Erlotinib Displays Long-Term DFS Benefit, Meaningful OS Improvement vs Chemotherapy in EGFR+ NSCLC

Erlotinib (Tarceva) continued to elicit a disease-free survival (DFS) and overall survival (OS) benefit vs vinorelbine/cisplatin chemotherapy in patients with EGFR-positive non–small cell lung cancer (NSCLC), according to updated OS data and an exploratory analysis from the phase 2 EVAN trial (NCT01683175).

At 43 months of follow-up, the 5-year DFS rate was 48.2% (95% CI, 29.4%-64.7%) with erlotinib in the intention-to-treat (ITT) population and 46.2% (95% CI, 27.6%-62.9%) in the per-protocol population. As patients treated with vinorelbine plus cisplatin either reached the end point or were censored at the end of follow-up, the 5-year DFS for this arm could not be determined. At the final data cutoff, the DFS benefit was significantly better with erlotinib than with chemotherapy in the ITT (HR, 0.38; 95% CI, 0.20-0.70; P < .001) and per-protocol (HR, 0.46; 95% CI, 0.24-0.88; P = .008) populations.

“On the basis of these and previous EVAN results, erlotinib, compared with chemotherapy with vinorelbine/cisplatin, is a promising therapeutic option for patients with R0 resected stage IIIA EGFR-mutant NSCLC,” lead study author, Dongsheng Yue, MD, of Tianjin Medical University Cancer Institute and Hospital in Tianjin, China, and colleagues, wrote in a discussion of the data.

Patients with stage IIIA NSCLC who have undergone R0 resection frequently recur—the 5-year survival rate is 25% or less. Osimertinib (Tagrisso), an EGFR TKI, is the current standard-of-care adjuvant therapy for stage II to III resected EGFR-mutant NSCLC. Additional TKIs, such as erlotinib, may also provide clinical benefit in this setting.

The randomized, open-label EVAN trial evaluated the DFS, OS, and safety of adjuvant erlotinib vs the chemotherapy combination vinorelbine plus cisplatin after complete resection in Chinese patients with stage IIIA EGFR-positive NSCLC. The primary end point results of this trial have been published. These updated findings represent updated DFS data, 5-year OS data, and exploratory results.

This study enrolled 102 patients, 51 each to the erlotinib and chemotherapy arms in the ITT population. The erlotinib per-protocol population excluded 5 patients, 1 of whom did not receive any study treatment and 4 of whom had major protocol violations, including no R0 resection (n = 3) and a lack of critical assessments (n = 1), for a total of 46 patients. The chemotherapy per-protocol population excluded 18 patients, 8 of whom did not receive any study treatment, and 11 of whom had major protocol violations, including no R0 resection (n = 5), a lack of critical assessments (n = 3), prior antineoplastic treatment (n = 1), other antineoplastic treatment (n = 1), and metastatic NSCLC before disease progression (n = 1).

Additionally, patients were excluded from the study if they had EGFR wild-type disease or pulmonary embolism before randomization.

Patients were randomly assigned to erlotinib or vinorelbine plus cisplatin. In the erlotinib arm, patients received oral erlotinib at 150 mg once daily for 2 years. In the chemotherapy arm, patients received four 21-day cycles of intravenous (IV) vinorelbine at 25 mg/m2 once daily on days 1 and 8 of each cycle and IV cisplatin at 75 mg/m2 once daily on day 1 of each cycle.

The primary end point was DFS, with secondary end points of OS, 5-year survival rate, and disease recurrence. The median follow-up was 54.8 months in the erlotinib arm and 63.9 months in the chemotherapy arm.

The median OS was 84.2 months (95% CI, 78.1-not evaluable [NE]) and 61.1 months (95% CI, 39.6-82.1) in the erlotinib and chemotherapy arms, respectively (HR, 0.318; 95% CI, 0.151-0.670).

The 5-year survival rates were 84.8% (95% CI, 72.0%-97.6%) and 51.1% (95% CI, 34.7%-67.5%) with erlotinib and chemotherapy, respectively. The OS probability HR with erlotinib vs chemotherapy was 0.373 (95% CI, 0.191-0.728; P = .003) in the ITT population and 0.375 (95% CI, 0.188-0.746; P = .004) in the per-protocol population, showing a significantly better OS with erlotinib vs chemotherapy in both populations.

A total of 43.1% and 54.9% of patients developed disease recurrence in the erlotinib and chemotherapy arms, respectively. Of these, 37.3% (n = 19) of patients in the erlotinib arm and 54.9% (n = 28) of patients in the chemotherapy arm received at least 1 antitumor therapy during follow-up. Frequently used antitumor therapies in the erlotinib and chemotherapy arms included TKIs (21.6% and 37.3%), radiotherapy (15.7% and 13.7%), chemotherapy (13.7% and 17.6%), and surgery (5.9% each). The most common sites of recurrence in the erlotinib and chemotherapy arms, respectively, were the chest (15.7%, n = 8; 19.6%, n = 10), brain (13.7%, n = 7; 15.7%, n = 8), and bone (11.8%, n = 6 in each).

Investigators conducted a whole exome sequencing exploratory analysis to assess the relationship between patient benefit and co-occurring variants in 34 patients in the erlotinib arm and 31 patients in the chemotherapy arm. This analysis showed that the most frequent genes with variants co-occurring at baseline were TP53, MUC16, FAM104B, KMT5A, and DNAH9. Additional EGFR variants were also identified, each with a similar prevalence, regardless of mutation subgroup. In the erlotinib arm, a single-nucleotide polymorphism mutation in UBXN11 was associated with worse DFS (P = .01), a novel finding which requires further study. The investigators observed no significant association between DFS and OS in the chemotherapy arm.

Of the 50 patients from the erlotinib arm included in the safety analysis during treatment, 58.0% (n = 29) presented with adverse effects (AEs). Of the 43 patients from the erlotinib arm included in the safety analysis during follow-up, 65.1% (n = 28) presented with AEs. Grade 3 or higher AEs occurred in 12.0% (n = 6) and 25.6% (n = 11) of the erlotinib and chemotherapy arms, respectively, during treatment.

Investigators observed serious AEs during treatment in 12.0% (n = 6) of patients in the erlotinib arm and 16.3% (n = 7) of patients in the chemotherapy arm. During treatment, 1 patient (2.0%) in the erlotinib arm developed interstitial lung disease, an AE of special interest. No AEs resulted in death.

Thirty-seven the 102 patients enrolled to the study died: 14 in the erlotinib arm and 23 in the chemotherapy arm. Disease progression was the most common cause of death in the erlotinib and chemotherapy arms (n = 9 and n = 19, respectively), followed by other causes (n = 5 and n = 4, respectively).

“The present results suggest that the effect of postoperative TKI treatment is more beneficial for patients with EGFR mutation–positive [NSCLC] than chemotherapy. A consensus has not been reached regarding the optimal duration of adjuvant therapy, but the present and past results indicate that 2 years of continuous treatment with TKIs yields good outcomes,” the study authors concluded.

Reference

Yue D, Xu S, Wang Q, et al. Updated overall survival and exploratory analysis from randomized, phase II EVAN study of erlotinib versus vinorelbine plus cisplatin adjuvant therapy in stage IIIA epidermal growth factor receptor+ non–small-cell lung cancer. J Clin Oncol. Published online August 26, 2022. doi:10.1200/JCO.22.00428