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Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non-Small-Cell Lung

Takashi Ninomiya¹, Nobuhisa Ishikawa², Koji Inoue³

¹Health Service Center, Okayama University, Okayama, Japan; Department of Respiratory Medicine and Allergy, Okayama University Hospital, Okayama, Japan.

Clinical Lung Cancer

|December 6, 2018

Abstract:

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.

Insights

This study investigates combining afatinib with bevacizumab for advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. The combination aims to improve progression-free survival (PFS) compared to afatinib alone in first-line therapy.

Area of Science:

Oncology
Pharmacology
Medical Research

Background:

Afatinib, an EGFR-TKI, shows survival benefits in EGFR-mutant NSCLC.
Bevacizumab combined with first-generation EGFR-TKIs offers favorable PFS and toxicity.
Previous research suggests potential for improved efficacy with combination therapies.

Purpose of the Study:

To hypothesize that combining bevacizumab and afatinib could enhance efficacy in first-line treatment for NSCLC.
To establish a recommended dose for afatinib and bevacizumab combination therapy.
To initiate a randomized phase 2 trial comparing the combination against afatinib monotherapy.

Main Methods:

Phase 1 study defined the recommended dose: 30 mg afatinib daily and 15 mg/kg bevacizumab every 3 weeks.
Randomized phase 2 trial enrolling 100 patients with nonsquamous NSCLC and common EGFR mutations.
Patients randomized 1:1 to receive either afatinib (30 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) or afatinib (40 mg daily) alone.
Treatment continues until disease progression or unacceptable toxicity.
Primary endpoint: Progression-free survival (PFS). Secondary endpoints: Overall survival, tumor response, time to treatment failure.

Main Results:

Phase 1 study established a well-tolerated and recommended dose for the combination therapy.
The phase 2 trial is currently enrolling patients to compare the combination's efficacy against afatinib monotherapy.
Statistical power is calculated to detect a significant difference in PFS, assuming a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group.

Conclusions:

The combination of afatinib and bevacizumab is hypothesized to be more efficacious than standard therapies for EGFR-mutant NSCLC.
This randomized phase 2 trial will provide critical data on the efficacy and safety of this novel combination regimen.
Further research is warranted to confirm the potential of this combination in improving outcomes for NSCLC patients.

Read full analysis

Keywords:

Anti-angiogenesis EGFR-TKI Molecular targeted therapy

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