Авапритиниб: новый тирозинкиназный ингибитор для лечения метастатических гастроинтестинальных стромальных опухолей. Обзор литературы и клиническое наблюдение

Филоненко Д.А., Медведева Б.М., Мещеряков А.А. Авапритиниб: новый тирозинкиназный ингибитор для лечения метастатических гастроинтестинальных стромальных опухолей. Обзор литературы и клиническое наблюдение. Современная Онкология. 2020; 22 (4): 96–100. DOI: 10.26442/18151434.2020.4.200409

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Filonenko D.A., Medvedeva B.M., Meshcheryakov A.A. Avapritinib: a new tyrosine kinase inhibitor for treatment of advanced gastrointestinal stromal tumors. The literature review and clinical case. Journal of Modern Oncology. 2020; 22 (4): 96–100.
DOI: 10.26442/18151434.2020.4.200409

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Аннотация

Для лечения метастатических гастроинтестинальных стромальных опухолей (ГИСО) применяются три препарата: иматиниб, сунитиниб и регорафениб. В январе 2020 г. появился еще один препарат – авапритиниб (BLU-285, Ayvakit). Авапритиниб – новый селективный тирозинкиназный ингибитор, блокирующий PDGFRA и KIT-мутации. На основании исследования NAVIGATOR авапритиниб одобрен FDA для лечения ГИСО с мутациями в экзоне 18, в том числе при мутации D842V. Авапритиниб включен в рекомендации NCCN в 1-ю линию при мутации D842V. По данным литературы описаны лишь единичные случаи эффекта при мутации D842V при применении иматиниба и регорафениба. Авапритиниб – первый препарат, обладающий высокой противоопухолевой активностью при мутации D842V. Авапритиниб высокоэффективен и при вторичных мутациях, что объясняет его активность в ≥4 линиях лечения. В нашей статье мы приводим результаты исследования NAVIGATOR и клиническое наблюдение применения авапритиниба у пациента с метастатической ГИСО в 6-й линии лечения. На фоне терапии достигнута частичная регрессия, длительность которой составила 9 мес. Самыми ранними побочными эффектами были периорбитальные отеки и повышенное слезотечение. Через 3 мес отмечена гематологическая токсичность, что потребовало коррекции дозы авапритиниба.

Ключевые слова: гастроинтестинальные стромальные опухоли, PDGFRA, авапритиниб, BLU-285, Айвакит.

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We have three drugs for treatment of gastrointestinal stromal tumors (GIST): imatinib, sunitinib and regorafenib. Avapritinib (Ayvakit, BLU-285) is one more drug that was approved in January 2020. Avapritinib is a new selective tyrosine kinase inhibitor of PDGFRA and KIT mutations. Based on NAVIGATOR trial avapritinib was approved by FDA for treatment of PDGFRA exon 18 mutant GIST including D842V. Avapritinib was included in NCCN guidelines in the first line therapy PDGFRA D842V mutant GIST. There are only several cases describe imatinib and regorafenib efficacy in D842V mutation in the literature. Avapritinib is the first drug with high efficacy in D842V mutant GIST. Avapritinib has high efficacy against second mutations that explain its activity in ≥4 lines of treatment. This article summarizes the results of NAVIGATOR trial and describes a clinical case of the patient with advanced GIST who received avapritinib in 6th line of treatment. Partial response was achieved that lasted 9 months. The earliest side effects were periorbital edema and increased lacrimation. Three months later the dose of аvapritinib was reduced because of hematological toxicity.

Key words: gastrointestinal stromal tumors, PDGFRA, avapritinib, BLU-285, Ayvakit.

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Список литературы

1. FDA prescribing information AIVAKIT (avapritinib) tablets, for oral use Initial U.S. Approval: 2020.
2. Corless CL, Schroeder A, Griffith D et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005; 23 (23): 5357.
3. Cassier PA, Fumagalli E, Rutkowski P et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012; 18: 4458–64.
4. Sheima Farag, Neeta Somaiah et al. Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients. Eur J Cancer 2017; 76: 76–83.
5. Grellety T, Kind M et al. Clinical activity of regorafenib in PDGFRA-mutated gastrointestinal stromal tumor. Future Science OA 2015; 1 (4).
6. Evans EK et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med 2017; 9: 1–11.
7. Heinrich M, von Mehren M, Jones RL et al. Avapritinib is highly active and well tolerated in patients with advanced GIST driven by a diverse variety of oncogenic mutations in KIT and PDGFRA. CTOS Annual Meeting; 2018; Rome, Italy.
8. Heinrich M, Jones R, Von Mehren M et al. Clinical response to avapritinib by RECIST and Choi Criteria in ≥4th Line and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST) (oral presentation). In: Connective Tissue Oncology Society annual meeting. 2019.
9. Heinrich MC, Jones RL, Von Mehren M, et al. Clinical activity of avapritinib in > fourth-line (4L+) and PDGFRA exon 18 gastrointestinal stromal tumors (GIST) (abstract no. 11022 and poster). J Clin Oncol Conf 2019; 37 (Suppl. 15).
10. George S, Bauer S, Jones RL et al. Correlation of ctDNA and response in patients (pts) with PDGFRa D842 GIST treated with avapritinib (abstract no. 1623P and poster). Ann Oncol 2018; 29 (Suppl. 8): viii584.
11. Joseph CP, Abaricia SN, Angellis MA et al. Avapritinib for the treatment of GIST: analysis of efficiency, safety, and patient management strategies at the recommended phase 2 dose (abstract no.3258000 and poster). In: Connective Tissue Oncology Society annual meeting. 2019.
12. Clinical Trials.gov. (VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST. ClinicalTrials.gov Identifier: NCT03465722.
13. Bauer S, George S, Kang Y-K et al. 1662TiPVOYAGER: an open-label, randomised, phase III study of avapritinib vs regorafenib in patients (pts) with locally advanced (adv) metastatic or unresectable gastrointestinal stromal tumour (GIST). Ann Oncol 2018; 29 (Suppl. 8): mdy299.058.
14. Эл. ресурс: Blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-top-line-results-phase-3-voyage
[Available from: Blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-top-line-results-phase-3-voyage (in Russian).]
15. NCCN Guidelines. Soft tissue sarcoma. Version 1.2020. National Comprehensive Cancer Network Portal. nccn.org

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1. FDA prescribing information AIVAKIT (avapritinib) tablets, for oral use Initial U.S. Approval: 2020.
2. Corless CL, Schroeder A, Griffith D et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005; 23 (23): 5357.
3. Cassier PA, Fumagalli E, Rutkowski P et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012; 18: 4458–64.
4. Sheima Farag, Neeta Somaiah et al. Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients. Eur J Cancer 2017; 76: 76–83.
5. Grellety T, Kind M et al. Clinical activity of regorafenib in PDGFRA-mutated gastrointestinal stromal tumor. Future Science OA 2015; 1 (4).
6. Evans EK et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med 2017; 9: 1–11.
7. Heinrich M, von Mehren M, Jones RL et al. Avapritinib is highly active and well tolerated in patients with advanced GIST driven by a diverse variety of oncogenic mutations in KIT and PDGFRA. CTOS Annual Meeting; 2018; Rome, Italy.
8. Heinrich M, Jones R, Von Mehren M et al. Clinical response to avapritinib by RECIST and Choi Criteria in ≥4th Line and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST) (oral presentation). In: Connective Tissue Oncology Society annual meeting. 2019.
9. Heinrich MC, Jones RL, Von Mehren M, et al. Clinical activity of avapritinib in > fourth-line (4L+) and PDGFRA exon 18 gastrointestinal stromal tumors (GIST) (abstract no. 11022 and poster). J Clin Oncol Conf 2019; 37 (Suppl. 15).
10. George S, Bauer S, Jones RL et al. Correlation of ctDNA and response in patients (pts) with PDGFRa D842 GIST treated with avapritinib (abstract no. 1623P and poster). Ann Oncol 2018; 29 (Suppl. 8): viii584.
11. Joseph CP, Abaricia SN, Angellis MA et al. Avapritinib for the treatment of GIST: analysis of efficiency, safety, and patient management strategies at the recommended phase 2 dose (abstract no.3258000 and poster). In: Connective Tissue Oncology Society annual meeting. 2019.
12. Clinical Trials.gov. (VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST. ClinicalTrials.gov Identifier: NCT03465722.
13. Bauer S, George S, Kang Y-K et al. 1662TiPVOYAGER: an open-label, randomised, phase III study of avapritinib vs regorafenib in patients (pts) with locally advanced (adv) metastatic or unresectable gastrointestinal stromal tumour (GIST). Ann Oncol 2018; 29 (Suppl. 8): mdy299.058.
14. Available from: Blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-top-line-results-phase-3-voyage (in Russian).
15. NCCN Guidelines. Soft tissue sarcoma. Version 1.2020. National Comprehensive Cancer Network Portal. nccn.org

Авторы

Д.А. Филоненко*, Б.М. Медведева, А.А. Мещеряков

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия
*shubina_d@mail.ru

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Daria A. Filonenko*, Bela M. Medvedeva, Andrey A. Meshcheryakov

Blokhin National Medical Research Center of Oncology, Moscow, Russia
*shubina_d@mail.ru

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