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The Lancet: What about EGFR-TKI resistance in lung cancer patients? Chinese scientists have a new method

Time:2022-12-10 05:58:56 author:Prevent anxiety Read:611次
The Lancet: What about EGFR-TKI resistance in lung cancer patients? Chinese scientists have a new method

About 70% of Chinese non-small cell lung cancer patients are non-squamous non-small cell lung cancer, and about 40% to 50% of non-squamous non-small cell lung cancer patients with EGFR mutation [1]. According to the 828,000 new cases of lung cancer in 2016, there are about 230,000 to 290,000 new cases of EGFR-mutated non-squamous non-small cell lung cancer in my country every year [2]. Currently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment options for non-squamous and non-small cell lung cancer patients with EGFR-sensitizing mutations. Existing EGFR-TKIs at home and abroad are very rich, including dozens of first-generation TKIs, second-generation TKIs, and third-generation TKIs. However, it is frustrating that patients with EGFR mutations will eventually develop drug resistance after being treated with EGFR-TKIs [3], and the treatment options after drug resistance are very limited, and the efficacy of traditional platinum-containing chemotherapy is not effective. Ideally, the army of cancer cells would soon "come back", causing the tumor to recur or grow. Therefore, the problem of drug resistance and the choice of treatment after drug resistance have become one of the focuses of clinical attention. The results of a new study, Orient-31, recently published in the journal Lancet Oncol, bring new hope to patients with non-small cell lung cancer who have developed resistance to EGFR-TKIs. The Orient-31 study, led by Professor Lu Shun from the Chest Hospital Affiliated to Shanghai Jiaotong University, and participated by 52 sub-centers, is a randomized, double-blind, multi-center prospective phase III clinical trial. - Significant survival benefit in patients with non-small cell lung cancer resistant to TKIs. Figure 1: Screenshot of clinical trial registration[4]

The treatment dilemma of EGFR-TKI-resistant patients

In the past, EGFR-positive patients were If drug resistance occurs after EGFR-TKI treatment, only platinum-containing doublet chemotherapy or bevacizumab can be selected. Transfer, there are not many options to choose from in the follow-up [5]. Continued use of EGFR-TKIs will not benefit patients. In recent years, the use of immune checkpoint inhibitors has brought new treatment options for cancer patients, especially in driver gene-negative NSCLC patients. So can EGFR-TKI-resistant patients break through the bottleneck through immunotherapy? Regrettably, for EGFR-positive patients, the previous target-immunization regimens mostly ended in failure:
  • Some studies suggest that compared with standard treatment regimens, they fail to improve the patient's self-efficacy. Progression survival;
  • Some studies terminated clinical trials early due to intolerable toxicity.
In addition, most immune-related clinical studies exclude EGFR mutation-positive patients at the time of enrollment. Figure 2: Summary of previous clinical trials in EGFR-TKI-resistant NSCLC When the subgroup analysis data of the IMPOWER150 study were published, there was a glimmer of hope for new treatment options for the EGFR-TKI-resistant population. In a post hoc analysis, the study found that the use of bevacizumab + atezolizumab + chemotherapy compared with a population control group demonstrated better efficacy in EGFR-positive and EGFR-TKI-resistant patients. However, the number of patients with EGFR mutations is small, accounting for only 10% of the total population, and the results are from post-hoc analysis, which does not answer the contribution of immunotherapy and anti-angiogenic therapy respectively. The results of the Orient-31 study further verified the feasibility of a similar regimen: the regimen of immunotherapy + anti-angiogenesis targeted therapy + chemotherapy, compared with standard treatment (chemotherapy alone), significantly prolonged the progression-free survival of patients. A total of 444 eligible patients with metastatic EGFR-mutant non-squamous non-small cell lung cancer (18-75 years old, PS score 0-1, squamous cell component >10%, and disease progression after EGFR-TKI therapy) were included in this study. ), were randomly assigned to receive the following 3 treatment regimens:
  • sintilimab + bevacizumab + chemotherapy;
  • Sintilimab + chemotherapy;
  • chemotherapy alone.
  • Study allows for crossover of sintilimab. Figure 3: The clinical trial of sintilimab combined with bevacizumab combined with chemotherapy [6] is the first interim analysis published in LANCET ONCOL, showing:
    • Compared with the chemotherapy alone group, the median progression-free survival (mPFS) of the sintilimab + bevacizumab + chemotherapy group was significantly improved, from 4.3 months to 6.9 months, and the data was statistically different.
    • Sintilimab+bevacizumab+chemotherapy group vs chemotherapy group PFS rate at 6 months was 59% vs 30%; 12 month PFS rate 28% vs 12%, respectively.
    • In terms of safety, sintilimab + bevacizumab + chemotherapy group vs sintilimab + chemotherapy group vs chemotherapy group, due to adverse effects of any grade The incidence of reactions was 98% vs 96% vs 97%, and the incidence of grade 3 and above adverse reactions was 55% vs 39% vs 51%, respectively. The more common grade 3 or higher treatment-related adverse reactions included neutropenia, leukopenia, and anemia. The safety of the two groups was basically similar, and the safety was controllable.
    At the ESMO conference held in September 2022, the results of the second interim analysis brought more surprises to people [7]. The results showed:
    • sintilimab + bevacizumab + chemotherapy group vs sintilimab + chemotherapy group vs mPFS (95%CI) in the chemotherapy group was 7.2 months (6.6, 9.3), 5.5 months (4.5, 6.1), and 4.3 months (4.1, 5.3)
    • The PFS benefit of sintilimab+bevacizumab+chemo vs chemotherapy was consistent with the first interim analysis.
    • Sintilimab + chemotherapy group vs chemotherapy group achieved a significant and clinically meaningful prolongation of mPFS with a hazard ratio (HR) of 0.723 (95%CI: 0.552, 0.948, P=0.0181), reaching the preset superiority standard.
    • In addition, the objective response rate (ORR) and duration of response (DOR) were also improved in the sintilimab + chemotherapy group compared with the chemotherapy group.
    However, the overall survival (OS) data is immature at present, and longer follow-up time is required, and we also look forward to the publication of the OS data. In conclusion, the Orient-31 study has brought new hope to these EGFR-TKI-resistant patients, and it has also given a boost to the long-daunted field of drug development. This research result confirms the huge application prospect of immunocombination therapy in such non-small cell lung cancer patients, meets the treatment needs of more patients, and brings new treatment options and hope for them. However, there are still some unresolved problems:
  • We hope to add a chemotherapy + bevacizumab treatment group in the future program design, so as to more clearly analyze immunotherapy and anti-vascular Generating the clinical value of targeted therapy separately.
  • The current OS data is immature. At present, this program prolongs the progression-free survival of patients, but whether it can translate into longer overall survival is unknown.
  • There are many similar phase III clinical trials of immune combination therapy underway: Figure 4: Ongoing phase III clinical trials of immune combination therapy after EGFR-TKI resistance We look forward to the early release of these data and the future There are more immunocombination treatment options to help patients with EGFR-TKI resistance to break through the treatment predicament. Disclaimer: This article is only the content of medical science and cannot replace the diagnosis and treatment opinions of clinicians. For specific circumstances, please refer to the diagnosis and treatment opinions of the attending physician. Reference: [1] Wang R, Zhang Y, Pan Y, et al. Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients[J]. Oncotarget, 2015, 6(33):34300-8. [2] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209 -249.[3] Gou LY, Wu YL. Prevalence of driver mutations in non-small-cell lung cancers in the People's Republic of China[J]. Lung Cancer (Auckl), 2014, 12(5):1-9 .[4] Sintilimab ± IBI305 Plus Chemotherapy (Pemetrexed + Cisplatin) for EGFRm + Locally Advanced or Metastasis Non-Squamous NSCLC Patients After EGFR-TKI Treatment Failure(EB/OL).[2022-09-14].https://[5] Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first- line gefitinib (IMPRESS): a phase 3 random ised trial[J]. Lancet Oncol, 2015 Aug;16(8):990-8.[6] Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non -squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23 (9):1167-1179.Epub 2022 Jul 28.[7] Lu S, Wu L, Jian H, et al. Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer ( EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: Second interim analysis of phase III ORIENT-31 study[J].Annals of Oncology, 2022, 33 (suppl_7): S808-S869.


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