Combining Avastin With Alecensa Shows Promise in Advanced ALK-Positive Lung Cancer

A phase 2 clinical trial found that adding Avastin (bevacizumab) to Alecensa (alectinib) significantly improved outcomes in advanced anaplastic lymphoma kinase (ALK)-positive lung cancer, which then delayed disease progression and protected the brain without compromising quality of life, according to a study published in Nature.

ALK genes are found in about 3% to 9% of non–small cell lung cancer (NSCLC) cases, the study shared.

These genes drive tumor growth by activating specific signaling pathways that help cancer cells survive and multiply.

Patients with ALK-positive NSCLC often respond well to ALK-targeted therapies known as tyrosine kinase inhibitors (ALK-TKIs).

Over the past decade, researchers of this study shared that newer ALK-TKIs have significantly improved patient outcomes, especially compared to earlier treatments such as Xalkori (crizotinib).

Alectinib, a second-generation ALK-TKI, has become a preferred first-line therapy due to its ability to delay disease progression and reach cancer in the brain much better.

However, resistance to ALK-TKIs eventually develops, and the brain remains a common site of relapse, the authors claim.

ALK genes are found in about 3% to 9% of non–small cell lung cancer cases.

To improve outcomes and delay resistance, researchers explored combining ALK-TKIs with other treatments.

One approach targets VEGF, a protein that helps tumors grow new blood vessels. Bevacizumab, an anti-VEGF antibody, is already used with chemotherapy in advanced NSCLC.

Previous studies suggest that combining alectinib with bevacizumab could have a stronger effect against cancer and help prevent brain metastases.

Based on early data, researchers conducted the phase 2 single-arm, open-label study at the National Cancer Institute in Mexico.

It included patients with untreated, advanced NSCLC who had to have measurable tumors and good physical function.

Molecular testing, including next-generation sequencing (NGS), was performed at diagnosis and again if the cancer progressed.

Patients received alectinib (600 mg twice daily) and bevacizumab (15 mg/kg every 3 weeks) until the cancer worsened or side effects became unacceptable.

Imaging scans were done every 6 weeks, and brain MRIs every 12 weeks.

The main outcome measured was progression-free survival (PFS) at 12 months. Secondary outcomes included overall survival, tumor response and patient-reported outcomes (PROs), such as quality of life and symptom changes, which were measured using questionnaires.

The study used a two-stage design to determine whether the treatment was effective enough to continue.

Data were analyzed using standard statistical tools such as the Kaplan-Meier curves for survival and mixed-effects models for PROs.

The trial completed enrollment, and the study includes results from up to 36 months of follow-up.

Between April 2020 and August 2022, 54 patients were evaluated in this trial, with 41 receiving the treatment. The median age was 50, and most were women.

All had advanced (stage IV) non-squamous lung cancer, and about 17% had brain metastases at diagnosis.

The most common genetic mutation was the EML4-ALK fusion, especially variants 1 and 3.

After about three years of follow-up, the treatment showed strong results: 100% of patients responded, 88% partially and 12% completely.

At 36 months, 64% did not see disease progression, and almost 88% were still alive.

It was also found that brain-related outcomes were positive, with nearly 88% free of brain progression at 3 years.

Side effects were common—as seen in 98% of patients— with diarrhea, protein in urine and anemia being the most frequent.

Serious side effects occurred in under 8%, and no deaths were linked to treatment.

Patient-reported outcomes improved significantly. Quality of life, especially physical and emotional functioning, got better over time.

Symptoms including pain, fatigue and cough improved, though diarrhea briefly worsened.

Overall, the treatment was effective, mostly well-tolerated and helped maintain or improve quality of life for most patients.

This trial’s strengths include standardized genomic testing and efficacy across diverse patient subgroups.

However, its single-arm, single-center design without a control group limits further conclusions.

Researchers note the high rate of bevacizumab discontinuation due to side effects such as proteinuria raises concerns about long-term tolerability.

Future studies should explore less bevacizumab dosing, distinguish quality-of-life outcomes by treatment phase and examine the resistance process.

Authors stated that a randomized phase III trial is needed to confirm whether adding antiangiogenic therapy offers added benefit over next-generation ALK-TKIs alone, especially in high-risk patients with limited access to third-generation TKIs.