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    Home > Active Ingredient News > Antitumor Therapy > 2022 ESMO Prof. Wen Xia: Oral SED's research explores current twists and turns, but it is still worth looking forward to

    2022 ESMO Prof. Wen Xia: Oral SED's research explores current twists and turns, but it is still worth looking forward to

    • Last Update: 2022-10-01
    • Source: Internet
    • Author: User
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    What are the latest research advances in oral SERD? What are the clinical implications behind it? Hurry up and punch in




    For HR+/HER2-breast cancer, endocrine therapy is indispensable



    Flovestrane has obvious advantages and is an important choice for endocrine therapy for breast cancer, but because injectable dosage forms may limit the use of such therapies, this has prompted the industry to start looking for a more convenient and more accessible new drug dosage form



    Recent research advances in oral SERD


    At present, a number of oral SERD have published Phase I II research data and attracted much attention, this paper focuses on ESMO conference reports, taking stock and analyzing the latest research progress of Menarini's oral SERD Elacestrant, Roche's Giredestrant, and Cerofi's Amcenestrant for the benefit of readers




    Amcenestrant's AMEERA series of studies has been full of twists and turns, and in Amcenestrant's Phase I/II AMEERA-1 study, Amcenestrant and Pipercil confirmed an ORR of 5/46 (10.



    The Phase II AMEERA-3 study was designed to evaluate the efficacy and safety


    Figure 1.



    Not only that, but Amcenestrant's Phase III AMEERA-5 study also failed, and based on the findings, in August of this year, Cerlofi officially announced that it would stop all of Amcenestrant's global development programs
    .

    The failure of Amcenestrant has undoubtedly sounded the alarm for the development of oral SERD
    .


    Research advances related to Giredestrant

    Giredestrant's previously published findings have shown good antineoplastic activity and tolerance in advanced breast cancer, either monotherapy or combination
    .

    Giredestrant's Phase I study, for example, showed [6] that Giredestrant showed good efficacy in patients with locally advanced or metastatic ER+/HER2-breast cancer who had previously received ≤ 2 treatments, and was equally effective
    in patients with ESR1 mutations.

    However, Giredestrant's Phase II acelERA BC results suffered a setback, and as early as April today, Roche published that the study failed to meet the main study endpoint of improving PFS,[7] and the detailed data was published
    at the ESMO conference.

    The Phase II acelERA BC study included advanced ER+/HER2-breast cancer who had previously undergone ≥2-line therapy (which must include endocrine therapy) to explore the efficacy and safety
    of Giredestrant as second- or third-line therapy compared with physician-selected endocrine therapy (PCET, fluvisran, or aromatase inhibitor).

    According to the data released this time[8], the CBR of Giredestrant and PCET group was 31.
    8% and 21.
    1%, respectively.
    The ORR was 12.
    6% and 7.
    2%,
    respectively.

    The investigators assessed PFS at 5.
    6 and 5.
    4 months, respectively, with HR=0.
    81 (95% CI: 0.
    60, 1.
    10, p=0.
    18).


    The OS data is immature
    .

    The results showed that acelERA BC did not meet the primary endpoint of INV-PFS and that Giredestrant only showed an improvement
    over PCET values.

    This seems to be another blow to the exploration of the emerging oral SERD
    .

    However, CBR and ORR values are higher, and it is worth noting that the benefit of PFS is more significant
    in patients with ESR1 mutations.

    Giredestrant appears promising in patients with ESR1 mutations, but larger sample size studies are needed to validate this
    .

    Figure 2.
    Primary and minor endpoints of the acelERA BC study (PFS results)

    Although Giredestrant's research in advanced breast cancer has not been satisfactory, its performance in the field of neoadjuvant therapy for early breast cancer is gratifying, and the Phase II coopERA study compares the efficacy and safety
    of Giredestrant and anastrozole in combination with piperoxie in the use of ER+/HER2-early breast cancer neoadjuvant therapy, respectively.

    The final analysis results showed [9] that the Giredestrant plus pipexilid group observed stronger inhibition of Ki67 during surgery than the anastrozole plus pipexilid group and achieved a greater degree of complete cell cycle block (CCCA; Ki67 ≤2.
    7%)

    But the ORR was similar in both groups (50% vs 49%)
    .

    The results of the biomarker subgroup analysis of the study[10] were published and the decline in Ki67 levels in the Giredestrant combination group for 2 weeks was observed in tumors with high-risk features such as high ACC stage, positive lymph nodes, and progesterone receptor (PgR)
    -negative.

    And ER and PgR proteins have also been observed to decline
    significantly.

    Figure 3.
    Biomarker analysis results of the coopERA study

    Not only that, Giredestrant has also actively explored
    in the field of adjuvant therapy for early breast cancer.

    LidERA is a phase III study comparing Giredestrant with endocrine monotherapy in patients with ER+/HER2-early breast cancer [11] and is currently ongoing
    .


    Research advances related to Elacestrant


    Although the above two oral SERD drugs have failed, it does not mean that oral SERD will continue to decline, and the emergence of Elacestrant brings hope
    to the development of oral SERD drugs.

    In its Phase III EMERALD study, patients who had previously received 1 or 2 endocrine treatments were included, and all patients were treated
    with CDK4/6 inhibitors.

    Randomized to Elacestrant and standard endocrine therapy groups (SOCs, including fluvixen, anastrozole, letrozole or ezemeter).


    The primary endpoint of the study was PFS in the general population and in patients with ESR1 mutations
    .

    Results published by SABCS in 2021 show [12] that the study reached two main endpoints
    .

    In the total population, the median PFS in the Elacestrant and SOC groups was 2.
    79 months and 1.
    91 months, respectively (HR=0.
    697 [95% CI: 0.
    552 to 0.
    88]; P=0.
    0018)

    In the ESR1 mutant population, the median PFS in both groups was 3.
    78 months and 1.
    87 months, respectively (HR=0.
    546 [95% CI: 0.
    387 to 0.
    768]; P=0.
    0005)

    The 2022 ESMO conference announced the results of the study's analysis of Elacestrant versus different endocrine therapeutic drugs[13], and Elacestrant had significant PFS benefits
    over flavixogroup and AI in both the general population and the ESR1 mutant subgroup.

    The potential
    of Elacestrant monotherapy in the second- or third-line treatment of ER+/HER2-advanced/metastatic breast cancer was further validated.

    Figure 4.
    PFS results of the EMERALD study

    Based on this research, the FDA has granted Elacestrant priority review in August this year,[14] which means that Elacestrant is expected to become the first oral SERD drug
    to be approved for marketing.

    At the same time, Elacestrant's success has re-established the confidence
    of researchers to continue to explore oral SERD.

    Expert reviews

    Flovissan is a serotonic SED, which has been fully confirmed by a series of previous studies in HR+ advanced breast cancer, and has become one of the cornerstones of
    endocrine therapy for HR+/HER2-advanced breast cancer.

    As early as the beginning of the advent of flovixan, there were attempts to develop oral dosage forms of
    SERD.

    The novel oral SERD class is chemically modified to improve the solubility and polarity of ER degraded compounds, and further improves bioavailability after several updated iterations [15
    ].

    And it is more convenient in the way of medication, which can effectively increase the patient's treatment compliance
    .

    However, while improving bioavailability and ease of use, whether its efficacy is better than flovixazole is a question
    being explored.

    In addition, ESR1 mutation is a difficult point in endocrine therapy, compared with flavirsten, whether oral SERD shows more advantages is also a hot topic of
    clinical concern in the future.

    Through this year's ESMO study data, we also draw some clinical implications
    .

    First of all, oral SERD and fluvixaphone are effective PK, which is better or worse?

    For patients with HR+/HER2-advanced breast cancer, flovixazole monotherapy or flovixoside combined with CDK4/6 inhibitors are commonly used as the standard treatment options
    for advanced stages.

    For the three oral SERD drugs mentioned above, from the perspective of the study enrollment population, the EMERALD study (100%) and the AMEERA-3 study (80%) both included a higher proportion of CDK4/6 inhibitor treated patients, while the acelERA BC study enrolled only 40% of CDK4/6 inhibitor-treated patients
    .

    In contrast, the EMERALD study enrolled a more backward population, which may be one of the reasons for the shorter PFS
    .

    In addition, it is worth noting that the proportion of patients with endocrine therapy drugs selected by doctors for florvestrone in the control group of the above clinical studies is high, and the three studies are 69%, 90% and 75% respectively, which can be said to be the main comparison with flavix.


    However, only EMERALD studies have achieved statistical differences in the total population, and this ESMO analysis of the efficacy of comparative flovixoset is consistent with
    the whole population.

    The other two oral SERs did not see a significant difference in efficacy, so there is no additional benefit in efficacy in addition to the dosage form advantage, and of course, more data are needed to confirm
    .

    Figure 5.
    Comparison of 3 oral SERD clinical studies

    Second, can oral SERD overcome endocrine therapy resistance caused by ESR1 mutations?

    Both clinical and preclinical studies [16-18] have shown that ESR1 mutations are mainly enriched in recurrent metastatic breast cancer after endocrine therapy, especially AI therapy, and can reach 30-40% in endocrine-resistant patients [19].


    And researchers have found that all patients with the ESR1 mutation have previously received AI treatment [20].


    Retrospective analysis of SoFEA and PALOMA-3 trials [22] showed that after AI treatment, those who could carry ESR1 mutations using ctDNA were still relatively sensitive to the treatment of flavirs, and subsequent combined SoFEA and EFECT analyses also confirmed the prognostic advantage of florvestrant in patients with ESR1 mutations [23].


    Therefore, for AI-resistant patients with ESR1 mutations, treatment options
    containing fluvivitres can be tried.

    Better overcoming resistance caused by ESR1 mutations is one of the engines on oral SERD, but what about specific efficacy?

    From the data of the study itself, for the ESR1 mutation subgroup, only Elacestrant currently had a significant benefit over the endocrine therapy drug selected by doctors, and the median PFS in the two groups was 3.
    8 months and 1.
    9 months (HR=0.
    65, P=0.
    0049),
    respectively.

    Two other oral SERD PFS had only numerical advantages, with Amcenestrant HR=0.
    9 and the study also discontinued; Giredestrant's PFS HR=0.
    6, P=0.
    06, considering the sample size, although no statistical difference was obtained, showed potential, and further data were
    needed.

    Suggesting that for patients with ESR1 mutation, the efficacy of different drugs may also vary greatly, and more data are expected to be explored
    .

    Figure 6.
    Treatment benefit of three oral SERD drugs in the ESR1 mutant subgroup

    Summary and outlook

    From the above research progress, although the research and development of oral SERD is not smooth, its exploration road is far from over, such as Giredestrant, Elacestrant is still continuing to carry out follow-up clinical layout, and many domestic and foreign pharmaceutical companies have achieved preliminary results in the field of oral SED research and development or are laying out
    .

    All these show that the application prospect of oral SERD is still worth looking forward to, and I hope that more research data can be disclosed as soon as possible to further enrich the endocrine treatment strategy
    of HR+/HER2-breast cancer.

    Expert profile

    Xia Wen

    Deputy Chief Physician, Department of Internal Medicine, Center for Cancer Prevention and Treatment, Sun Yat-sen University, Master Supervisor

    Ph.
    D.
    , Peking Union Medical College (Tsinghua University School of Medicine).

    The 6th "Yangcheng Youth Good Doctor"

    Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Association of Research Hospitals

    Member of the Standing Committee of the Breast Disease Prevention and Treatment Committee of Guangdong Society of Chest Diseases

    Member of the Youth Committee of the Breast Cancer Professional Committee of the Guangdong Anti-Cancer Association

    Member of the Genetic Oncology Professional Committee of Guangdong Anti-Cancer Association

    Member of the Breast Cancer Professional Committee of Guangdong Chest Cancer Prevention and Control Research Association

    JCO Chinese Youth Editorial Board Member
    of University Hospital, Cleveland affiliated with Case Western Reserve University, and Pitie-Salpetrere, Paris, France
    .

    CN-103093 Expiration Date: 2023-9-22

    Disclaimer: This material is supported by AstraZeneca and is for the information of healthcare professionals only

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