Erlotinib shows long-term DFS advantage, significant improvement in OS over chemotherapy in EGFR+ NSCLC

Erlotinib shows long-term DFS advantage, significant improvement in OS over chemotherapy in EGFR+ NSCLC
Erlotinib shows long-term DFS advantage, significant improvement in OS over chemotherapy in EGFR+ NSCLC

Erlotinib (Tarceva) continued to provide benefit in terms of disease-free survival (DFS) and overall survival (OS) compared to vinorelbine/cisplatin chemotherapy in patients with EGFR-positive non-small cell lung cancer (NSCLC), based on updated OS data and an exploratory analysis from the Phase 2 EVAN trial (NCT01683175).

At 43 months 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 reached endpoint or were censored at the end of follow-up, the 5-year SSM for this arm could not be determined. At the final data cutoff, the benefit of DFS was significantly better with erlotinib than with chemotherapy in ITT (HR, 0.38; 95% CI, 0.20-0.70; P P = 0.008) populations.

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

Patients with stage IIIA NSCLC who have undergone R0 resection frequently relapse – the 5-year survival rate is 25% or less. Osimertinib (Tagrisso), an EGFR TKI, is the current gold standard adjuvant therapy for stage II-III resected patients EGFR– Mutant NSCLC. Other TKIs, such as erlotinib, may also provide clinical benefit in this setting.

The open-label, randomized EVAN trial evaluated the SSM, OS and safety of adjuvant erlotinib compared to the combination of vinorelbine plus cisplatin chemotherapy after complete resection in Chinese stage IIIA patients EGFR– Positive NSCLC. The main results of the endpoints of this trial have been published. These updated results represent updated DFS data, 5-year OS data, and exploratory results.

This study enrolled 102 patients, 51 each in the erlotinib and chemotherapy arms in the ITT population. The erlotinib per-protocol population excluded 5 patients, 1 of whom received no study treatment and 4 had major protocol violations, including no R0 resection (n=3) and no critical evaluations (n ​​= 1), for a total of 46 patients. The per-protocol chemotherapy population excluded 18 patients of whom 8 received no study treatment, and 11 of whom had major protocol violations, including no R0 resection (n=5), lack of critical assessments (n=3), prior antineoplastic therapy (n=1), other antineoplastic therapy (n=1), and metastatic NSCLC before disease progression (n=1).

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

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

The primary endpoint was SSM, with secondary endpoints 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.

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% to 97.6%) and 51.1% (95% CI, 34.7% to 67.5% ) with erlotinib and chemotherapy, respectively. The HR for probability of OS with erlotinib versus chemotherapy was 0.373 (95% CI, 0.191-0.728; P = 0.003) in the ITT population and 0.375 (95% CI, 0.188-0.746; P = 0.004) in the per-protocol population, showing significantly better OS with erlotinib compared to 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 treatment during follow-up. Frequently used tumor therapies in the erlotinib and chemotherapy arms included TKIs (21.6% and 37.3%), radiation therapy (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 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 an exploratory whole-exome sequencing analysis to assess the relationship between patient benefit and concurrent variants in 34 patients in the erlotinib arm and 31 patients in the chemotherapy arm. This analysis showed that the most frequent genes with co-occurring variants at baseline were TP53, MUC16, FAM104B, KMT5Aand DNAH9. Additional EGFR variants have also been identified, each with similar prevalence, regardless of mutation subgroup. In the erlotinib arm, a single nucleotide polymorphism mutation in UBXN11 was associated with a deterioration in SSM (P = 0.01), a new finding that requires further study. The investigators observed no significant association between DFS and OS in the chemotherapy arm.

Of the 50 patients in the erlotinib arm included in the on-treatment safety analysis, 58.0% (n=29) experienced adverse reactions (AEs). Of the 43 patients in the erlotinib arm included in the safety analysis during follow-up, 65.1% (n=28) experienced 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 of the 102 patients included in 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 current results suggest that the effect of postoperative TKI treatment is more beneficial for patients with EGFR positive mutation [NSCLC] than chemotherapy. A consensus has not been reached regarding the optimal duration of adjuvant therapy, but current and past results indicate that 2 years of continuous treatment with TKIs yields good results,” the study authors concluded.

Reference

Yue D, Xu S, Wang Q, et al. Update of Overall Survival and Exploratory Analysis of the Randomized Phase II EVAN Study Comparing Erlotinib to Vinorelbine Plus Cisplatin Adjuvant Therapy in Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer stage IIIA. J Clin Oncol. Published online August 26, 2022. doi:10.1200/JCO.22.00428

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