In total, 116 patients were randomized to each arm with safety data reported for 115 in each arm. The baseline characteristics between the gefitinib and cisplatin/vinorelbine cohorts were well balanced, with a majority of patients being female (62.1% and 61.2%, respectively) and reporting an ECOG score of 0 at baseline (81.0% and 78.4%). The median age for both arms was 64 years (range, 34-74).

In an analysis of the mutational profiles, nearly half of patients in each had either an exon 19 deletion (55.2% and 50.9%, respectively) or an exon 21 L858R mutation (44.8% and 48.3%). One patient (0.9%) in the cisplatin/vinorelbine arm had both mutations.

In total, 61.2% of patients completed 24-month treatment cycle of gefitinib and 77.6% of patients complete up to 4 courses of cisplatin/vinorelbine. The discontinuation rates were 38.8% and 22.4%, respectively. the leading cause of discontinuation in the gefitinib arm was relapse or second cancer (16.4%) and patient request (8.6%) in the cisplatin/vinorelbine arm. Of note, 3 treatment-related deaths occurred in the cisplatin/vinorelbine arm.

For patients who experienced local relapse, a majority of patients had local lymph node disease and comprised 15 and 17 patients with gefitinib and cisplatin/vinorelbine, respectively. The most common site of distant metastasis was the brain occurring in 26 and 14 patients, respectively.

The data also included an analysis of subsequent treatments pursued following relapse. In 76 patients with relapse following gefitinib, 67% proceeded to treatment with a tyrosine kinase inhibitor (TKI), including 14 patients who went on to receive osimertinib (Tagrisso). Tada noted that of the 98% of patients in the cisplatin/vinorelbine arm who experienced relapse went on to treatment with a TKI; 7 patients were enrolled in clinical trials including 1 patient to the RELAY trial (NCT02411448) and 2 patients to the FLAURA trial (NCT02296125).

“Eleven patients in the gefitinib arm and 6 patients in the cisplatin arm were not treated a drug, most of them were treated with radiation therapy,” Tada said.

In terms of safety, more patients reported grade 3 and 4 neutropenia and leucopenia compared with gefitinib. Specifically, grade 3 and 4 neutropenia incidence rates were 26.1% and 60.9%, respectively, with cisplatin/vinorelbine compared with 0.9% and 0% with gefitinib. Grade 3 and 4 leucopenia incidence rates were 47.0% and 10.4% with cisplatin/vinorelbine; no incidences of grade 3 or 4 leucopenia were reported with gefitinib.

“On the other hand, [treatment with] gefitinib showed frequent hepatotoxicity and skin events,” Tada noted. Alanine transaminase and aspartate transaminase levels were increased in patients treated with gefitinib with grade 3 and 4 events reported in 22.6%/4.3% and 14.8%/0.9% of patients, respectively. Events of any grade were reported for 68.7% and 65.2% of patients treated with gefitinib, respectively.

No incidences of grade 3 or 4 skin-related events were reported with cisplatin/vinorelbine compared with 4.3% of patients experiencing grade 3 dermatitis acneiform and 4.3% with grade 3 rash. Over half of patients treated with gefitinib had dermatitis acneiform of any grade (58.3%) and 46.1% of patients treated cisplatin/vinorelbine had alopecia of any grade.

_Reference

_{Tada H, Mitsudomi T, Yamanaka T, et al; West Japan Oncology Group.Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): a randomized phase 3 trial. J Clin Oncol. 2021;39(suppl 15):8501. doi:10.1200/JCO.2021.39.15_suppl.8501}