BELIEF Validates Dual Blockade of EGFR and VEGF

The BELIEF trial, led by the ETOP IBCSG Partners Foundation, is an international, multicenter, single-arm Phase 2 study enrolling 109 treatment-naïve patients with progressive non-squamous non-small cell lung cancer (NSCLC). Roche’s Tarceva (erlotinib) inhibits epidermal growth factor receptor (EGFR) tyrosine kinase, while Avastin (bevacizumab) neutralizes vascular endothelial growth factor-A (VEGF-A). Researchers administered erlotinib 150mg daily and bevacizumab 15mg/kg every three weeks to simultaneously block tumor proliferation and angiogenesis. As a single-arm design, the trial did not directly demonstrate superiority over erlotinib alone, but it served as a proof-of-concept study providing a foundation for subsequent randomized trials.

Notable Clinical Signals in T790M-Positive Patients

The median progression-free survival (mPFS) for all patients was 13.8 months. Among the 37 patients with pre-treatment EGFR T790M mutations, mPFS was 16.0 months, compared to 10.5 months in the 72 T790M-negative patients. The unadjusted hazard ratio (HR) between the two subgroups was 0.52, with a 95% confidence interval of 0.30–0.88 and a p-value of 0.016. Among the 106 patients analyzed for safety, five experienced Grade 4 or higher adverse events, including two cases of colonic perforation and one death due to sepsis, highlighting the importance of managing bleeding and perforation risks associated with anti-angiogenic combination therapy as much as efficacy. BRCA1 mRNA analysis was exploratory for patient stratification, while clinically validated companion diagnostic criteria remained EGFR activating mutations and T790M testing.

Approval History and Current Treatment Standards

Tarceva was first approved by the U.S. Food and Drug Administration (FDA) on November 18, 2004, as a second-line treatment for progressive NSCLC, and its indication was expanded in 2013 to include first-line treatment for metastatic NSCLC with EGFR exon 19 deletions or L858R mutations. Avastin received FDA approval on October 11, 2006, as a first-line treatment for non-squamous NSCLC in combination with carboplatin and paclitaxel, but the erlotinib combination in BELIEF is not an FDA-approved regimen in the U.S. The current standard of care is AstraZeneca’s Tagrisso (osimertinib), a third-generation tyrosine kinase inhibitor (TKI) that inhibits EGFR, including the T790M mutation. Therefore, BELIEF should be evaluated more as a foundational rationale for combining EGFR inhibitors with non-EGFR mechanisms, rather than a late-stage clinical trial likely to change current prescribing practices.

Competitive Landscape and Commercial Implications

On August 19, 2024, the FDA approved Johnson & Johnson’s Rybrevant (amivantamab-vmjw) in combination with Lazcluze (lazertinib) as a first-line treatment for NSCLC with EGFR exon 19 deletions or L858R mutations. In the Phase 3 MARIPOSA trial, this combination reduced the risk of disease progression or death by 30% compared to Tagrisso, with mPFS of 23.7 months versus 16.6 months. The global NSCLC treatment market was estimated at $91.5 billion in 2024, with Tagrisso’s 2025 regional sales alone reaching $1.971 billion in emerging markets, $1.423 billion in Europe, and $796 million in other developed markets, underscoring the commercial significance of EGFR-targeted therapies. While the dual blockade hypothesis in BELIEF is valid, its current competitive position is lower than Tagrisso and the Rybrevant-Lazcluze combination, which are supported by randomized Phase 3 data and longer PFS.