TL;DR
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A single-arm phase II trial found that amivantamab, lazertinib and bevacizumab produced a 39% best overall response rate and median progression-free survival of 10.9 months in EGFR-mutant advanced non-small cell lung cancer that had progressed on a third-generation EGFR inhibitor. The results are promising but do not establish that the chemotherapy-free combination is better than current treatment options; randomized testing is needed, and treatment-related side effects were common.
A single-arm phase II trial found that the chemotherapy-free combination of amivantamab, lazertinib and bevacizumab showed antitumor activity in people with advanced EGFR-mutant non-small cell lung cancer whose disease progressed on a third-generation EGFR inhibitor. The regimen produced a median progression-free survival of 10.9 months, but without a comparison group the study cannot show whether it is more effective than available alternatives.
Among the 61 patients enrolled in the ETOP 18-21 AMAZE-lung trial, the objective response rate at 12 weeks was 33%, and the best overall response rate was 39%. Median duration of response was 13.9 months. Updated results put median overall survival at 19.9 months. The researchers reported that the trial met its primary outcome, which was based on the 12-week response rate.
The patients had advanced cancer that had progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor. Amivantamab targets EGFR and MET, lazertinib is an EGFR inhibitor, and bevacizumab acts on the angiogenic pathway. The researchers said the combination is a chemotherapy-sparing approach that targets these three pathways. The study was conducted at 17 sites in Europe.
Side effects and treatment changes were frequent. The most commonly reported treatment-related adverse events were infusion-related reactions, in 58% of participants, and acneiform rash, in 50%. Grade 3 or 4 treatment-related adverse events occurred in 43%; serious treatment-related events were reported in 20%. No treatment-related deaths were observed. Treatment-related events led to interruptions for 67% of patients, dose reductions for 37% and permanent discontinuation of at least one study drug for 20%.
A Possible Option After EGFR Resistance
Resistance and progression commonly develop after treatment with third-generation EGFR inhibitors, leaving a need for effective options once these medicines stop controlling the cancer. The trial’s 10.9-month median progression-free survival and 13.9-month median duration of response are among the longest reported in this treatment setting, according to the investigators and an accompanying commentary. Those results suggest the three-pathway approach could merit further study for some patients.
However, the findings do not establish that patients live longer or fare better on this regimen than they would with chemotherapy or another treatment. The response rate and duration of disease control are different measures, and the study’s single-arm design makes direct comparison difficult. The adverse-event burden also matters when weighing a potential chemotherapy-free option: some participants needed treatment interruptions, dose reductions or discontinuation.
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Treatment After First EGFR Inhibitors
Third-generation EGFR inhibitors, including osimertinib and lazertinib, are standard first-line treatments for advanced NSCLC with common sensitizing EGFR mutations, the report notes. Cancer can acquire resistance to these drugs, after which treatment choices are more limited and often involve chemotherapy-based combinations.
Amivantamab is already approved with lazertinib for first-line treatment, based on the phase III MARIPOSA trial. The phase III MARIPOSA-2 study also found that amivantamab, with or without lazertinib, added to standard second-line chemotherapy improved median progression-free survival compared with chemotherapy alone after progression on osimertinib. Those regimens include chemotherapy; AMAZE-lung examined a three-drug combination without chemotherapy in a later-treatment setting.
“The trial provides preliminary evidence for the potential benefit of combined amivantamab, lazertinib, and bevacizumab.”
— Rolf A. Stahel, MD, and colleagues
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How the Results Compare With Alternatives
The study had no randomized control group, so it cannot determine whether the triplet improves outcomes compared with chemotherapy or other current regimens. Fan also questioned the relevance of the historical response-rate benchmark used to power the study: she noted that contemporary platinum-based chemotherapy has reported response rates of 27% to 43%, while some more recently approved combinations exceed 50%. These are comparisons across studies, not direct trial results.
It is also unclear which patients are most likely to benefit, whether the results apply broadly beyond the study population, and how the regimen’s side effects compare with alternatives. Treatment-related venous thromboembolism was reported in 17% of patients at any grade and in 3% at grade 3 or 4; Fan described this as a substantial burden, noting that most participants received preventive anticoagulation. The trial enrolled a relatively small group, and the findings are not proof of superiority.
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Randomized Testing Needed
The next step is further study with a randomized comparison against relevant treatment options. Such a trial could help determine whether the chemotherapy-free triplet improves response duration, progression-free survival or overall survival, and clarify its risks relative to other regimens. The investigators said randomized studies are needed; the source report does not identify a specific next trial or its expected start date.
Until comparative evidence is available, the phase II findings are best understood as a signal of potential activity, not a new established standard. Further data would also need to clarify which patients might be suitable for the combination and how its treatment burden should be weighed against potential benefit.
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Key Questions
What combination did the trial study?
It studied amivantamab, lazertinib and bevacizumab without chemotherapy in advanced EGFR-mutant NSCLC that had progressed after a third-generation EGFR inhibitor.
What outcomes did researchers report?
The 12-week objective response rate was 33%, the best overall response rate was 39%, median duration of response was 13.9 months and median progression-free survival was 10.9 months. Updated median overall survival was 19.9 months.
Does the study prove the regimen is better than chemotherapy?
No. It was a single-arm phase II trial with no randomized comparison group, so it cannot establish superiority over chemotherapy or other treatment options.
What side effects were reported?
Infusion-related reactions and acneiform rash were the most common treatment-related events. Grade 3 or 4 events occurred in 43% of participants, and treatment-related events led to permanent discontinuation of at least one drug for 20%.
What evidence is needed next?
Randomized studies are needed to compare the regimen with relevant alternatives and better establish its benefits, risks and the patients most likely to benefit.
Source: rss
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