In December 2020, the US FDA officially approved osimtinib as the first postoperative adjuvant therapy to treat non-small cell lung cancer patients carrying egfr mutations; in April 2021, China's Drug Administration also approved osimtinib as an indication for postoperative adjuvant therapy.
Subsequently, the multinational Food and Drug Administration (Health Canada [HC], Singapore Health Sciences Authority [has], Swiss Medicines Authority [SMC]) jointly involved in the ORBIS project published an official review in CLIN Cancer Res, summarizing in detail the basis for the approval of osimtinib[1].
In the adaura study, the disease-free survival time (dfs) of the osimtinib group had a significant benefit, and the Markov model was used as evidence to successfully predict the 5-year survival rate of 83.2% of patients, do not underestimate this 83.2%, it is a symbol of cure! No wonder the FDA wants to speak out again for such a top good drug, and make a positive evaluation of the effectiveness and safety of osimertinib in postoperative adjuvant therapy, so that more patients have better options for preventing postoperative recurrence.
Reduces the risk of postoperative recurrence
For patients with early-stage lung cancer, surgery is the most important treatment, and postoperative recurrence is undoubtedly one of the biggest nightmares for patients. According to statistics, the percentage of patients who have relapsed or died after surgery remains high (within two years, 45% of patients with stage Ib and 76% of patients with stage III A) [2, 3]. Therefore, how to reduce the chance of postoperative recurrence, whether to carry out adjuvant therapy after surgery, and whether to use adjuvant chemotherapy or adjuvant targeted therapy have always been concerned.
The adaura study provides strong evidence for lung cancer patients to delay postoperative recurrence. In the Adaura study, a total of 682 patients with stage ib-iiia non-small cell lung cancer with completely removed tumors and carrying egfr mutations were included, comparing the disease-free survival times (dfs) of the two groups after receiving adjuvant targeted therapy with osimerinib and placebo, respectively.
The advantage in disease-free survival time (dfs) means that patients who receive postoperative targeted adjuvant therapy will have more potential survival benefits. The results of the study show that the use of osimpirantinib after surgery can significantly prolong the patient's disease-free survival time (dfs), reduce the risk of recurrence or death for patients, and the long-term survival probability of patients is as high as 83%; this data is unprecedented in the current lung cancer research field, bringing hope for cure for postoperative lung cancer patients.
Figure 1
Figure 2
Adaura study DFS survival curve (Figure 1, stage II-IIIA patients; Figure 2, IB-IIIA patients) [1]
Data from studies have shown that all patients with stage IB-IIIa non-small cell lung cancer who are egfr positive are enrolled in postoperative adjuvant therapy, including stage IB. At the same time in the adaura study, enrolled patients were allowed to have previously received adjuvant chemotherapy; surprisingly, osimatinib was effective for all enrolled patients, regardless of whether they had received adjuvant chemotherapy or not. This also provides a good basis for exploring whether adjuvant chemotherapy + adjuvant targeting benefits more than adjuvant chemotherapy alone or adjuvant targeting.
In the "Guidelines for Adjuvant Therapy after Complete Resection of Stage i to IIIB Non-Small Cell Lung Cancer (2021 Edition)", the use of osimertinib and a generation of tki are mainly recommended as postoperative adjuvant therapy, and the use of osimimil is particularly recommended. So what is it that makes osimertinib so brilliant in preventing postoperative recurrence?
The postoperative recurrence model shows that when patients receive a generation of tki postoperative adjuvant therapy, the most common site of distant metastasis is the central nervous system (cns), that is, brain metastases [4], while osimertinib has central nervous system (cns) activity, which is more likely to penetrate the blood-brain barrier of normal adults, occupying the high ground of the "central nervous system" [5], showing excellent intracranial efficacy. To a large extent, the common problem of brain metastases in the adjuvant treatment of tki is largely addressed; patients benefit from DFS and have also become the approved criteria for osimertinib as a postoperative adjuvant targeted therapy.
The Markov model predicts a median overall survival (os) of 11.42 years after surgery with oscitinib adjuvant therapy!
In the Adaura study data, the OS data is not yet mature, but researchers around the world can't wait to predict the possible OS benefits of the Oscitinib group through various models, and today, we will also verify it through the Markov model.
The Markov model, like a "digital in the cloud" clinical trial, inferred the patient's local recurrence time (LRR) and distant metastase site (DM) from a standard parametric model to simulate the lifetime course of patients with IB–iiia egfr-sensitive mutation-positive non-small cell lung cancer; and a combined risk comparison method was used to analyze the overall survival (OS) of patients in the oscitinib group.
Figure 3: Disease-free survival time is simulated on 5-year, 10-year, and 20-year nodes
Based on this model, it is speculated that osiminib treatment can prolong the expected survival of patients with stage ib-iiia egfr mutation non-small cell lung cancer compared with placebo, with a 5-year survival rate of up to 83.2% and a median survival time of more than 11 years. We all know that for cancer patients, 5 years is cured, and the survival time of more than 10 years is a great breakthrough on the road to lung cancer cure.
Whether it is disease-free survival time (dfs) or overall survival (os), we can see that oscitinib showed overwhelming efficacy compared to the placebo group, and the comments of the FDA and the multinational food and drug administration once again praised the top good drug of osimertinib!
Let targeted therapy benefit more lung cancer patients
Lung cancer is one of the most common types of cancer in the world and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer accounts for about 80% of the total lung cancer. Approximately 35 percent of patients with non-small cell lung cancer carry epidermal growth factor receptor (egfr) mutations[6]. Mutations in this protein can cause rapid cell growth and help the cancer spread, so the need for disease treatment is more urgent in egfr-positive patients, including patients with earlier stages. Although 30% of patients with confirmed lung cancer can have their tumors removed surgically [7], how to reduce the risk of recurrence in postoperative lung cancer patients and improve the quality of life of patients has always been the goal of clinical research.
Osimerinib was first approved by the FDA in 2015 for the treatment of patients with egfr-positive, drug-resistant non-small cell lung cancer with t790m mutations. Approved in 2018 for extended indications for first-line treatment of patients with metastatic non-small cell lung cancer with egfr exon 19 deletion or exon 21 l858r mutation in tumors. From the second-line use for t790m drug-resistant mutations, to the first-line sensitive mutations that can be used directly, to the potential therapeutic benefits for surgical lung cancer patients today, the therapeutic potential of this targeted drug has been continuously tapped! At the same time, we also expect other targeted drugs to continue to explore like osimertinib to extend the survival time for more patients.
bibliography: 1https://mp.weixin.qq.com/s/u2yfeumxjb-osr77pw2lug 2 kris mg, gaspar le, chaft je, et al. adjuvant systemic therapy and adjuvant radiation therapy for stage i to iiia completely resected non-small-cell lung cancers: american society of clinical oncology/cancer care ontario clinical practice guideline update. j clin oncol 2017;35:2960-2974. 3 pignon j-p, tribodet h, scagliotti gv, et al. lung adjuvant cisplatin evaluation: a pooled analysis by the lace collaborative group. j clin oncol 2008;26:3552-3559. 4 n engl j med 2020; 383:1711-1723.doi: 10.1056/nejmoa2027071 5doi: 10.1200/jco.2018.78.3118 journal of clinical oncology 36, no. 33 (november 20, 2018) 3290-3297. 6 shigematsu h, gazdar af. somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. int j cancer. 2006 jan 15;118(2):257-62. doi: 10.1002/ijc.21496. pmid: 16231326. 7 datta d, lahiri b. preoperative evaluation of patients undergoing lung resection surgery. chest 2003;123:2096-2103.
Author: Mi Jian Xiao Shu
Editor-in-Charge: Mi Jian Xiao Shu
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