Aim: The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. Methods: The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. Results: In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. Conclusions: ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response.

Background. By 2020, breast cancer (BC) has become the most frequent malignancy in the world. The most common type of BC is HR+/HER2-negative cancer,2540% of which harbors PIK3CA mutations that affect the catalytic subunit of the PI3K protein. PIK3CA alterations are actionable, as such neoplasms can be treated with a combination of fulvestrant and the PI3K inhibitor alpelisib. As PIK3CA mutations have an extremely versatile effect on the characteristics of a tumor cell, numerous associations of PIK3CA mutations and various clinico-pathological characteristics of BC can be traced. Aim. Our aim was to clarify the information on the frequency and spectrum of PIK3CA mutations in Russian patients with HR+/HER2- advanced BC, and to study the association of PIK3CA mutations with clinical and pathological parameters of BC. Materials and methods. Tissue samples from 694 patients with HR+/HER2- advanced BC (mixed population of primary metastatic and relapsed tumors) who received any line of anti-cancer treatment in Dec 2020 to June 2021 in Russian Federation were analyzed by high-resolution melting, allele-specific PCR, digital droplet PCR and Sanger sequencing (exons 7,9, and 20 of the PIK3CA gene). Mutation rates in different BC subgroups were compared using the Fishers exact test. The age at diagnosis in patients with different PIK3CA status was compared using the MannWhitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the CochraneArmitage test for trends. Luminal A and B BC expression subtypes were distinguished with surrogate IHC markers according to St.-Gallen recommendations (2013). Results. Mutations were identified in 220/694 (32%) BC patients. The three most frequent missense substitutions in the PIK3CA gene (p.E542K, p.E545K, and p.H1047R) accounted for 190/220 (86%) mutations. Associations of PIK3CA mutations with luminal A subtype of BC, low proliferation index, small size of the primary tumor, and absence of signs of hereditary cancer were revealed. Associations of mutations in the kinase domain of PIK3CA (p.H1047R) with late recurrence of locally advanced BC and with non-Slavic ethnic origin of patients were found. Conclusion. PIK3CA mutation rate of 32% confirms high prevalence of mutation in Russian population, with some differences reflecting the ethnic origin of patients.

Background: Several targeted drugs have been recently approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC). This study aimed at a comprehensive evaluation of the spectrum of PIK3CA alterations in Russian BC patients. Methods: The tumor material from 1872 patients with ER+/HER2− BC was tested by a combination of PCR-based methods. Results: Mutations were detected in 693/1872 (37%) cases, including 46 BC with two PIK3CA lesions. The three most common substitutions (E542K, E545K, and H1047R) were identified in 542/693 (78%) PIK3CA-mutated cases, while as many as 5.5–12% of identified mutations were not potentially detectable by common commercial kits. The study included patients of Slavic and non-Slavic ethnicities residing in regions with different climate conditions, however, these factors did not influence the distribution of PIK3CA mutations. The presence of PIK3CA variants was associated with older patient age at diagnosis (p = 0.0002), smaller tumor size (p = 0.005), lower grade (p = 0.005), Ki67 <20% (p = 0.0001) and progesterone receptor-positive status (p = 0.002) at the initial disease diagnosis, and fewer distant metastases at the time of the detection of BC spread (p = 0.0001). In a subgroup of 413 BC patients who received adjuvant tamoxifen or aromatase inhibitors, PIK3CA mutations were not associated with resistance to either type of treatment. Conclusions: The results of this study highlight the need to extend the PIK3CA testing beyond the hotspot regions of this gene. Although PIK3CA alterations contribute to the pathogenesis of HR+/HER2− BC and represent a target for several novel drugs, they are not intrinsically associated with unfavorable clinical characteristics of this subtype of cancer disease.

Introduction. Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue neoplasms that occur predominantly in young adults. IMTs occur most commonly occur in the lungs, are localised and have a favourable prognosis. The pathogenesis of IMTs is based on translocation of the ALK gene in more than half of the cases. Case description. This article presents two clinical observations of the use of the ALK inhibitor crizotinib in young patients with advanced extrapulmonary IMTs with ALK gene alterations. In both cases, the duration of response to therapy was more than 10 years. In the first observation, a patient with inoperable IMT achieved disease stabilisation while receiving targeted therapy. In the second case, a patient with multiple lung, bone and lymph node metastases achieved a partial response to crizotinib therapy at the first follow-up evaluation, which persisted thereafter. In both cases, the therapy was well tolerated and no new adverse events were observed. Conclusion. The use of the ALK inhibitor crizotinib in the advanced form of IMTs with ALK translocation made it possible to achieve long-term responses to the therapy (more than 10 years). Введение. Воспалительные миофибробластические опухоли (ВМО) являются редкими новообразованиями мягких тканей, которые встречаются преимущественно у молодых лиц. Чаще всего ВМО возникают в легких, представляют собой локализованные формы и имеют благоприятный прогноз. В более половины случаев в основе патогенеза ВМО лежат транслокации гена ALK. Описание случаев. В данной статье представлены два клинических наблюдения применения ингибитора ALK кризотиниба у молодых пациентов с распространенной внелегочной формой ВМО с наличием изменений гена ALK. В обоих случаях длительность ответа на терапию составила более 10 лет. В первом наблюдении у пациентки с неоперабельной ВМО на фоне приема таргетной терапии достигнута стабилизация заболевания. Во втором случае у пациента с множественными метастазами в легких, костях и лимфатических узлах после первой контрольной оценки на фоне терапии кризотинибом достигнут частичный ответ, который сохранялся и в последующем. В двух наблюдения терапия переносилась удовлетворительно, новых нежелательных явлений не отмечалось. Заключение. Применение ингибитора ALK кризотиниба при распространенной формой ВМО с транслокацией ALK позволило достичь длительного (более 10 лет) ответа на терапию.

Background. Capmatinib has demonstrated high anti-tumor activity, as well as a manageable safety profile, in patients with advanced NSCLC with MET exon 14 (METex14) mutation in the Phase II Geometry mono-1 study. Aim. Estimation of the efficacy and safety of capmatinib in the Russian subgroup of patients in the Geometry mono-1 study. Materials and methods. Patients were enrolled in the Geometry mono-1 study according to their MET status and line of therapy. The Russian subgroup included patients treated with capmatinib as first- and second-line therapy. Capmatinib was administered at a dosage of 400 mg twice daily. The primary endpoint was objective response rate (ORR), and clinical benefit rate (CBR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS) and safety profile. Results. The analysis included 13 patients (4 males and 9 females) aged 59 to 82 years with metastatic NSCLC with METex14 mutation. ORR was 50% and CBR was 100% in the patients treated with capmatinib in the 1st line (n=6). ORR was 14.3%, and CBR was 71.4 in the 2nd line of the therapy (n=7). The median duration of response, regardless of therapy line, was 5.7 months. The median PFS with administration of capmatinib in the 1st line was 21.3 months, and in the 2nd line ― 3.5 months. The median OS, depending on the line of the therapy, was as follows: in the 1st line ― 21.3 months, and in the 2nd ― 24.6 months. The most common treatment-related adverse events (AEs) were peripheral edema (69.2%), hypocalcemia (53.8%), increased creatinine (46.2%); most of them were grade 1/2. No unexpected AEs were registered. Conclusion. A high response to capmatinib treatment was registered in the Russian population. The therapy was well tolerated. Введение. Капматиниб во II фазе исследования Geometry mono-1 продемонстрировал высокую противоопухолевую активность у пациентов с распространенным НМРЛ с мутацией в 14 экзоне гена MET (METex14), а также контролируемый профиль безопасности. Цель. Оценка эффективности и безопасности капматиниба в российской подгруппе пациентов исследования Geometry mono-1. Материалы и методы. В исследовании Geometry mono-1 пациенты распределены в зависимости от статуса MET (амплификация либо мутация METex14) и линии терапии. В российской подгруппе были включены пациенты, которым проводилось лечение капматинибом в качестве терапии первой и второй линии с мутацией METex14. Капматиниб назначался в дозе 400 мг два раза в сутки. В качестве первичной конечной точки использовалась частота объективных ответов (ЧОО) со стороны опухоли и частота клинической пользы (ЧКП), а ключевыми вторичными точками были продолжительность ответа, выживаемость без прогрессирования заболевания (ВБП), общая выживаемость (ОВ) и профиль безопасности. Результаты. В анализ было включено 13 пациентов (4 мужчины и 9 женщин) в возрасте от 59 до 82 лет с метастатическим НМРЛ с мутацией METex14., что сопоставимо с демографическими характеристиками в общей популяции исследования Geometry mono-1. У пациентов, получавших капматиниб в 1 линии (n=6), ЧОО составила 50% (95% ДИ 11,8 – 88,2%) и ЧКП – 100% (95% ДИ 60,7 – 100,0%), а во 2 линии (n=7): ЧОО равна 14,3% (95% ДИ 0,4 – 57,9%), а ЧКП – 71,4% (95% ДИ 29,0 – 96,3%). Медиана длительности ответа независимо от линии терапии составила 5,7 месяцев (95% ДИ 2,2 – 21,2 месяца). Медиана ВБП при назначении капматиниба в 1 линии составила 21,3 месяца (95% ДИ 5,6 – 25,1 месяц), а во 2 линии– 3,5 месяца (95% ДИ 0,9 – 36,8 месяцев). Медиана ОВ в зависимости от линии терапии была следующей: в 1 – 21,3 месяца (95% ДИ 9,9 – 51,5 месяцев), а во 2– 24,6 месяцев (95% ДИ 0,9 – 36,8 месяцев). Наиболее частыми нежелательными явлениями (НЯ), обусловленными лечением, были периферические отеки (69,2%), гипокальциемия (53,8%), увеличение креатинина (46,2%); большинство из них- 1/2 степени токсичности. Заключение. В российской популяции также был отмечен высокий ответ на лечение капматинибом, терапия сопровождалась хорошей переносимостью. Не выявлено каких-либо неожиданных НЯ.

Aim: This study aimed to evaluate the real-world efficacy and safety of lorlatinib in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior ALK tyrosine kinase inhibitor (TKI). Methods: The dataset included 82 subjects with metastatic NSCLC, who received lorlatinib upon compassionate use program or routine treatment between January 2017 and May 2025. All patients involved in this study responded to a prior ALK inhibitor for at least 4 months and switched to the above drug due to disease progression. Results: The overall objective response rate (ORR) was 64.6%, with the disease control rate (DCR) of 96.3%. Among 65 patients with brain metastases, the intracranial ORR and DCR were 66.2% and 96.9%, respectively. After a median follow-up of 82.7 months, the median progression-free survival (PFS) was 66.7 months (95% CI, 40.5–75.0 months), while the median overall survival (OS) was not reached (NR) (95% CI, NR–NR). Patients who had benefited from prior ALK TKI for more than 12 months achieved significantly longer PFS (NR vs. 34.0 months; p = 0.013) and OS (NR vs. 39.4 months; p = 0.002). Multivariate analysis showed that prior response to ALK TKI of less than 12 months was an independent negative predictor of survival (PFS: p = 0.039, OS: p = 0.027). Treatment-related adverse events (AEs) were reported in 75.6% of patients, with 8.1% experiencing grade 3 or higher toxicity; no treatment-related AEs led to permanent discontinuation of lorlatinib. Conclusions: This real-world dataset demonstrates an unusually pronounced benefit from lorlatinib in selected patients who progressed on early-generation TKIs, especially in long-term responders to prior therapy. However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance.