Professor Cheng Ying: Osimitinib adjuvant treatment indications were approved, rewriting the domestic operable EGFR mutation treatment model

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What is the status of EGFR-TKI in the adjuvant treatment of early lung cancer? See what the big guys say! For patients with early and mid-stage non-small cell lung cancer (NSCLC), complete surgical resection is still the key to improving the survival rate of patients, and postoperative adjuvant treatment is an important part of radical surgical resection.

In recent years, with the fiery research and development of targeted therapy drugs in NSCLC, in addition to being applied to advanced patients, they have also achieved outstanding results in adjuvant treatment in early and mid-term patients.

In April 2021, based on the results of the ADAURA study, osimertinib was approved in China for postoperative adjuvant treatment of patients with EGFR mutation-positive resectable NSCLC.
In this regard, the Medical Oncology Channel invited Professor Cheng Ying from Jilin Provincial Cancer Hospital to share Related content in the field of adjuvant therapy.

Postoperative adjuvant therapy is progressing rapidly, and the prognosis of early and mid-term patients is improved.
Adjuvant therapy as an effective method to prevent postoperative recurrence and metastasis has always played an important role in the treatment of early NSCLC.

Previous studies have found that platinum-containing dual-agent adjuvant chemotherapy can bring statistically significant prognostic improvement to patients with stage II-IIIA NSCLC, thereby establishing the status of platinum-containing dual-agent chemotherapy as an adjuvant treatment after surgery.

In addition, radiotherapy, especially precision radiotherapy technology, is also one of the important methods of postoperative adjuvant treatment.

However, chemotherapy and radiotherapy still have many problems in adjuvant therapy.
For example, the efficacy of chemotherapy is relatively limited [the risk of death is only reduced by 11%, and the 5-year overall survival (OS) rate is only increased by 5%], and the side effects are relatively large, leading to The proportion of patients who cannot complete the full dose and full course of treatment is as high as 30%; the role of adjuvant radiotherapy in NSCLC patients after complete resection is also a lot of controversy.
Multiple previous meta-analysis indicated that only N2 patients receiving adjuvant radiotherapy have a trend of OS benefit, 2020 The results of the Lung ART study published at the European Society of Medical Oncology (ESMO) meeting in 2016 showed that for patients with IIIA-N2, adjuvant radiotherapy did not have significant benefits of disease-free survival (DFS) and OS, and increased cardiopulmonary-related adverse events Therefore, people have been trying to find more effective adjuvant treatment methods and models.

 With the widespread application of targeted drugs in patients with driver-positive advanced lung cancer, people have gradually explored the feasibility of TKI adjuvant therapy.

Among the EGFR mutation population, the ADJUVANT study and the EVAN study accurately screened the EGFR sensitive mutation population, and mainly stage II-IIIA patients, confirming that a first-generation EGFR-TKIs adjuvant therapy can bring significant DFS benefits to patients, especially N2 patients with stage IIIA benefit more significantly, which has set off the enthusiasm of EGFR-TKIs adjuvant therapy research.

The ADAURA study has pushed this exploration to a climax, expanded the beneficiary population to stage IB-IIIA, and obtained the indications for adjuvant therapy, which truly opened the door to the precise treatment of early lung cancer.

 ALK-TKIs are also being explored in early lung cancer patients with ALK fusion mutations, such as ALCHEMIST-ALK research is ongoing.

In addition, more and more studies have found that immune checkpoint inhibitors have a certain role in neoadjuvant therapy, and multiple immune drugs have also been deployed in adjuvant therapy.
At the end of March this year, the phase III study of adjuvant therapy, IMpower010, announced that it has reached The primary endpoint, DFS, is the first clinical study to show that immunotherapy as an adjuvant therapy can improve DFS in early lung cancer in a phase III clinical trial.
Other immunological drugs such as PEARLS, ANViL, BR31 and other studies are also in progress. ADAURA Phase III study confirms that adjuvant treatment of osimertinib greatly improves the benefit of DFS.
As the world's first registered clinical study for adjuvant treatment of EGFR-TKI, the ADAURA study not only successfully promoted osimertinib to become the world's first approved adjuvant treatment for NSCLC.
It has been written into the National Comprehensive Cancer Network (NCCN) guidelines to completely rewrite the adjuvant treatment strategy for lung cancer.

The key to ADAURA's success lies in the innovation of research design.
These innovations also provide a reference for subsequent clinical research on adjuvant therapy.

First of all, in terms of the selection of the study population, the ADAURA study enrolled stage IB-IIIA EGFR-mutant NSCLC patients after complete resection, which is wider than the population in ADJUVANT and EVAN studies.
The results also confirm that it is in stage IB, II and IIIA patients.
The benefits of DFS for 2 years are consistent, which makes ADAURA the first clinical study in the world that has significant benefits of DFS in patients with stage IB-IIIA, further expanding the applicable population of TKI assistance.

 ADAURA study DFS results Secondly, in clinical practice, for high-risk stage IB patients and stage II-IIIA patients, postoperative adjuvant chemotherapy is usually recommended to reduce disease recurrence.

The ADAURA study more follows clinical treatment principles and ethical considerations in the research design.
It does not adopt the design of targeted head-to-head chemotherapy.
Patients can receive adjuvant chemotherapy first and then receive adjuvant osimertinib or placebo according to the stage.
This design method It can better target and assist the benefiting population.

The data released at the 2020 World Conference on Lung Cancer (WCLC) further suggest that whether or not adjuvant chemotherapy is used, the adjuvant targeted group DFS is better than the placebo group.

Regardless of whether there is adjuvant chemotherapy, the osimertinib group can benefit.
In addition, in the choice of study endpoints, the ADAURA study uses DFS in patients with stage II-IIIA as the primary endpoint, DFS and safety in patients with stage IB-IIIA, etc.
As a secondary endpoint of the study, the method of alpha transmission in Type I error control effectively avoided the negative results that would result from the rash inclusion of stage IB patients in the analysis. In other words, even if there are negative results in the entire population, it can ensure that positive results are obtained in stage II-IIIA patients, which greatly increases the probability of success of the study.

The results also proved that osimertinib completely exceeded the expected curative effect and was unblinded in advance under the recommendation of the independent data research committee.

 Furthermore, the ADAURA study extended the time of adjuvant medication based on the results of previous studies.
All patients received osimertinib treatment for 3 years.

Although there is currently no sufficient evidence to provide the best targeted adjuvant medication duration, in the ADAURA study, the median sustained exposure time of osimertinib was as long as 22.
5 months.
The benefit of DFS may be related to the duration of medication.

The health-related quality of life (HRQoL) data published on the 2020WCLC also showed that during the adjuvant targeted therapy period, the HRQoL of the osimertinib group and the placebo group remained unchanged, and no clinically significant difference was observed between the two groups.

Therefore, extending the time of adjuvant treatment may be the future treatment trend.

 Finally, the osimertinib used in the ADAURA study, as the world's first third-generation EGFR-TKIs, has shown very good intracranial efficacy in the AURA3 study and the FLAURA study; ADAURA studies the recurrence/metastasis of the central nervous system (CNS) Data analysis showed that osimertinib also reduced the risk of brain metastasis or death by 82%.

This shows that powerful intracranial control also adds weight to the success of the research.

Accelerated approval of domestic indications, osimertinib opens the "new world" of EGFR-TKI adjuvant therapy in China In April 2021, the National Medical Products Administration (NMPA) formally approved osimertinib for IB-IIIA EGFR 19DEL or 21 Adjuvant treatment of NSCLC patients with L858R mutation and previous surgical resection, and it is up to the doctor to decide whether to accept or not to accept adjuvant chemotherapy.

The approval of this indication satisfies the long-term unmet needs of adjuvant therapy for patients with early-stage lung cancer in China, although the previous Chinese Society of Clinical Oncology (CSCO) lung cancer diagnosis and treatment guidelines and other domestic normative guidelines and consensus have been based on ADJUVANT research According to the results of the EVAN study, gefitinib and erlotinib are recommended for postoperative adjuvant treatment options for patients with operable stage III EGFR mutations, but they have not been able to obtain the indications for "certified work", which is only used as level II Treatment recommendations.

The approval of osimertinib not only makes osimertinib the only targeted drug that has been dually approved by the U.
S.
Food and Drug Administration (FDA) and NMPA in the adjuvant treatment of NSCLC, it has also changed The pattern of adjuvant therapy for NSCLC patients in China has become a new era of targeted drug adjuvant therapy.

 In addition, the approval of osimertinib will not only further promote the standardization of early stage lung cancer adjuvant therapy in China, avoid the past phenomenon of targeted drug abuse and overtreatment, but also establish a new benchmark for early stage lung cancer adjuvant therapy research, and further improve the future.
The development of multi-innovative research provides guidance and reference.

 From first-line treatment to adjuvant therapy, osimertinib provides treatment options for patients with early, middle and late stages of EGFR.
At present, there are a wide variety of EGFR-TKIs available in China.
A variety of first-, second- and third-generation drugs have been approved for marketing, and clinical options are even greater.
For diversification, whether the "1+3", "2+3" and "3+X" models are better or worse is still the focus of academic debate.

Regardless of economic factors, osimertinib takes the lead with first-line treatment with median progression-free survival (PFS) of 18.
9 months and OS 38.
6 months, making it the preferred recommendation for first-line treatment.

 In the past, due to cost reasons, many patients could not be the first choice for osimertinib treatment, which affected the treatment effect.

In recent years, the government has promoted dozens of expensive anti-tumor drugs and entered the medical insurance catalog through a number of measures such as national drug negotiations and expansion of the medical insurance catalog.
This has provided Chinese patients with more treatment opportunities and greatly reduced the price.
economic burden. The successful inclusion of osimertinib in the medical insurance catalogue is another measure that has benefited the people’s livelihood as a result of the efforts of the government and the full cooperation of pharmaceutical companies.
The cost of osimertinib has been reduced by 64%, and the price has become more affordable to the people.
Japan officially implemented a full-line reimbursement policy for patients with EGFR mutations in advanced NSCLC, which greatly increased the clinical availability of osimertinib, and changed the dilemma of Chinese patients who gave up treatment due to expensive drugs.
It will not only greatly improve the survival time and survival of patients with EGFR mutations.
The quality of life will also achieve a win-win situation between curative effect and pharmacoeconomics, allowing more Chinese patients to benefit from treatment.

  Expert profile Professor Cheng Ying, second-level professor, doctoral tutor, post-doctoral workstation tutor enjoys special allowances from the State Council, and outstanding contributions from the Ministry of Health, young and middle-aged experts, Secretary of the Party Committee of Jilin Provincial Cancer Hospital, Director of Jilin Provincial Cancer Center, Jilin Provincial Cancer Hospital, integrated diagnosis and treatment of malignant tumor clinical research Director of the Center Director of the Jilin Provincial Lung Cancer Diagnosis and Treatment Center Vice Chairman of the Chinese Society of Clinical Oncology (CSCO) Vice Chairman of the CSCO Small Cell Lung Cancer Professional Committee Chairman of the CSCO Clinical Research Expert Committee Vice Chairman of the Chinese Anti-Cancer Association Lung Cancer Professional Committee Vice Chairman of CSCO Non-Small Cell Lung Cancer Vice Chairman of the Professional Committee Vice Chairman of the CSCO Oncology Big Data Expert Committee Vice Chairman of the Lung Cancer Specialty Committee of the Chinese Medical Association Oncology Branch Deputy Chairman of the Chinese Medical Doctor Association Multidisciplinary Cancer Diagnosis and Treatment Committee Deputy Chairman of the Chinese Medical Doctor Association Lung Cancer Training Professional Committee National Doctors Periodic Assessment of Oncology Editors Professional Committee Deputy Chairman Member of the National Health and Family Planning Commission Common Tumor Standardized Diagnosis and Treatment Expert Group Member of the Jilin Provincial Medical Association Oncologist Branch Chairman of the Oncology Professional Committee of the Jilin Provincial Medical Association Chairman of the "Chinese Journal of Oncology" and many others Magazine Editorial Board