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Purpose Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. Methods The standard dose-escalation design 3 + 3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50–350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. Results 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58–5.68) and 7.0 (95% CI 3.82–10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. Conclusions The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. ClinicalTrials.gov identifier: NCT04071184

Purpose: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. Conclusions: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

PDF file - 77K, CONSORT diagram.

Supplementary Figure from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

PDF file - 105K, Ability of the high RORP group to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

Supplementary Table from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

PDF file - 104K, Association of the PAM50 Proliferation, RORS and RORP continuous scores with response and event-free survival (EFS).

PDF file - 44K, Clinical-pathological comparison of the NOAH and the transNOAH gene expression (GEP) tumor samples.

Supplementary Data from Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

PDF file - 93K, Distribution of the PAM50 intrinsic subtypes based on RORP score groups.

PDF file - 57K, Quality control profiles of the samples.

PDF file - 102K, Clinical-pathological characteristics of the various pathology-defined subtypes.

Purpose: We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial.Experimental Design: Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2+) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated.Results: HER2-enriched (HER2-E) tumors predominated within HER2+ disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumab-based chemotherapy for HER2+/HER2-E and HER2+/RORP-high were 5.117 (P = 0.009) and 8.469 (P = 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2+/HER2-E and HER2+/RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2+/HER2-E and HER2+/RORP-high tumors compared with patients with HER2+/non-HER2-E and HER2+/non-RORP-high tumors, respectively.Conclusions: As determined by EFS and pCR, patients with HER2+/HER2-E tumors, or HER2+/RORP-high tumors, benefit substantially from trastuzumab-based chemotherapy. The clinical value of this genomic test within HER2+ disease warrants further investigation. Clin Cancer Res; 20(2); 511–21. ©2014 AACR.

PDF file - 104K, Ability of the HER2-E subtype to predict pCR in 91 patients with clinically HER2-positive disease treated with trastuzumab-based chemotherapy in the ISPY-1, MDACC and XeNA studies.

Purpose:To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.Patients and Methods:In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.Results:Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively.Conclusions:Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

PDF file - 92K, Affymetrix U133A 2.0 probes used for in this study for PAM50 subtyping.

PDF file - 119K

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

PURPOSE Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)–positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 intravenously weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade {greater than or equal to}3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade {greater than or equal to}3 diarrhea reported in 16.2% and 1.4%, respectively.Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade {greater than or equal to}3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

301 Background: FGFR2 status of a patient with metastatic gastric adenocarcinoma could be an important factor in determining optimal treatment strategy with FGFR2 inhibitors and antibodies. The question remains how well different assays agree on the FGFR2 status of the same patient and whether one test can be substituted by another. Methods: Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8] and one FISH test. One hundred and nine formalin-fixed, paraffin embedded samples (including 64 primary tumors and 45 metastases of same patients) were obtained and were stained with FGFR2 IHC assays. Two trained pathologists independently evaluated the percentages of tumor staining and their intensity. FGFR2 FISH was performed as described previously [Su, BJC 2014]. The concordance analysis was performed to assess (1) correlation of FGFR2 expression/amplification between different assays in primary and metastases, (2) the predictive properties of one test of another. Results: After evaluating the expression in the first 19 patients, further study was carried out only using the Abсam assay due to pronounced nuclear staining with other IHC tests. FGFR2 any level expression was detected in 29 (47%) primary tumors and 18 (40%) metastases with concordance of 91%. The prevalence of FGFR2 amplification was 9.4% and intratumoral heterogeneity was observed in 33% of FGFR2 amplified cases. Pearson Correlation Coefficients (PCC) were: 0.89, 0.38 and 0.35 between IHC3+/FISH, IHC≥1% stained cells/FISH and IHC≥10%/FISH, respectively. The table represents how well one assay can predict the same outcome (positivity or negativity) of another assay. Conclusions: Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC. [Table: see text]

PURPOSE The overall survival (OS) results in patients with ALK-positive metastatic non–small-cell lung cancer (NSCLC) have rarely been reported. The aim of this prospective-retrospective cohort study was to obtain real-world data on the use of crizotinib or chemotherapy in patients with ALK-positive metastatic NSCLC in Russia. PATIENTS AND METHODS Patients with epidermal growth factor receptor–negative metastatic NSCLC were screened in 23 cancer centers. To be eligible, patients were required to have confirmation of ALK rearrangement. Patients were treated with crizotinib (250 mg twice daily; n = 96) or the investigator’s choice of platinum-based chemotherapy (n = 53). The primary end point was OS. RESULTS A total of 149 ALK-positive patients were included. Mean age was 53 years in both groups. Patients were predominately women (59%) and never-smokers (74%), and most patients had adenocarcinoma histology (95%). At a median follow-up time of 15 months, 79 of the 149 patients included in the analysis had died. Median OS from the start of treatment was 31 months (95% CI, 28.5 to 33.5 months) in the crizotinib group and 15.0 months (95% CI, 9.0 to 21.0 months) in the chemotherapy group ( P < .001). The objective response rate was 34% in the crizotinib group. Among patients with brain metastasis, one complete response (6%) and five partial responses (31%) were achieved. Grade 3 adverse events were observed in three patients (3%) in the crizotinib group. CONCLUSION The improved OS observed in crizotinib clinical trials in ALK-positive NSCLC was also observed in the less selective patient populations treated in daily practice in Russia. The use of standard chemotherapy in these patients remains common but seems inappropriate as a result of the effectiveness of newer treatments, such as crizotinib.

Aim. To conduct a systematic review and meta-analysis of studies on the effect of starting dose of regorafenib on overall survival (OS) of patients with chemorefractory metastatic colorectal cancer. Materials and methods. We searched for research data in the PubMed. The analysis included all publications till 08.20.2019 which compared OS depending on the starting dose of regorafenib (160 mg or less) in the 1st course of therapy. Meta-analysis was conducted using Review Manager Ver. 5.3. Results. Two studies demonstrated decreased OS at starting dose of less than 160 mg (A. Adenis et al., 2016: risk ratio - RR 1.26, 95% confidence interval - CI 1.01-1.56; A. Aljubran et al., 2019: RR 2.25, 95% CI 0.93-5.43). Two studies showed an improvement in OS with a starting dose of less than 160 mg in the 1st course (T. Bekaii-Saab et al., 2018: RR 0.72, 95% CI 0.47-1,11; J. Gotfrit et al., 2017: RR 0.46, 95% CI 0.17-1.22). In two other studies, there was no effect of a starting dose of regorafenib on OS (K. Yamaguchi et al., 2019: RR 0.95, 95% CI 0.82-1.1; G. Argiles et al., 2019: RR 0,86, 95% CI 0.65-1.13). The meta-analysis did not reveal the effect of starting dose of the drug on OS: RR 0.97, 95% CI 0.78-1.21; p=0.79; I2=64. Conclusions. Reducing the starting dose of regorafenib in the 1st course does not decrease OS and can be recommended for routine clinical practice.

Definitive concurrent chemoradiation (cCRT) is offered to only 3% of Russian patients with stage III NSCLC. To determine the patterns of care and barriers to cCRT utilization in Russia, we conducted a survey of practicing radiation oncologists (ROs). Electronic IRB-approved survey containing 15 questions was distributed to Russian ROs. Fisher’s exact test or Cochran-Armitage test of trend was used to assess the associations between clinical experience, practice type, and patterns of care. We analyzed 58 questionnaires completed by ROs—16 respondents from tertiary referral hospitals, and 42 from community or private centers. A total of 88% of respondents formulate treatment recommendations in multi-disciplinary tumor boards. For unresectable stage III NSCLC, the most common recommendation is sequential CRT (50%), followed by concurrent CRT (40%), with an observed higher utilization of cCRT in tertiary centers (9/16, 56% vs 14/42, 33%). Of the respondents, 31% do not offer cCRT to their pts. Among reasons for avoiding cCRT are (1) poor performance of pts (76%); (2) high toxicity of therapy (55%); (3) lack of consensus among tumor board members (33%); and (4) preference for sequential CRT (31%). Only 3% do not irradiate elective LNs. Eighty-six percent of respondents counsel their NSCLC pts regarding smoking cessation. Despite level 1 evidence, cCRT is rarely used in Russia for pts with locally advanced NSCLC, and preference for sequential therapy and concerns over high toxicity are the most common barriers. Education of Russian ROs may increase cCRT utilization, leading to improved survival, notably in the era of maintenance immunotherapy.

Alofanib is a potent, small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms. Phase 1b clinical study (RPT835GC1B) met its primary endpoints and recommended phase 2 dose was described early. Here, we present pharmacokinetics (PK) and results of biomarker analysis. Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels using a 3 + 3 design. 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver (43%) and bone (14.3%) metastases, 19% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). The PK and biomarker analysis set included 18 patients. FGFR2 amplification was accessed by FISH with ZytoLight SPEC FGFR2/CEN 10 Dual Color Probe and FGFR2 expression was accessed by IHC with antibody 1G3 (Abcam (ab 5820). Table summarizes PK data. The geometric mean values of Cmax, AUC0-t, T1/2, Vd increased and CL, Kel decreased approximately dose-proportionally after single dosing, similar to previous preclinical studies. The decrease in the mean value of the Vd for a dose of 350 mg/m2 may be associated with a significant increase in AUC0-t. No correlations between PK values and objective response rate (n=2; 9.5%), progression-free (median 3.63 months (95% CI, 1.58 - 5.68) and overall (median 7.0 months (3.82 - 10.18) survival as well as in patients with liver metastases were found (all P>0.1). A positive FGFR2 IHC expression was observed in all tumor cells and a weak positive reaction in normal epithelium. FGFR2 amplification was confirmed by FISH in 1 (5.6%) patient.Alofanib PK in a gastric patient population is well characterized, supporting the use of a once-daily 350 mg/m2 dose. In further studies, the evaluation of FGFR2 amplification seems to be important. Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 50 mg/m2 100 mg/m2 165 mg/m2 250 mg/m2 350 mg/m2 Cmax, mcg/ml (CV%) 21.4 (32.3) 23.7 (18.4) 44.7 (15.5) 72.8 (64.3) 145.9 (42.7) AUC0-t, mcg*h/ml (CV%) 2.3 (31.9) 6.6 (14.2) 13.3 (49.9) 23.8 (8.7) 74.0 (57.5) Vd, ml/m2 (CV%) 4006.1 (28.3) 4907.5 (14.7) 5676.8 (26.6) 6686.7 (11) 3823.0 (63.8) CL, ml/h/m2 (SD) 19609.5 (7740) 14028.2 (1990) 11910.5 (8740) 10011.0 (827) 4183.0 (2420) Kel, 1/h (CV%) 4.9 (15.3) 2.9 (2.8) 2.1 (41.2) 1.5 (3.8) 1.1 (47.0) T1/2, h (SD) 0.1 (0.024) 0.2 (0.01) 0.3 (0.118) 0.5 (0.0171) 0.6 (0.293) Citation Format: Grigory Raskin, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, Natalia Besova, Anastasia Mochalova, Ivan Rykov, Vladimir Moiseyenko, Igor Utyashev, Sergei Iugai, Nadezhda Dragun, Dmitry Reznikov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu. Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3481.

e15608 Background: in 2021 ASCO has updated guidelines on adjuvant therapy for stage II colon cancer with the statement: “Patients with T4 tumors are at higher risk of recurrence and should be offered adjuvant chemotherapy, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT”. We performed a single-center retrospective study to assess the prognostic role of postoperative tumor stage T4 and T3 with ≥2 negative prognostic factors in patients with resected stage II colon cancer. Methods: We retrospectively analyzed 1457 pts with stage I-III colon cancer treated in Russian Cancer Research Center n.a. N.N. Blokhin from 2001 to 2015. We included pts with resected stage II colon cancer with following negative prognostic factors: T4; sampling of fewer than 12 lymph nodes in the surgical specimen; perineural or lymphatic invasion; poorly or undifferentiated tumor grade; intestinal obstruction; and tumor perforation. Three cohorts were studied: pts with pT4N0M0 with no other high-risk factors (group A), pts with pT4N0M0 with additional high-risk factors (group B), and pts with pT3N0M0 with ≥2 high-risk factors (group C). The primary study endpoint was 3-year disease-free survival (DFS). The secondary endpoint was 5-year overall survival (OS). Statistical analysis was done with SPSS v.20. Results: 164 pts met the inclusion criteria with 17 (10%) pts in group A, 90 (55%) pts in group B, and 57 (35%) pts in group C. Adjuvant chemotherapy was performed in 8 (47%), 25 (28%), and 9 (16%) pts, respectively (p = 0.035). At a median follow-up of 62 months (range, 2-135 months), the 3-year DFS was 82%, 68%, and 78% for groups A, B, and C, respectively (HR, 1.55; 95% CI, 0.99-2.4; p = 0.053). No difference in 3-year DFS was found between group A and C (HR, 1.0; 95% CI, 0.34-3.2; p = 0.9). The 5-year OS was 75%, 65%, and 78% for groups A, B, and C, respectively (HR, 1.38; 95% CI, 0.84-2.3; p = 0.2). Conclusions: Patients with pT4 with additional high-risk features had worse overall survival compared to other subgroups with resected stage II colon cancer. There was no difference in survival rates between patients with pT4 with no additional negative prognostic factors and pT3 with ≥2 negative prognostic factors. Therefore, we propose that patients with pT4 as well as with pT3 with ≥2 negative prognostic factors are at a higher risk of recurrence and should be offered adjuvant chemotherapy.

e13032 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have dramatically changed therapeutic landscape of hormone receptor-positive HER2-negative advanced breast cancer (HR+ HER2- aBC). There are three iCDK4/6 in Russia, which are available and included into the clinical guidelines as a preferred first line treatment option beginning since 2018. The aim of this study was to assess evolution of treatment approaches to HR+ HER2- aBC and identify demographic and disease characteristics in correlation with available groups of therapy (chemotherapy, endocrine therapy ±mTOR inhibitors/ CDK4/6i). Methods: Аdult patients diagnosed with de novo or recurrent HR+ HER2- aBC in 2014-2021 identified in outpatient departments of Moscow state oncology hospitals were included into our non-interventional, descriptive, retrospective cohort study. Primary objective of this real-world study was to describe the rate of CDK4/6i usage in the first line setting. As a secondary objective, we describe patient and disease characteristics in iCDK4/6 group, as well as in the endocrine monotherapy and chemotherapy groups. Results: From the cohort of 1000 patients (full-set analysis population) 874 cases were selected, who received treatment since 2018. 45.9% (95% CI 42.6, 49.2) patients were treated with CDK4/6i in combination with endocrine therapy in the first-line setting. From them in the subgroups of patients with or without visceral metastases 50.5% (95% CI 45.5, 55.5) and 42.1% (95% CI 37.7, 46.5) were treated with CDK4/6i in the first line setting, respectively. Among 874 cases 78.0% (95% CI 75.3, 80.7) patients received endocrine therapy ± targeted therapy; in the subgroups of patients with or without visceral metastases 69.5% (95% CI 64.9, 74.1) and 84.9% (95% CI 81.7, 88.1) were treated with endocrine therapy ± targeted therapy in the first line setting, respectively. Conclusions: Endocrine therapy is a predominant therapeutic option in the first line setting for HR+ HER2- aBC. Clinical trial information: NCT04852081. [Table: see text]

e17551 Background: recurrent ovarian cancer (OC) patients with platinum-free interval (PFI) < 6 mo. are usually considered platinum-resistant and treated with non-platinum chemotherapy. However, this practice is not based on proper-conducted randomized trials. Methods: we queried the PubMed database for all full-text articles and abstracts on the treatment of patients with platinum-resistant ovarian cancer (PROC) in 01/01/2000-01/06/2019 timeframe. The PRISMA tool was used to ensure transparent reporting of the results. Inclusion criteria were: 1) histologically confirmed epithelial OC; 2) recurrent disease within 6 months after completion of platinum chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) defined response rate (RR) and assessment criteria. Proportion meta-analysis (random-effect model) and beta-regression were conducted to assess the impact of platinum agents on response rate as well as significance of other variables. In the beta-regression model response rate was a dependent variable, while platinum agents (yes or no), used non-platinum drugs and method of response assessment were independent variables. Statistical analysis was dose with meta and betareg packages of R software. Results: we identified 7156 articles and screened them for title and abstract, 157 studies for further analysis. Efficacy of non-platinum- and platinum-based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively. In meta-proportion random-effect model RR among patients treated with platinum-based and non-platinum chemotherapy RR was 36% (95% CI 30-41; I2 = 62%) and 16% (95% CI 14-19; I2= 70%) respectively. Multiple beta-regression model is presented in the Table below. For sensitivity analysis various regression models were made with different subsets of the trials and additional variables (including year of the trial, percentage of serous subtype of OC and median of prior therapy lines). Platinum was the strongest predictor of response in every developed model. Conclusions: this meta-analysis shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents. These results support recent ESMO-ESGO consensus on treatment of recurrent ovarian cancer and randomize trials are required to refine the role of platinum in early relapsed OC.[Table: see text]

e16077 Background: Alofanib (RPT835) is a first-in-class allosteric inhibitor that induces conformational changes in the extracellular domain of FGFR2. Here, we present the final results of the phase Ib clinical study (RPT835GC1B) of alofanib. Methods: Patients with metastatic gastric adenocarcinoma resistant to standard therapy with measurable disease were eligible. The dose finding part used a 3+3 design, starting with a dose level of 50 mg/m2, intravenously, 5 days on, 2 days off. Five dose levels were foreseen. Primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included toxicity, PK, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: 21 patients were enrolled. 4 (19.1%), 14 (66.7%), 9 (43%), 3 (14.3%), and 12 (57%) patients had ECOG PS 2, ≥2 metastatic sites, liver metastases, bone metastases, and 3-6 lines previous therapy, respectively. The MTD has not been reached and dose of 350 mg/m2 has been declared as recommended phase II dose. With median follow-up of 13.0 months 15 (71.4%) patients had any grade treatment related adverse events (TRAE). Grade 3-4 TRAE occurred in 6 (28.6%) patients. Two (9.5%) patients discontinued treatment due to grade 3 diarrhea and grade 4 reactions immediately after injections. There were no treatment-related deaths in the study. One partial response (5.26%) with a duration of 18.53 months was identified. Disease control rate (DCR) was 68.4% and median duration of stable disease was 4.91 months. Median PFS was 3.63 (95% CI 1.58–5.68) months. Median OS was 7.0 (3.82–10.18) months. 6-month OS rate was 57.1%. OS was almost 2 times better in patients with DCR (median 10.05 vs. 5.9 months) and without bone metastases (8.6 vs. 3.1). Only one patient (4.8%) had FGFR2 amplification (time to death was 7 months). PK parameters linearly changed depending on the dose level, but no correlation with efficacy was found. Table summarizes rate of TRAE and DCR in dose cohorts. Conclusions: Alofanib was feasible and showed early signals of efficacy in heavily-pretreated patients with metastatic gastric cancer. A phase 2 randomized trial is planned. Clinical trial information: NCT04071184. [Table: see text]

Objective: to demonstrate an efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in management of malignant ascites (MA) in patients with platinum-refractory ovarian cancer (OC).Background: MA in OC patients can dramatically affect quality of life. HIPEC is an investigational treatment modality that can be effective in MA setting but evidence-based data supporting this method are lacking. Cases presentation: 2 women 50-year-old, FIGO stage IV and 60-year-old, FIGO stage IIIC presented at our center, both had recurrent MA. Patients were treated with HIPEC after platinum-refractory recurrence. The first one had total control of MA with no evidence of disease at the time of last follow-up examination. The 2nd had 9 months of disease control – a relatively long time considering her MA recurrence rate.Conclusions: HIPEC can be successfully used for MA management in selected patients with epithelial OC refractory to standard chemotherapy, however more data are needed from randomized clinical trials.

Trimodality bladder preservation (BP) is an accepted alternative to radical cystectomy for patients with muscle invasive bladder cancer (MIBC). The global utilization of BP is variable, and practice patterns have not been previously studied in Russia. We sought to elucidate the contemporary BP practice patterns in Russia and determine the impact of the BP workshop on attitudes of Russian radiation oncologists (ROs) towards BP. The workshop was focused on patient workup, selection for BP, chemotherapy choices, radiation therapy (RT) contouring and planning, patient counseling. A total of 77 pre- and 32 matched post-workshop IRB-approved surveys, based on the workshop content, were analyzed using descriptive statistics to determine baseline clinical experience and patterns of care. The impact was judged by changes in participants’ responses. A total of 56% of respondents had experience with delivering bladder-directed RT, and 60% of those treated both operable and inoperable MIBC patients. Only 10% felt uncomfortable offering an operable patient BP modality. Prior to the workshop, almost half of respondents estimated universal poor bladder (44%) and erectile functions (47%) after BP. The workshop resulted in dramatic change in participants’ attitudes towards long-term urinary (Stuart-Maxwell test, p

The goal of the CLOVER study was to perform a pairwise comparison of four tests based on the same patient population with non-small cell lung cancer (NSCLC): three validated PDL1 immunohistochemistry (IHC) assays (Ventana SP142, Ventana SP263, Dako 22C3) and one PCR test. Four hundred seventy-three NSCLC samples were obtained from a biobank and were stained using PDL1 IHC assays. Four trained pathologists independently evaluated the percentage of tumor cells (TC) and immune cells (IC) that stained positive at any intensity. PDL1 transcripts were quantified in 437 patients by a standard Taqman RT-PCR assay using SDHA as a reference gene. A concordance analysis was performed to assess (1) the correlation of TC and IC between different assays and (2) the predictive properties of one test for another. “High” RNA expression was detected in 187 of 437 (43%) patients. The percentage of PDL1-positive cells (≥1%) was higher among the IC than the TC in all IHC three assays. The Pearson correlation coefficients (PCC) for TC were 0.71, 0.87, and 0.75 between 22C3/SP142, 22C3/SP263, and SP263/SP142, respectively. The PCC for IC were 0.45, 0.61, and 0.68 for the same pairs. A low correlation was observed between the PCR test and each of the three IHC assays; however, if a patient tested low/negative by PCR, then they were likely to test negative by any single IHC test with a high probability (92–99%). Among patients who tested positive by PCR, only 9–45% tested positive by IHC assays. There was excellent positive and negative agreement (>91%) between 22C3 and SP263 staining using the recommended individual cutoffs for first-line treatment. PCR RNA expression analysis is not equivalent to IHC. However, this method may have some potential for the identification of PDL1-negative tumors. 22C3 could be considered as a substitute for SP263 in first-line treatment.

The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with pancreatic cancer (PC). We performed PubMed and Embase database queries. We included 4 studies into the meta-analysis and 16 studies in the systematic review. Our systematic analysis showed that the average weighted median overall survival (OS) in patients with HRD with advanced PC was 19.8 and 15.6 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 23.8 and 17.1 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 8.3 and 12.0 months in patients without HRD. For resected PC, our meta-analysis demonstrated that HRD status did not affect the prognosis (HR 1.03, 95% CI 0.46 to 2.33), but results were rather heterogeneous (I2=83%, p=0.003). Our systematic analysis showed that the average weighted median OS in patients with HRD was 34.6 and 27.0 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 46.1 and 36.3 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 24.2 and 42.9 months in patients without HRD. Results of our meta-analysis and systematic review support the idea of platinum use in patients with HRD both in resected and metastatic PCs, although a randomised trial is warranted to make a more reliable conclusion. PROSPERO REGISTRATION NUMBER: CRD42019121914.

304 Background: FGFR2 promotes gastric cancer progression, suggesting that inhibition of FGFR2 may be an important therapeutic strategy. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms with IC50 < 10 nM. Methods: RPT835GC1B is a Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) as a primary endpoint. Secondary endpoints included pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels: 50, 100, 165, 250, and 350 mg/m2. All patients received alofanib until disease progression or unacceptable toxicity. Results: As of 20 September 2021, 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 14% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). All enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. 17 (81%) patients had at least one treatment-related adverse event (trAE). Grade 3 or higher trAEs (5/23.8%) have included raised ALT/AST at 50 mg/m2, neutropenia at 50 mg/m2, diarrhea at 165 mg/m2, headache at 165 mg/m2, increased serum amylase at 350 mg/m2, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia) at 350 mg/m2. Three (14.3%) patients discontinued treatment due to trAEs. Most common Grade 1-2 adverse events included reactions immediately after intravenous injections, diarrhea, thrombocytopenia, arthralgia, and headache. Grade 1 hyperphosphatemia was found in 1 (4.8%) patient. Table summarizes efficacy data. Conclusions: The MTD has not been reached and dose of 350 mg/m2 has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. Clinical trial information: NCT04071184. [Table: see text]

Fibroblast growth factor receptor 2 (FGFR2) is associated with an unfavorable prognosis in patients with gastric cancer. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active site of FGFR2 extracellular domain. RPT835GC1B (NCT04071184) is an ongoing Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. Secondary endpoints include pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate. All patients received alofanib until disease progression or unacceptable toxicity. As of data cutoff on December 30, 2020, 13 patients have been enrolled in the trial. Patients were predominantly male (85%), 54% had 2 and more metastatic sites, including liver metastases (54%), and were heavily pretreated (60% received previous 3-6 lines of therapy). To date, all enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. Grade 3 or higher drug related adverse events have included raised ALT/AST at 50 mg/m2, diarrhea at 165 mg/m2, and hyponatremia at 350 mg/m2. 93% of patients had any grade adverse events. Most common Grade 1-2 adverse events included fatigue, diarrhea, nausea, anemia, thrombocytopenia, increased alkaline phosphatase, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia). Grade 1 hyperphosphatemia was founded in 25% of cases. One patient discontinued treatment due to drug related Grade 3 uncontrolled diarrhea. Alofanib has demonstrated evidence of biologic activity in 12 patients in the first 4 dose levels evaluated to date. Disease control rate was 75% (1 durable partial response (13 months) at 50 mg/m2 and 8 stable diseases at 50-250 mg/m2). After a median follow-up of 4.5 months, the median PFS and OS was not reached. In conclusion, dosing up to 350 mg/m2 of alofanib was well tolerated, DLT and MTD were not reached. The early biologic activity of alofanib in the late-line treatment of metastatic gastric cancer is encouraging. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the AACR meeting. Citation Format: Ilya Tsimafeyeu, Galina Statsenko, Anastasia Mochalova, Natalia Trenina, Vyacheslav Kurakin, Natalia Besova, Kristina Novoselova, Natalia Abramova, Ekaterina Obarevich, Alina Kashanova, Margarita Suetina, Vladimir Moiseyenko, Mikhail Byakhov, Elena Artamonova, Liubov Vladimirova, Sergei Tjulandin. Preliminary data on a phase 1b, first-in-human study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT113.

Objectives Limited understanding exists of epidermal growth factor receptor (EGFR) mutation frequency in less common subgroups of advanced non-small-cell lung cancer (aNSCLC) (e.g. squamous cell carcinoma [SCC]), and to what extent local practices exclude patients from EGFR testing based on their clinical characteristics. Materials and methods IGNITE (non-comparative/-interventional; NCT01788163) was conducted in 90 centres (Asia-Pacific/Russia). Eligible patients: local/metastatic aNSCLC; chemotherapy-naive, newly-diagnosed/recurrent disease after resection; ineligible for curative treatment. Patients provided a tissue/cytology (all) and a blood plasma (China/Russia/South Korea/Taiwan) sample. Primary endpoint: EGFR mutation frequency in aNSCLC patients (adenocarcinoma [ADC]/non-ADC), as per local practices. Results 3382 patients were enrolled. EGFR mutation frequencies for evaluable tissue/cytology samples in Asia-Pacific and Russian patients: 49.3% (862/1749) and 18.0% (90/500) for ADC tumours; 14.1% (74/525) and 3.7% (15/402) for non-ADC; 9.9% (40/403) and 3.7% (13/349) for SCC. Of Russian patients with SCC tumours harbouring common, activating EGFR mutations, 6/9 were never-/former-smokers. Mutation status concordance between 2581 matched tissue/cytology and plasma samples: 80.5% (sensitivity 46.9%, specificity 95.6%). Conclusion EGFR mutation testing should be considered in all Asian aNSCLC patients. Also, as activating EGFR mutations were observed in a small number of Caucasian squamous NSCLC patients, testing here may be appropriate, particularly in those with no/remote smoking history. Circulating free tumour-derived DNA is feasible for mutation analysis employing well-validated and sensitive methods, when tumour samples are unavailable.

Radiation oncologists in Russia face a number of unique professional difficulties including lack of standardized training and continuing medical education. To combat this, under the auspices of the Russian Society of Clinical Oncology (RUSSCO), our group has developed a series of ongoing in-person interactive contouring workshops that are held during the major Russian oncology conferences in Moscow, Russia. Since November 2016 during each workshop, we utilized a web-based open-access interactive three-dimensional contouring atlas as part of our didactics. We sought to determine the impact of this resource on radiation oncology practice in Russia. We distributed an IRB-approved web-based survey to 172 practicing radiation oncologists in Russia. We inquired about practice demographics, RUSSCO contouring workshop attendance, and the clinical use of open-access English language interactive contouring atlas (eContour). The survey remained open for 2 months until November 2017. Eighty radiation oncologists completed the survey with a 46.5% response rate. Mean number of years in practice was 13.7. Sixty respondents (75%) attended at least one RUSSCO contouring workshop. Of those who were aware of eContour, 76% were introduced during a RUSSCO contouring workshop, and 81% continue to use it in their daily practice. The greatest obstacles to using the program were language barrier (51%) and internet access (38%). Nearly 90% reported their contouring practices changed since they started using the program, particularly for delineation of clinical target volumes (57%) and/or organs at risk (46%). More than 97% found the clinical pearls/links to cooperative group protocols in the software helpful in their daily practice. The majority used the contouring program several times per month (43%) or several times per week (41%). Face-to-face contouring instruction in combination with open-access web-based interactive contouring resource had a meaningful impact on perceived quality of radiation oncology contours among Russian practitioners and has the potential to have applications worldwide.

Objective: Little evidence is available on the management of patients with metastatic and/or unresectable gastric cancer (mGC) after the failure of first-line treatment. This study presents real-world data on characteristics and treatment patterns of patients with mGC in Russia. Methods: Eligible patients were ≥18 years old, diagnosed with mGC ≥ January 1, 2012, received first-line chemotherapy followed by second-line chemotherapy or best supportive care (BSC), had ≥3 months of follow-up after the start of second-line chemotherapy or BSC (except in cases of death), and had not participated in a clinical trial. Data were summarized using descriptive statistics. Results: A total of 88 physicians provided data from 202 charts. Mean age at mGC diagnosis was 53.7 (standard deviation: 11.2) years; 70.8% of patients were male. Reasons for first-line treatment discontinuation included disease progression (50.5%) and adverse events/toxicity (39.1%). There were 52 unique treatment regimens prescribed in second-line; capecitabine (14.5%), paclitaxel (9.3%), and capecitabine + oxaliplatin (8.7%) were the most frequent. Reasons for second-line treatment discontinuation included disease progression (39.8%) and patient refusal to continue (37.5%). During 2nd-line treatment, the most common treatment-related symptoms were nausea/vomiting (75.0%), while pain (73.8%) was the most common disease-related symptom. Antiemetics (63.4%), chemotherapy (61.6%), non-narcotic analgesics (48.3%), endoscopy (45.9%), and nutritional support (35.5%) were most frequently used as supportive care. Conclusions: Second-line treatment patterns for patients with mGC in Russia are heterogeneous. Results of this study indicate the need for more intensive implementation of the most active regimens in second-line treatment of mGC according to international and national guidelines.

Background Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. Methods Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC

e15549 Background: Role of metastasectomy in pts with mBRAF metastatic CRC is still controversial. We performed analysis of prospective multicentric database of pts with mBRAF mCRC to evaluate the efficacy of metastasectomy in such group of pts in the real clinical practice. Methods: We analyzed a database of pts with mCRC in 7 cancer clinics in Russia and chose pts with metastasectomy with different mutational status. The primary endpoints were disease free survival (DFS) and overall survival (OS), which were calculated from the time of metastasectomy. Analysis was performed with the SPSS v.20 software package. Results: The study included 126 pts: 26 pts with mBRAF, 57 pts with mRAS and 43 pts with wtRAS/BRAF. Pts with mBRAF more often had synchronous metastases (50%/19,3/11,6%, p

88 Background: There are no direct prospective randomized studies supporting the need for antiangiogenic drugs in the treatment of patients with the m BRAF mCRC. However, subgroup analysis of different studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy anti-angiogenic targeted therapy with chemotherapy and chemotherapy alone in patients with m BRAF mCRC in terms of progression free survival (PFS), and overall survival (OS). Methods: We performed a search of all prospective randomized phase III studies in PubMed, ASCO and ESMO congresses for all years before September, 2020, compared chemotherapy (CT) plus bevacizumab or aflibercept or ramucirumab and CT alone at the first-line or second-lines with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary–HR for OS and 95%CI. Fixed effects were used for analysis. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 4 trials (AVF2107g, AGITG MAX, VELOUR and RAISE), which included 120 patients with mBRAF (anti-angiogenic plus CT–65 (54%) and CT alone–55 (46%). According to results of the meta-analysis there was a tendency for significant improvement in PFS (HR 0.64, 95% CI 0.4-1.02; p = 0.06; I2 = 0%, p for heterogeneity 0.7; 53trials) and significant improvement in OS (HR 0.51, 95% CI 0.32-0.82; p = 0.005; I2 = 0%, p for heterogeneity 0.52; 4 trials) in group of ani-angiogenic therapy. Conclusions: Addition of anti-angiogenic therapy to chemotherapy showed improvement in the PFS and OS in pts with m BRAF compared with chemotherapy alone. A prospective randomized trial is needed to determine the optimal regimen of systemic therapy for pts with m BRAF mCRC.

Peritoneal dissemination and growth of tumor cells in the ascitic fluid in stages III and IV of recurrent ovarian cancer is difficult to treat; resistance to many anticancer drugs used in the treatment of solid ovarian cancer is observed at this stage. The author’s hypothesis that the differences in the molecular phenotype of tumor cells for various types of the disease could be an explanation for this. A comparative evaluation of the expression and coexpression of a number of molecular markers (immunofluorescence assay with flow cytometry) was performed using solid and ascitic ovarian cancer cells. In contrast to solid ovarian cancer, ascitic ovarian cancer cells present leukocyte common antigen CD45 and mesenchymal marker vimentin in addition to epithelial marker cytokeratin. In addition to the inhibition of anoikis (specific mechanism of epithelial cell death in a liquid medium in the absence of contact with the substrate), ascitic ovarian cancer cells are characterized by (1) emperipolesis (intracellular migration of leukocytes without damage to the tumor cell), and (2) phenotype of epithelial-mesenchymal transition. Thus, the data on clinically significant molecular differences between solid and recurrent ascitic ovarian cancer was first obtained, opening up opportunities for anticancer therapy, which previously was not used in the treatment of ovarian cancer.