Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab. Comparison of the patient's MSI loci patterns with MSI+ colorectal adenocarcinoma samples showed a lower fraction of unstable loci, low resolution of a second peak in the repeat length spectrum of unstable short tandem repeats in the patient's sample, and a lower length of indels (3.7 vs 4.5 base pairs, p < 0.01).

Введение: Появление в клинической практике возможности комплексного молекулярного профилирование (КМП) и регистрация новых таргетных препаратов привело к развитию прецизионного подхода в онкологии. Задачей работы являлась оценка опыта применения КМП у пациентов с распространенными опухолями желудочно-кишечного тракта (ЖКТ) в Российской Федерации. Материалы и методы: Проведен ретроспективный анализ клинических данных и отчетов КМП пациентов с опухолями ЖКТ. Цель исследования — оценка доли пациентов, которые получают молекулярно-направленную терапию (МНТ) после КМП, а также определение клинической пользы, которая оценивалась как длительность ответа на МНТ ≥ 6 месяцев. Также проведена оценка распределения альтераций по шкале ESCAT в зависимости от нозологии, частота объективных ответов и ОВ при назначении МНТ или стандарта терапии. Результаты: С марта 2018 по июнь 2023 гг. КМП было проведено 147 пациентам с опухолями ЖКТ (КРР — 64 %, РПЖ — 14,3 %, РЖ- 12,2 %, ХЦР — 9,5 %). Средний возраст составил 58 лет, лица мужского и женского пола были представлены в равной степени, среднее число линий до КМП — 2. МНТ проведена 19 (13 %) пациентам, клиническая польза зафиксирована у 6 больных (4 %). Одногодичная ОВ: 47,4 % против 29,5 % в группе МНТ и стандарта терапии (ОР = 2,147, 95 % ДИ 1,075–4,289, p = 0,020). КМП позволило выявить 12,1 % пациентов с максимальным уровнем ESCAT — I, 1,3 % — ESCAT II, 31,5 % — ESCAT III и 16,8 % — ESCAT IV. У 38,2 % пациентов обнаруженные при КМП альтерации не являлись предиктивными. За пределами ESCAT I, II клиническая польза была достигнута лишь у двух пациентов (1,3 %). Выводы: Несмотря на увеличение частоты объективных ответов и выявленные различия в ОВ, проведение доступных вариантов КМП приводит к смене тактики лечения у небольшой доли пациентов. Лишь 4 % пациентов в нашем исследовании получили клиническую пользу от МНТ, что соответствует данным литературы.

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

e21512 Background: Improved overall survival in patients undergoing metаstasectomy for melanoma have been reported in several retrospective studies before era of modern therapy in melanoma. Rapid progress in BRAF and MEK targeted therapy (TT) and immunotherapy (IT) has led to significant improvements in objective response rates and survival rates in advanced melanoma patients. Unfortunately, part of patients have a resistance to modern therapy in one or more lesions. In 2019 Nelson DW et al published data when surgery followed by modern therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival (MSS) versus modern therapy alone (58.8% vs. 38.9%, p = 0.049). But data about modern therapy in BRAF + advanced melanoma with metastasectomy during therapy are limited. Methods: We conducted an observational retrospective chart review study and evaluated a subset of patients which underwent surgery (metastasectomy) with V600 BRAF-mutant advanced melanoma, who received therapy in a real-world setting in Russia. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Results: The observed population included 382 patients in Russia. The date of the first enrollment after all approvals was 8 October 2018, and the date of the last completed register was 27 April 2019. Among 382 patients, 107 (28%) patients received surgical treatment for advanced melanoma during modern therapy (removal of metastases from the brain, lungs, soft tissues and other organs). Surgery during first line therapy was performed in 60pts (56%), as second – in 25pts (23.4%) and third or higher line in 22pts (20.6%). Comparison of overall survival curves for all patients depending on the surgical treatment showed that the survival in the subgroup of patients with the presence of surgical treatment was higher than among patients who did not undergo metastasectomy: 24-months OS was 76.7 (95%CI, 65.6 – 84.6) and 53.7% (95%CI, 46.4-60.4), p = 0,0027). Conclusions: Our findings suggest that resection of distant metastases associated with improved overall survival despite all limitations in retrospective nature of the study. While modern systemic therapy have improved outcomes in advanced melanoma, metastasectomy remains associated with favorable survival. Surgery have to be a part of multidisciplinary care for patients with advanced melanoma.

434 Background: Combination of anti-VEGF compounds and immune checkpoint inhibitors is an approved therapy across multiple solid tumors, including advanced HCC. This phase Ib study (NCT03468426) is assessing BI 836880 (bispecific VEGF/Ang2 nanobody) + ezabenlimab (anti-PD-1 antibody) in pts with advanced solid tumors. The recommended phase 2 dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg given IV every 3 weeks was determined in Part 1. In Part 2, RP2D was assessed in 7 expansion cohorts. We report data from cohorts in HCC after prior sorafenib/lenvatinib (cohort F) and untreated unresectable HCC (cohort G). Methods: Pts with locally advanced or metastatic HCC, Child-Pugh class A, not eligible for surgical or locoregional therapies were enrolled. Cohort F enrolled pts who had progressed on or after first-line treatment with sorafenib or lenvatinib or who had discontinued due to poor tolerability after ≥2 weeks of treatment. Cohort G enrolled pts who had received no prior systemic therapy for HCC. Treatment continued until disease progression, undue toxicity or consent withdrawal. Primary endpoint is objective response rate (ORR) by RECIST 1.1. Results: As of Aug 2021, 30/31 pts have been treated in cohorts F/G: 87/77% male; median age 65/64 yrs. Follow-up is ongoing in both cohorts. 9/19 pts in cohorts F/G remain on treatment; median (range) duration of treatment is 175 (42–532)/ 169 (42–336) days in cohorts F/G. All pts were evaluable for response in cohort F: confirmed ORR to date is 40% (1 complete response; 11 partial responses [PRs]). Of 28 evaluable pts in cohort G, confirmed ORR to date is 21% (6 PRs). 12 (40%) pts in cohort F and 18 (64%) in cohort G have stable disease. In cohort F, AEs were reported in 28 (93%) pts, most frequently hypertension and proteinuria (each 30%). In cohort G, AEs occurred in 26 (84%) pts, most frequently ascites (26%) and thrombocytopenia (19%). 24 (80%) pts in cohort F and 15 (48%) in cohort G had treatment-related AEs (TRAEs). Most frequent TRAEs were proteinuria (27%), infusion-related reactions (IRRs) and hypertension (each 20%) in cohort F, and hypertension (13%), IRRs, hypothyroidism and diarrhea (each 10%) in cohort G. There were 3 pts with G5 AEs in cohort F (COVID-19 pneumonia [n = 1]; low Glasgow coma score and dyspnea [n = 1]; hepatic cirrhosis [n = 1]) and 1 G5 AE in cohort G (hepatic failure); none were considered related to treatment. AEs leading to discontinuation occurred in 2 pts in cohort F (G3 hepatic encephalopathy and G2 duodenal ulcer) and 3 in cohort G (G5 hepatic failure [n = 1]; G2 acute kidney injury and G1 decreased appetite [n = 1]; G2 diarrhea [n = 1]). Conclusions: BI 836880 + ezabenlimab had a manageable safety profile and showed promising activity in pts with untreated and second-line post-sorafenib/lenvatinib advanced HCC. Data continue to mature, particularly in cohort G. Cohort F has been expanded by a further 30 pts. Clinical trial information: NCT03468426.

e15584 Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.

e15090 Background: Next-generation sequencing (NGS) has been moving rapidly from pure cancer genomics research towards clinical oncology to provide a rigorous personalized approach to treating cancer. Still there is a number of limitations to overcome before we are ready to fully introduce NGS into everyday clinical decision-making. Here we are sharing our experience with using targeted NGS platforms in clinical practice. Methods: We retrospectively evaluated the NGS results and the treatments, provided to the patients after NGS testing between Marсh 2019 and January 2021. The patients’ clinical characteristics, response to treatment and genomic mutation profiles were reviewed. Coprimary endpoints were the percentage of patients with NGS revealed targeted therapy options and the percentage of patients who received mutation-driven therapy. Results: Samples from 95 patients were tested, most frequently GI tumors (n=25, 26%), hepatobiliary tumors (n=11, 12%), breast cancer (n=10, 11%) gynecological tumors (n=10, 11%), central nervous system tumors (n=7, 7%) and others (n=32, 33%). An average of two gene alterations were identified per patient (range 0-15). The 95% (n=90) of samples had at least one detected mutation, and in 42% (n=40) of cases gene mutations happened to be targetable with existing drugs, including off-label prescriptions. Mutation-driven therapy was performed in 9,5% cases (n=10) with clinically meaningful response in 5 patients (2 patients with ovarian cancer, 2 patients with colon cancer and 1 melanoma). Conclusion: Mutational profiling using a targeted NGS panel has identified potentially targetable alterations in a vast majority of advanced cancer patients. The assay has revealed additional therapeutic options in 42% of patients. However, due to the short-term follow-up, just a small number of patients have received mutation-driven therapy. Further study will be required to determine if the mutation-driven therapy will prove to be clinically meaningful in these patients.

Combining anti-VEGF/Ang2 and anti-PD-1 therapy promotes an immunopermissive state, supportive of T-cell-mediated tumour cell destruction. This phase Ib study is assessing BI 836880 plus ezabenlimab in patients (pts) with advanced solid tumours. In Part 1 (dose escalation in pts with advanced NSCLC), the recommended phase 2 dose (RP2D) was determined as BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results, including data from Part 2 (expansion cohorts).

Introduction Treatment representation is an important factor of motivation and well-being during treatment (Horne, 2002). Objectives The aim was to reveal the relationship between treatment representation and well-being in oncological patients first referred to chemotherapy. Methods 40 oncological patients (10 males, 20-72 years old, mean age 50.49±13.75 years old, localizations included gastrointestinal tract and genitourinary system) first referred to chemotherapy filled Satisfaction with Life Scale (Diener et al., 1985), Scale for Positive and Negative Experiences (Diener et al., 2009), Hospital Anxiety and Depression Scale (Zigmond, Snaith, 1983) and Beliefs about Medication Questionnaire (Horne, 2002) that was slightly modified for the situation of chemotherapy. Disturbance of functioning was assessed in the interview as an opportunity to cope with job, home responsibilities or self-care (1-5-point Likert scale). Results Cronbach’s alphas for Necessity and Concern scales were .69 and .76. Despite high appraisals of necessity of chemotherapy (mean 4.24±.53 on 1-5 Likert scale), concern about it was rather high (2.83±.82). Hierarchical regression analyses revealed that, after adjusting for disturbances in social functioning, concern about chemotherapy (but not its subjective necessity) predicted more severe negative emotions (β=.32, p<.05, ΔR 2 =10.0%). After control for general level of anxiety and depression, this relationship became weaker but marginally significant (β=.32, p<.10, ΔR 2 =8.4%). Conclusions Concern about chemotherapy in patients first referred to this treatment could be important predictor of well-being demanding for interventions aimed at stabilization of emotional reaction to chemotherapy regardless belief in its necessity.

e20567 Background: We aimed to evaluate clinical and quality of life (QoL) outcomes of Nivo as 2+ line treatment in NSCLC pts within expanded access program and real world practice. Methods: Adult pts with advanced refractory NSCLC were enrolled in 11 centers in RF. All the pts received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1, adverse events (AEs) – NCI CTCAE v3.0. Patients filled out RAND SF-36 and ESAS-R at baseline, 1, 3, 6 and 12 mos after treatment start. Overall survival (OS) and progression-free survival (PFS) curves were evaluated by the Kaplan-Meyer method and compared by the log-rank test. GEE method was used for QoL analysis; χ2 test – for disease control rate (DCR) comparison. Results: The preliminary analysis was performed in the group of 200 pts with median follow-up 7.4 mos (65% – males; median age – 62 y.o.; ECOG 0-1 – 81%; former/current smokers – 70.5%; non squamous NSCLC – 64%; ≥2 lines of previous treatment – 53%, bone mts – 22%). DCR was revealed in 60.3% pts (108/179 pts, median first evaluation – 2.1 mos); 13 pts died before first response evaluation; 8 pts were not evaluated for response at cut-off. DCR was higher in squamous NSCLC (66%, squamous vs 51%, non squamous; χ2 = 4.0, p = .045). Median OS – 11.5 mos (95%CI 8.3–14.7), median PFS – 4.2 mos (95%CI 3.5–4.9). Patients with poor ECOG (ECOG 2-3 vs 0-1: median OS – 5.6 mos vs 12.4 mos, median PFS – 2.7 vs 4.2 mos) and those with bone mts (with mts vs without mts: median OS – 5.0 vs 12.5 mos, median PFS – 2.8 vs 4.1 mos) had worse survival; log-rank p < 0.05. QoL improved during 6 mos of treatment in more than 50% pts; average increase by 60% of mean Integral QoL Index (IQoLI) at different time-points was observed. Upon GEE, IQoLI improvement during 12 mos was revealed (p < .0001). The severity of fatigue and dyspnea, which had the highest burden at base-line, decreased during 6 mos of treatment in more than 50% and 30% pts, consequently. AEs were registered in 32.7% pts (median of Nivo treatment – 2 mos); among them 17 pts had grades 3-4 AEs; 5 pts – SAEs. Conclusions: Preliminary results of this study support the acceptable efficacy and safety of Nivo in NSCLC pts. Nivo treatment leads to meaningful QoL improvement and decrease of symptom burden in this patient population.