Mutations in the EGFR gene are very common in lung cancer, with 90% of the mutations being non-frameshift deletion mutations in exon 19 and L858R mutations. The current first-line drug commonly used for this type of mutation is osimertinib. In the FLAURA clinical trial, the third-generation targeted drug osimertinib improved the progression-free survival of lung cancer patients compared with the first-generation targeted drug. However, no matter what type of targeted drug it is, in fact, there is the problem of drug resistance in the end. Genetic testing analysis after osimertinib resistance showed that up to 50% of lung cancer patients did not have a definite mechanism of drug resistance, which brought challenges to subsequent treatment.
Amivantamab (Chinese translated as evantumab) is known as the fourth generation of targeted drugs, which can target two targets, EGFR and MET. Evantuzumab in combination with chemotherapy or as a single agent is currently approved for exon 20 insertion mutations in the EGFR gene. For patients resistant to osimertinib, the combination of avantumab and lazetinib, another third-generation targeted drug, improved survival. In the CHRYSALIS study, the median progression-free survival of evantumab plus lazetinib was greater than 36 months for untreated EGFR-mutated advanced lung cancer, and 85% of patients survived more than 3 years. To this end, scientists have conducted three phase of clinical trials, and the results of the research have just been published in the internationally renowned academic journal "New England Medicine".
Schematic diagram of reference publications
The first- and fourth-generation targeted drug Vantumab is used for the first-line treatment of lung cancer
The clinical trial, called MARIPOSA, enrolled a total of 1,074 patients with advanced lung cancer with mutations that are typical of common mutations (19del or L858R) and were divided into three groups, 40% of patients were treated with avantumab plus lazetinib, another 40% were treated with the third-generation targeted osimertinib, and the remaining 20% were treated with lazetinib monotherapy.
Progression-free survival of patients with different medications
As shown in the chart above, the median progression-free survival of evantumab plus lazetinib was 23.7 months, which was significantly longer than the 16.6 months of osimertinib. Eighty-six percent of patients in the avantumab plus lazetinib arm experienced a treatment response, compared with 85 percent in the osimertinib arm. The median duration of response was 25.8 months for the combination of evantumab plus lazetinib and 16.8 months for osimertinib.
The adverse reactions observed in clinical trials were mainly EGFR-related toxicity, with the incidence of discontinuation of all drugs due to treatment-related adverse events in 10% and 3%, respectively, and the incidence of adverse reactions in the combination of avantumab and lazetinib was larger, which is a combination of two drugs.
Image source: Photo.com
II. Discussion and Enlightenment
Attentive readers may notice that the median progression-free survival of riosimertinib in the first-line treatment of advanced lung cancer in the above clinical trial is 16.6 months, rather than 18.9 months in another clinical trial, which is why clinical trials need to compare the two drugs together, rather than comparing the data of one clinical trial with the data of another clinical trial, because the data of different clinical trials cannot be directly compared in the strict sense.
Based on the above data, we can understand that the fourth-generation targeted drug Evantuzumab combined with lazetinib is more effective than the third-generation targeted drug, and perhaps this combination will soon be approved for the first-line treatment of advanced lung cancer. But does this mean that this combination of drugs can be used directly for first-line therapy? After all, this is the use of two drugs together, and 10% of patients will stop the drug because of adverse reactions, followed by the need for intravenous injection of evantumab (some studies have shown that subcutaneous injection is also possible), which will bring some inconvenience to the patient's life. Of course, there is one last question: if both evantumab and lazetinib are resistant, what should be used for the subsequent resistance mechanism? That will be an even more problematic group of superdrug-resistant cancer cells, and you are welcome to leave a message to discuss this problem that we have to face.
The "Genetic Testing, Accessible to Everyone" public welfare program launched by Cancerology and Geinga has a minimum of 3,000 yuan to detect 50 genes of tumor targeted drugs, escorting targeted therapy for patients! You can follow the Cancer's WeChat public account or download the Cancer's app to consult a cancerous medical consultant.