Recently, the internationally renowned oncology journal "Journal of Clinical Oncology" published online the final overall survival (OS) data of a phase III clinical study (ACTION study) led by Chinese scholars. Research has shown that for advanced non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutations, targeted treatment with gefitinib API powder combination therapy significantly prolongs overall survival compared to gefitinib monotherapy. The median OS increases from 26.8 months in the monotherapy group to 34.1 months in the combination group, and the risk of death decreases by 32% (HR=0.68, P=0.008).This is the world's first phase III study to confirm that the combination of anti angiogenic pharmaceutical ingredients and EGFR-TKI can bring clear overall survival benefits to patients with advanced EGFR mutant NSCLC, providing a new standard treatment option for this population.
Research background: Cracking the dilemma of drug resistance and exploring new pathways for combination therapy
Since its launch in 2003, gefitinib, as the first generation EGFR-TKI, has become the first-line standard treatment for advanced NSCLC patients with EGFR sensitive mutations. However, in clinical practice, about 50% of patients develop drug resistance after about 10 months of medication, and the median progression free survival (PFS) is about 10-11 months. How to delay drug resistance and prolong survival has become an urgent problem to be solved in clinical practice. Previous studies have shown that anti angiogenic drugs may have a synergistic effect with EGFR-TKI by improving the tumor microenvironment, inhibiting neovascularization, and other mechanisms. The ACTION study (CTONG1706) is based on this theoretical foundation, exploring the effectiveness and safety of the regimen of gefitinib complex material (VEGFR-2 inhibitor).
This study was led by Professor Zhang from the Cancer Prevention and Treatment Center of Sun Yat sen University, with participation from 27 centers across the country. It was launched in 2017 and included 314 newly diagnosed patients with advanced EGFR mutant NSCLC. They were randomly assigned to different classification groups in a 1:1 ratio. The primary endpoint of the study was progression free survival (PFS) evaluated by an independent review committee (IRRC), while secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.
Key data: Clear survival benefits and controllable safety
1. Breakthrough in survival data: The final OS results released this time showed that after a median follow-up time of 48.5 months, the median OS of gefitinib composite material reached 34.1 months (95% CI: 30.2-38.0 months), significantly better than other groups, and the risk of death was reduced by 32% (HR=0.68, 95% CI: 0.51-0.91, P=0.008). This data suggests that the combination therapy can prolong the median survival of patients by more than 7 months and increase the 3-year survival rate to 48.2%. Previously, this study had reported that PFS benefits were ultimately successfully converted into OS benefits.
2. Consistent benefit in subgroup analysis: In the predetermined subgroup analysis, regardless of patient age, gender, smoking status, EGFR mutation type (exon 19 deletion or L858R mutation), and the presence of brain metastasis, the combination regimen showed a trend of OS benefit. Of particular note is that for patients with TP53 mutations (approximately 40%), the benefit of gefitinib combination therapy is more significant, with a median OS of 32.5 months. TP53 mutations usually indicate poor prognosis, which has important guiding significance for clinical practice.
3. Balance of efficacy and safety: In terms of efficacy, the objective response rate (ORR) of VEGFR-2 inhibitors is 77.1%, and the disease control rate (DCR) is 95.5%, both of which are superior to other groups. In terms of safety, the incidence of grade 3 and above adverse events was 84.1%, significantly higher than the 37.7% in the monotherapy group. The main adverse reactions included hypertension, proteinuria, hand foot syndrome, etc., but most of them could be controlled through fine-tuning or symptomatic treatment, and no new safety signals appeared. The proportion of treatment termination due to adverse reactions during the study period was relatively low, and the difference was controllable.
Clinical significance: Rewriting the treatment paradigm and providing new standard protocols
The final OS data from the ACTION study has multiple clinical implications. Firstly, this is the first phase III study to confirm that the combination of anti angiogenic drugs and EGFR-TKI can bring clear OS benefits to patients with advanced EGFR mutant NSCLC. Although previous studies have shown that combination therapy can prolong PFS, there has been controversy over whether it can translate into OS benefits. The results of this study not only confirm the benefits of PFS, but also achieve a significant extension of OS, providing the highest level of evidence-based medicine evidence for this joint strategy.
Secondly, the composite approach greatly enhances the convenience of treatment. Especially with the use of harsh anti angiogenic monoclonal antibodies such as bevacizumab. This has important practical significance for advanced cancer patients who require long-term treatment.
Thirdly, provide precise treatment options for specific populations. Grouping analysis showed that patients with TP53 mutations benefited more significantly from the combination therapy, suggesting that in the future, genetic testing may be used to screen for advantageous populations and achieve more precise personalized treatment. In addition, for patients with limited economic conditions who cannot afford third-generation TKIs (such as AZD-9291), API Powder gefitinib composite materials provide a more cost-effective treatment option.
Future outlook: Exploring more possibilities from late to early stages
Based on the positive results of the ACTION study, the research team has initiated multiple follow-up explorations. The current ongoing studies include: evaluating the efficacy of this combination therapy for adjuvant treatment of early-stage EGFR mutant NSCLC after surgery (ACTIVE-ADJ study); Exploring the efficacy differences of first-line treatment with third-generation TKIs using combination therapy (ACTIVE-3 study); And optimization of combination therapy strategies targeting different resistance mechanisms, such as MET amplification and HER2 mutations.
In addition, with the emergence of more anti angiogenic materials Lenvatinib powder and novel EGFR-TKI, more Gefitinib composite regimens may be formed in the future to provide personalized choices for patients with different clinical characteristics. Meanwhile, precise screening based on biomarkers such as TP53 mutation status and dynamic monitoring of circulating tumor DNA is expected to further enhance the efficacy of the combination therapy. If you hope to make a difference in this area and would like to receive the above raw material support, please contact Xi'an Faithful BioTech Co., Ltd.
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