Of every 100 lung cancer patients, 85 are non-small cell lung cancer, and about 35-40 of them carry a specific gene mutation – EGFR (epidermal growth factor receptor) gene mutation. This mutation is closely related to the occurrence of lung cancer, and drugs targeting it can control the progression of the disease, which is called “targeted drugs”.
Currently, six EGFR-targeted drugs [scientifically known as EGFR tyrosine kinase inhibitors (EGFR-TKI)] are available in China, and the following table provides an inventory. All of them can be the first choice (i.e. “first-line treatment”) for patients with advanced lung cancer with corresponding mutations. So, are they better or worse? How should they be chosen? Let’s see where each of them is “useful” and what to pay attention to in their use.
Table The six EGFR-targeting drugs currently available in China
| Commercial name | Manufacturing Company | Generation of drug | |
| Gefitinib | Eserisal | AstraZeneca | First generation |
| Erlotinib | Trokine | Roche | First generation |
| Ecetinib | Camry | Zhejiang Beda Pharmaceutical | First Generation |
| Afatinib | Gitaira | Boehringer Ingelheim | Second generation |
| Daclatinib | Vizimpro | Pfizer | Second Generation |
| Oshitinib | Tyrosa | AstraZeneca | Third Generation |
Gefitinib, erlotinib, erlotinib
Key words: EGFR common mutations, affordable
There are many types of EGFR mutations, and the two most common are “exon 19 deletion” and “exon 21 L858R mutation”, which account for 90% of all mutations[ 1]. For both types of mutations, gefitinib, erlotinib, and erlotinib are effective. The first two of them are imported drugs, and erlotinib is a domestic drug.
From the clinical trial results, more than 67% of patients taking gefitinib achieved remission and half had progression-free survival of more than 10.9 months, with an overall survival of nearly 1 year. The efficacy of the other two drugs was similar[2][3]. In contrast, with chemotherapy (platinum + paclitaxel), only 41% achieved remission, with a median progression-free survival of 7.4 months and a shorter overall survival[1][4].
The side effects of the three targeted drugs are also similar, mainly rash, diarrhea, nausea, and vomiting, which are largely tolerated by patients and do not require discontinuation of the drug. However, erlotinib requires three doses per day and is easy to miss, while the other two drugs require only one dose per day.
Currently, all three drugs are reimbursed by Medicare, with prices reduced by up to 70% or more. From the price information in the table above, these three drugs are relatively “affordable”. A box of Gefitinib (10 tablets, 0.25g/tablet) costs 2350 RMB, a box of Erlotinib (7 tablets, 150mg/tablet) costs 1365 RMB, and a box of Exatinib (21 tablets, 125mg/tablet) costs 1345.05 RMB.
Afatinib
Key words: EGFR rare mutation, EGFR exon 19 deletion mutation, affordable, long-lasting effect
As mentioned above, 90% of EGFR mutations are “exon 19 deletion” or “exon 21 L858R mutation”, but there are some rare mutations, such as S768I, L861Q, G719X and so on. In this case, the efficacy of the generation of targeted drugs is very poor, so it is the turn of afatinib to come into play. It maintained disease remission for more than 1 year in 52% of patients and more than 1.5 years in 1/3 of patients, significantly outperforming chemotherapy and first-generation drugs [5].
In addition, afatinib was also more effective than gefitinib in patients with “exon 19 deletion. In clinical studies, 27% of patients in the afatinib group were progression-free by 18 months compared with 15% in the gefitinib group; at 2 years, the gap was still 10%; and at 3 years, 10% of patients in the afatinib group remained in remission[6].
However, the efficacy of afatinib was poor for another common mutation, exon 21 mutation.
Currently, afatinib is also reimbursed by Medicare at a price of $1400/box (a box of 7 tablets, 40 mg/tablet).
Dacitinib
Key words: common mutations in EGFR, better efficacy than all first- and second-generation drugs, more severe adverse effects
Daclatinib is a new drug launched in the US in 2018 and is not yet available in China. It is indicated for patients with common mutations in EGFR. In clinical trials, half of the patients taking daclatinib were able to maintain progression-free disease for more than 14.7 months, a figure that not only extends a full 5 months over chemotherapy [7], but also beats all first- and second-generation EGFR-targeting drugs currently on the market.
However, it is important to note with caution that 2 out of 3 patients taking dacitinib tapered because they could not tolerate the adverse effects, significantly more than gefitinib (8%).
Oshitinib
Key words: EGFR common mutation, record-breaking efficacy, expensive
Ocitinib is a new third-generation drug that has been launched in China. It has an efficacy statistic that broke all previous records for first-line treatment – patients had a progression-free survival time of 18.9 months, almost twice that of the first-generation drug. After 1 year of treatment, 64% of patients still had sustained disease remission [8]. Moreover, the progression-free survival benefit was seen early in treatment in patients treated with oxitinib, with a faster onset of action than several other EGFR TKI.
However, it is more expensive, and despite the assistance program of the China Charity Federation, it requires four months of out-of-pocket expenses (RMB 50,000 per month) before it can be granted for eight months. The latest good news is that since October 10, 2018, ositinib has been included in the national health insurance and the monthly cost has been reduced to 15,300 RMB.
In fact, the drug Ocitinib was originally developed to overcome the resistance of a generation of EGFR TKI. Studies also confirmed that the use of oseltinib after resistance to a generation of drugs significantly prolonged patient survival. However, later studies confirmed that oseltinib was also very effective as first-line therapy, which led to the above recommendation. So, is it worthwhile to bring forward the use of oseltinib?
Let’s calculate the survival benefit time for both uses. If oxitinib is used after a generation of EGFR TKI therapy resistance, the patients’ progression-free survival adds up to about 20 months; whereas if oxitinib is used at the beginning, the progression-free survival time is 18.9 months, and the mechanism of oxitinib resistance is still unclear, and if it is resistant and dual-drug chemotherapy is recommended, then the combined progression-free survival time should be more than 20 months.
Summary
EGFR-targeted agents are preferred for patients with advanced lung cancer who have EGFR mutations. Of the 6 drugs that are available.
- Patients with common mutations in EGFR, all 6 drugs are available. All are currently reimbursed by Medicare except for daclatinib.
- Oxitinib has the best efficacy, followed by dacitinib, afatinib, and finally the 3 generation drugs, but dacitinib has more severe adverse effects than the others.
- For patients with rare mutations in EGFR, afatinib is preferred.