At this year’s CCMO Congress, the topic of discussion in the special lung cancer expert workshop session was whether epidermal growth factor receptor (EGFR) mutations need to be routinely detected in lung cancer patients in clinical practice. The discussion was divided into pro and con sides, with debaters from the Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, with Dr. Li Junling on the pro side and Dr. Wang Yan on the con side. The chairs of the conference were Prof. Mei-Lin Liao from Shanghai Chest Hospital and Prof. Yuan-Kai Shi from Cancer Hospital of Chinese Academy of Medical Sciences. The seminar experts were Prof. Cheng Gang from Beijing Hospital, Prof. Chen Liang’an from 301 Hospital of PLA and Prof. Cheng Ying from Jilin Cancer Hospital.
Prof. Mei-Lin Liao gave an overview of the current issues in the field of targeted therapy for non-small cell lung cancer (NSCLC), such as whether to test for EGFR, the methods of testing, the accuracy and comparability of results. Prof. Liao said, “Since these issues exist, there will be controversies, so let’s listen to the opinions from each side of this debate, and then invite expert professors who are well-known in the field to comment afterwards.”
The positive side’s view
Li Junling: In the first-line treatment of advanced NSCLC, the efficacy of platinum-containing two-drug chemotherapy has reached a bottleneck, and the overall survival (OS) after chemotherapy is 7.4 to 10.3 months, with a 1-year survival rate of 26% to 43%. Although there are some three-drug combinations as well as non-platinum-based combination regimens, the efficacy has not been further improved, and therefore some new therapeutic strategies are clinically needed to improve the survival of patients. The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has brought new hope for the treatment of lung cancer. Numerous clinical studies have confirmed that small molecule TKI drugs (gefitinib or erlotinib) are more effective in patients with EGFR mutations.
The value of EGFR mutation testing is not negligible and the cost is affordable
EGFR mutations mainly refer to exon 19 deletions and point mutations in exon 21, which account for the majority of EGFR mutations. There are two opposing views on whether EGFR should be routinely tested in clinical practice, and I agree with the view that EGFR should be routinely tested. Prospective clinical studies as well as retrospective analysis of phase II clinical studies have shown that testing for EGFR mutations increases the chances that patients will choose and benefit from targeted drug therapy. So far, prediction of EGFR mutation positivity by clinical characteristics, patient’s pathological type and smoking status alone is inadequate. the IPASS study selected patients with lung adenocarcinoma, non-smokers or very low smokers, who had an EGFR mutation rate of approximately 60%, with higher rates in female patients and elderly patients.
In clinical practice, if cost is not a consideration, then the value of EGFR testing should not be overlooked, as it can indeed provide many benefits to patients. In clinical practice, our daily tasks include collecting and organizing data, recommending treatment options from evidence-based medicine and reliable clinical studies, following a strategy of standardized and individualized treatment, and communicating with patients so that they accept the physician’s treatment philosophy to maximize the benefit from the treatment.
From the patient’s point of view, the EGFR test does not lose anything. It is a one-time test, which does not harm the patient, and when the opportunity arises to choose a targeted therapy, this very valuable information can be used without having to spend a long time waiting for the results. And the cost of testing is affordable compared to the cost of treatment. Once patients know their mutation status, they can decide their treatment mode, whether to choose chemotherapy or targeted therapy first, and can communicate better with their doctors.
EGFR mutations are a better predictor of TKI treatment efficacy
How can I tell if EGFR testing is worthwhile? EGFR testing is valuable if it is highly specific in predicting patient benefit compared to other treatment options. mutations were less effective with TKI.
Results from another large phase III clinical study (i.e., the Erlotinib Spain study) showed a significant benefit of erlotinib treatment in NSCLC patients with EGFR mutations, with a complete remission (CR) rate of 13.3% in patients with mutations, an overall efficacy rate of 71%, an OS of 24 months for the entire group, 27 months for effective patients and patients with exon 19 mutations, and a median OS for chemotherapy patients of only The median OS for chemotherapy patients was only 11 months, with a time to tumor progression of 5 months and an efficiency rate of 20% to 30%. erlotinib treatment in patients with EGFR mutations was 2 to 3 times more effective than chemotherapy. These survival and remission rate benefits are impressive and undoubtedly the first clear target for individualized EGFR-TKI therapy and a new milestone in the treatment of NSCLC.
The SATURN study is a phase III clinical study of maintenance treatment with erlotinib after benefit from first-line chemotherapy. The results showed a 41% prolongation of PFS in the maintenance treatment group compared to the observation group, along with significantly higher efficiency and disease control rates. In patients with EGFR mutations, the risk ratio for PFS was 0.10 in those on maintenance therapy compared to 0.78 in EGFR wild-type patients, a significant difference.
Should we routinely test for EGFR in clinical practice? The answer is yes. Based on the results of the IPASS study and the Spanish study, EGFR mutations should be routinely detected in non-smoking patients. Based on the results of the SATURN study, lung cancer patients who are to be treated with maintenance EGFR-TKI should be tested for EGFR mutations. Thus, a large body of clinical data supports routine testing for EGFR in clinical practice.
Opposing viewpoints
Yan Wang: EGFR testing is discussed in the following three aspects: the necessary conditions for routine testing in lung cancer treatment, the feasibility of routine testing, and the problems that exist.
EGFR is not yet required as a routine test
As a routine test to guide the treatment of lung cancer, the prerequisites should be: if the test result is negative, it suggests that TKI therapy is ineffective; if the test result is positive, TKI therapy is the irreplaceable choice and the earlier it is used, the better, and it can also be beneficial when used in the early stage of the disease.
The SWOG 0126 study showed that some of the alveolar cell carcinoma patients who survived more than 4 years on TKI therapy did not have EGFR mutations. In the SATURN study, patients with EGFR wild type also benefited from maintenance treatment with erlotinib. Therefore, EGFR-negative does not equate to ineffective TKI therapy. Wild-type patients can benefit from second-line or higher TKI therapy with similar efficacy to chemotherapy.
In contrast, TKI therapy is not an irreplaceable option in the first-line treatment of patients with EGFR mutations. The current evidence suggests that the results of the EGFR mutation testing in the IPASS study are retrospective and the representativeness of the sample is questionable. TKI therapy is not clinically preferable the earlier it is used, and the benefit of using TKI at early stages of the disease has yet to be confirmed by clinical studies.
Issues such as the feasibility of routine testing remain to be addressed
In the completed phase III clinical studies on TKI for advanced NSCLC, the number of specimens available for analysis was low, only 26% in the INTEREST study and 36% in the IPASS study. There is a lack of simple and easy-to-use assays for EGFR and a commonly accepted technical platform.
In addition, there are still some questions that need to be addressed, such as the difference between the IPASS and SATURN studies in the results of mutation detection and TKI efficacy, whether this difference is due to ethnicity or drug differences? What should be done if tissue specimens are not available during clinical treatment? How to treat false-negative test results when standards are not uniform?
In clinical practice, it is seen that patients with EGFR wild type can benefit from second-line TKI therapy and beyond, with similar efficacy to chemotherapy, without the need to select TKI therapy based on genetic test results. Therefore, whether TKI therapy is superior to chemotherapy in patients with EGFR mutations is inconclusive and needs to be verified in prospective clinical studies. Most patients in first-line treatment do not require treatment selection based on genetic testing results. In addition, there is a need to find a standard test that is easy to perform and can be widely used.
Expert opinion
Prof. Liangan Chen: I support the detection of EGFR mutation in clinical practice. In tumor treatment, with the advancement of technology, we have entered the stage of personalized treatment, and we need to have some indicators for individual patient characteristics to guide treatment.
Existing clinical studies, including some prospective and convincing phase II clinical studies, have confirmed that patients with EGFR mutations can achieve better efficacy with TKI therapy.
In our clinical practice, the disease control rate of these patients can reach about 70%, therefore, I support the positive side’s view.
Prof. Cheng Gang: I think there is no final result after discussion and controversy on whether EGFR testing is routinely performed in clinical practice. Both the pro side and the con side have presented sufficient evidence, but both have extracted the evidence in their favor from various trials, while ignoring the other evidence. It is more complicated to have different evidence for the same trial.
The evidence from studies on EGFR testing and TKI therapy also varies between first-line and second-line therapy. the IPASS study showed that gene mutations are clearly associated with efficacy. The Spanish study also confirmed that the benefit in patients with EGFR mutations is unattainable with chemotherapy. The efficacy of TKI treatment in these patients is clearer.
There is also some evidence (e.g., the INTEREST study) that the efficacy of second-line TKI treatment in the mutation population is different from first-line, with an efficacy rate of 70% in patients with mutations treated in first-line and 35% to 40% in patients with mutations treated in second-line. That is, the effect of this mutation on the efficacy is completely different between first-line and second-line treatment. From this point of view, I think that for first-line treatment to use TKI therapy, the EGFR mutation needs to be detected and the mutated patient only receives first-line TKI therapy. In second-line treatment, the situation is different, the efficacy is the same in all populations, and testing or not testing for EGFR mutations does not have much impact on clinical efficacy and survival. In terms of the order of chemotherapy and TKI use, a phase III randomized clinical study is still needed to confirm.
Prof. Ying Cheng: I agree with Prof. Gang Cheng’s view. In addition, there may be some other pathways that need further clinical exploration.
However, the current recommendation should be to actively test for EGFR mutations as long as they are available before choosing a treatment strategy.
Prof. Yuan-Kai Shi: Individualized therapy is the highest goal pursued by oncologists, but how to achieve this highest goal, or how many obstacles to overcome on the way to achieve it, is what we have to face. This discussion question chosen today represents two different views or two facts that currently exist in our academic community in the field of lung cancer treatment, there are facts that support the positive side and facts that support the negative side. But in any case, EGFR testing should be on our agenda in clinical practice, whether we do it or not, how to do it and with what kind of method, we may have to wait for more and more clinical study results to answer, but in any case, we have to focus on or actively try to confirm these questions.