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    Home > Medical News > Medical World News > Four generations of EGFR inhibitors: opportunity or chicken ribs?

    Four generations of EGFR inhibitors: opportunity or chicken ribs?

    • Last Update: 2020-10-22
    • Source: Internet
    • Author: User
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    Leaves lung cancer is the most common cancer species in the world, of which about 85% are non-small cell lung cancer (NSCLC), while most NSCLC patients with exons 19 or 21 often mutate (45% and 40%, respectively), and activate the tyrosine kinase domain subjects (EGFR) in the skin growth factors, leading to further proliferation and differentiation of malignant tumor cells.
    discovery of EGFR tyrosine kinase inhibitors (TKI) is considered a milestone in the treatment of lung cancer.
    EGFR-TKI first-line therapeutic sensitivity EGFR mutations extend PFS, improve health-related quality of life, and reduce serious treatment-related side effects compared to patients receiving standard chemotherapy.
    EGFR mutation occurs in about 38.4% of patients in China, compared with 14.1% in Europe (Oncotarget, Vol. 7, No. 48:78985).
    EGFR-TKI has now developed to the third generation, especially the third generation of the drug oxytinib, but also created the LONGEST mPFS and mOS in the history of EGFR-TKI, reaching 18.9 months and 38.6 months, respectively, is undoubtedly a new peak in the history of treatment.
    drug resistance is an eternal topic, and oxytinib is no exception, leading to the development of EGFR's fourth-generation drugs.
    four-generation EGFR drug positioning is mainly focused on the fight against oxytinib resistance, especially C797S drug resistance mutations, strategically also through the development of targeted C797S, T790M/C797S, L858R/T790M/C797S or/and ex19del/T790M/C797S.
    if we want to be clear about whether four-generation EGFR drugs are an opportunity or chicken ribs, let's start by thinking about three questions: The name: the name is not there, what is the name? The concept of four-generation EGFR drugs is to solve the problem of oxytinib resistance, mainly refers to the C797S mutation.
    , however, a 2019 literature shows that the first- or second-line drug resistance spectrum of oghithini is also changing.
    by testing circulating tumor DNA (ctDNA) in patients participating in the Oghitini AURA3 trial, the probability of C797S mutation was approximately 14%, which was reduced to 7% in first-line medications (BrJ Cancer. 2019; 121:725-737).
    : Br J Cancer. 2019; 121:725-737 The same trend was reported at the 2019 ASCO Conference, where studies from memorial Sloan-Kettering Cancer Center showed that Ohidini's primary and back-line treatments showed different drug resistance spectrums.
    by collecting 71 cases of tumor tissue in patients treated with oxitinist, histological transformation occurred in 19% of initial cases and 14% of all cases.
    The early emergence of drug resistance mechanisms rarely included targeted resistance (1/16 cases of obtained EGFR G724S mutations), and the potential resistance mechanisms for obtainability included CCNE1 and MYC amplification, as well as MTOR and MET H1094Y mutations.
    also notes that histological transformation (including scaly cell transformation) is the primary drug-resistant mechanism in first-line therapy, and that these are not accurately detected in plasma testing (ctDNA) and have disappeared from C797S.
    2019 ASCO Poster 9028 of course, these two studies do not fully represent the real world, especially the 2019 conference report, after all, included a smaller patient population (71 cases).
    , however, as a scientific study or drug development, how can this trend be ignored?
    There is no way: confidants know each other, a hundred wars are not so-called confidants know each other, a hundred wars are not lost, since the pair of Ogichtini, then, Oghidini in the real world how to perform.
    1. The market size and crowd size of Oghidini, which debuted in China in 2017, has seen a significant increase in sales despite rising sales, after second-tier medications were included in the coverage of Medicare reimbursements.
    , according to medical Rubik's Cube data, in 2019 Oshidini domestic sales exceeded 2 billion yuan, it seems that Oghidini has a huge market share, in fact, it is not.
    According to the medical Rubik's Cube winning database, the winning bid price of ochitinist is 510 yuan / grain, let alone that the patient is fully tolerated, using oral daily recommended drug treatment program, the annual cost of the individual is about 18. 60,000, the population of about 12,000 people, regardless of the domestic lung cancer patient stock, only compared to 780,000 new lung cancer patients in 2015, the accessability of oxytinibs still has great room for improvement.
    can say that for the simple pursuit of market thinking, four generations of EGFR drugs is not desirable.
    because of the domestic second-line drug eligibility into health insurance, combined with the growth of sales point in time and trend, there is reason to believe that the current domestic use of oxytinist patients are mainly second-line treatment.
    In addition, the domestic three-generation drug amedinib and other products have been approved and listed, as well as the patent period of Oghidini, it can be expected that Oghithini and the other three generations of EGFR-TKI's main battleground must be in the first-line drug.
    in the first-line drug, the probability of C797S occurrence is a big problem after all? 2. The therapeutic potential of oxytinib is unquestionable, but the two four-generation EGFR drugs currently in clinical use do not appear to show central system activity.
    and in searchable clinical studies, four generations of drugs have excluded patients with symptomatic central system transfer.
    how can patients who voluntarily give up brain metastasis, when they are labeled oxytinibs, not have drug-resistant mutations?" It is well known that the central system metastasis of cancer is an important cause of death, and the current domestic patients are mainly in second-line treatment, no brain metastasis of patients will have how many? Does this have an impact on the clinical patient recruitment and research process of the drug? First of all, Oghitini has a better central system disease control role.
    the literature (BrJ Cancer. 2019; 121:725-737) and ESMO2020 conference data show that oxytinib has a better disease control effect on brain-turned patients and reduces recurrence.
    in Clinical Phase III.phase (AURA3) studies, the second-line use of Ositeni's medium CNS PFS was 11.7 months, while chemotherapy was only 5.6 months (HR: 0.32; 95% CI: 0.15-0.69; P -0.004).
    at the ESMO conference in 2020, the ADAURA study once again highlighted the role of oxytinib in controlling CNS patients.
    had a lower recurrence or mortality rate than placebo (11% vs 46%), the mid-level time of CNS lesions recurrence was not reached and 48.2 months, respectively, and the CN of the Oghidini group S recurrence rate is significantly lower (1% vs 10%), HR is 0.18 (95%, 0.10-0.33, P<0.0001).
    source: ESMO20203. L858R or ex19del currently available four-generation EGFR drugs, in addition to single-target C797S and dual-target T790M/C797S, there is a class of L858R/T790M/C797S or/and ex19del/T790M/C797S.
    this is also the field of Oxitinib's advantage, once the Oghithini C797S drug-resistant mutation spectrum is offset, the fourth generation of EGFR drugs will face the three generations of TKI competition represented by oxytinib.
    , I'm afraid Oghidini's patent period is over and Oghidini's generics will be on the stage.
    to this point, you might as well look at a four-generation EGFR drug, BLU-945.
    also at the 2020 ESMO conference, BLU-945 disclosed preclinical research data that, while also targeting ocythione, provided us with ocythione's cellular activity.
    source: ESMO2020 can be seen that Oghithini on L858R or L858R/T790M and ex19del or ex19del/T790M will have a strong inhibitory effect;
    is Ossiny's in vitro data translated into in vivo effectiveness? The answer is given in the analysis of the results of the FLAURA study of Chinese patients in ESMO2020.
    this study is an international multi-clinical study of the Chinese subgroup analysis, the design of the experiment has been L858R or ex19del as one of the criteria for patients into the group, and eventually the Oghithini group recruited a total of 71 Chinese patients.
    source: ESMO2020 Final study analysis shows that flaURA China subgroups are in line with international studies, and Oghitini also embodies good disease control and long-term total survival benefits, with OS reaching 33.1 months.
    source: ESMO2020 Because Oztini is still in the patent period, even if already facing competition from domestic three-generation TKI, the current price is still out of reach for most patients.
    whether Oghidini will succeed in the upcoming health-care negotiations, we'll see.
    , however, time is always not allowed to wait, especially for about half of rural patients (in the 2015 analysis of the prevalence of malignant tumors in China).
    recently, Grigg Ingham published the final analysis of the GioTag study, which may be worth referring to.
    GioTag is a real-world, retrospective, observational study designed to evaluate the efficacy of first-line afatinib in patients with advanced non-small cell lung cancer in EGFR M plus (Del19, L858R) and the emergence of T790M mutations after failure, and second-line prologue ocytinib therapy.
    of the 203 patients included in the analysis, the medium total survival (OS) of patients treated with afatinib sequential oghithinib was 37.6 months (90% CI:35.5-41.3) and the time of failure of the medium treatment (TTF) was 27.7 months (90% CI: 26.7-29.9).
    asian patients and Del19 patients had a total survival of 44.8 months and 41.6 months, respectively, and the total survival of the middle was 45.7 months for Asian patients with a combined Del19.
    Source: Bronger Ingeham China's official website Afatini has two generic drugs on the market, the original drug has also been included in health insurance, although the overall competition is not very fierce, but also a patchwork of three, under the collection, patient affordability is strong.
    in particular, the failure of the medium treatment for more than two years (27.7 months) meant that half of the patients treated were still receiving treatment after two years, and that the accessability of oxytinist had changed two years later.
    the fourth generation of EGFR drugs on the market, even if oghithini is still in the patent period, I am afraid that from an economic point of view, therapeutic effects (including brain rotation) and survival considerations, for EGFR L858R or ex19del mutation patients, the preferred drug may not be the new four generations of EGFR.
    of course, once carrying C797S, it becomes a potential drug user of four generations of EGFR drugs, so the bet on four generations of EGFR drugs remains the C797S mutation.
    4. AstraZeneca's consideration is not known, since oxytinist mutation resistance is objective, especially the C797S mutation.
    we can see that more and more Oghitini united is beginning to increase.
    although some of the co-uses do not appear to be related to the C797S, such as oxytinib and Met inhibitors.
    may also be exploring the effects of co-therapy against C797S mutations, regardless of the results, but as researchers of four generations of EGFR drugs, we should also be concerned about the changes behind these phenomena, such as whether the drug resistance spectrum after co-use has changed, and whether the rate of C797S mutations has been affected by co-drug therapy.
    Embroidery Spring Knife: Shuro Battlefield, the beginning of the 1. Shun, anti-C797S mutation to say back, Oseitini for the C797S mutation is not useless, no way, when the C797S mutation into a trans-structure (Trans), you can choose a joint generation (Elotini, Gifeitini) to continue treatment.
    , and in the latest NCCN guidelines, it is recommended to continue receiving esotinib treatment in different drug-resistant situations.
    Clin Cancer Res; 21 (17): 39242. Amivantamab-lazertinib Amivantamab (JNJ-6372) is a dual-specific antibody targeting EGFR and MET that not only blocks ligand binding to EGFR and MET, promotes the degradation of the subject, but also triggers antibody-dependent cytotoxicity.
    Lazertinib is an efficient, oral, irreversible third-generation TKI that is being developed to treat NSCLC patients with EGFR gene mutations.
    The clinical study of the Amivantamab injection/Lazertinib tablet combination was published on September 15, 2020 in CDE, and the adaptations included NSCLC patients who were used to treat EGFR 19 exon loss or L858R activation mutations, and who were treated with oghitinib or other approved third-generation EGFR TKI and progression of the disease after platinum-containing double-drug chemotherapy.
    the latest clinical data at this year's ESMO conference.
    the dose-expanding cohort in the study and assessed the effectiveness of Amivantamab-Lazertinib in patients in the osetinib-resistant group (n-45).
    although Amivantamab had previously disclosed data on the effectiveness of single-drug treatment C797S (ASCO2019), 10 of the 47 patients treated with 3-generation TKI, including 4 patients with C797S mutations, received PR.
    in this joint therapy study, although the effectiveness of resistance to oxytinist has been confirmed again, the effectiveness of the drug resistance mechanism.
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