Background Osimertinib (Osi) is a 3rd generation TKI that crosses the blood-brain barrier (BBB), which has been shown to be effective in both the second and first line of treatment in patients with NSCLC with an EGFR mutation. In use of Osi in patients with T790M associated progression during therapy with earlier TKIs, the median PFS was 10.1 months. The duration of treatment may vary significantly for each patient. The study of the mechanisms of resistance to 3rd generation TKIs is the subject of clinical studies, among the most common variants of resistance - the appearance of the gate-keeper mutation C797S - in 7% of cases. Methods It is prospective, single-center study we examined the appearance of resistance in patients receiving Osi treatment.The search for the C797S mutation was carried out using an original diagnostic platform based on real-time PCR, using the BioRad Real-Time CFX96 amplifier. Primers and fluorescent probes were synthesized by Applied Biosystems compony. The study included patients with progression during therapy with Osi. Before treatment, and then every 2 months until progression of the disease appease, blood sampling was performed to conduct a qualitative assessment of ctDNA (ex19del, L858R, T790M, C797S). Results From August 2016 to August 2019, in 12/22 patients, progression of the disease during the Osi. Emong them, 66.7% (7/12) are women, 33.3% (4/12) are men. The average age is 64.6 years (55-80). 1/12 smoked for over 30 years. The molecular genetic profile in 58.3% (7/12) of the patients is ex19del, 33.3% (4/12) of L858R, 8.4% (1/12) is a combination of rare mutations G719S + S768I. The median PFS during the Osi treatment was 9.6 months. (0.7 - 18.4).The analysis of ctDNA was performed in 11/12 patients: an activated mutation was detected in all cases, 1/12 recorded the mutation C796S (NGS), T790M and C797S (cis/ trans) were not detected.Histological material was taken from 4/12 patients, 2 of which showed the transformation of the tumor into small cell lung cancer. Conclusions The investigation of appearence the resistance mechanisms in the treatment with osimertinib did not reveal the EGFR C797S mutation, which may be associated with a small number of patients included in the study.Grant supported RUSSCO / RakFond 2018-01-YS-ECI. Legal entity responsible for the study St. Petersburg Clinical Research Center of Specialized Types of Care (Oncology). Funding RakFond (Russia). Disclosure All authors have declared no conflicts of interest.

Background Resistance on the 1st or 2nd generation TKIs in patients with EGFR mutated NSCLC to the therapy occurs on average after 8-12 months. The most common (49-60%) resistance mechanism is the appearance of the T790M. Its determination is possible by different methods of examination: ctDNA (false-negative probability 23%) and tumor tissue (sensitivity of 88%). The appointment of osimertinib in the second line allows to increase ORR, but also PFS relative to standard chemotherapy. Methods In this study we investigated the effect on PFS by the dynamic determination of ctDNA. Included patients with metastatic EGFR-associated NSCLC, in whom, a T790M mutation was detected during treatment TKIs of 1-2 generations.Patients received osimertinib therapy 80 mg / day, daily, until progression of the disease appears. Blood test was taken to conduct a qualitative assessment of ctDNA in dynamics by the RT-PCR method, fist test was done before starting treatment, and then every 2 months. Results From August 2016 to December 2018, 22 patients were identified T790M + associated progression of EGFR + NSCLC. 81.9% (18/22) are women, 18.1% (4/22) are men. The average age is 61.2 years (50-75). 1/22 had smoking experience for more than 30 years. The molecular genetic profile in 16 is represented by ex19del, 5 L858R, 1 - a combination of rare mutations G719S + S768I. The effect of therapy was evaluated in 20/22 patients. PR and SD were registered in 9/20 (45%) and 10/20 (50%) patients, respectively. Median PFS – 18.9 months (CI 95%, 10.6 - 27.1). In 12/22 patients was observed the disappearance of ctDNA T790M + after 2 months of osimertinib therapy. PFS is 24.4 months (CI calculation is NA), in patients with no mutation detected in the second month of treatment compared with the group of patients in which the ctDNA was determined (PFS 7.6 months) (CI 95%, 3.0 –12.9) (p = 0.003). The confidence interval for one of the medians cannot be calculated the 75% percentile was 3.4 +/- 3.3 and 18.8 +/- 6.3. Conclusions The disappearance of ctDNA in plasma after 2 months of treatment with osimertinib is associated with an increase in PFS and can be considered as a predictive marker in patients with metastatic NSCLC EGFR T790M + Grant supported RUSSCO / RakFond 2018-01-YS-ECI. Legal entity responsible for the study St. Petersburg Clinical Research Center of Specialized Types of Care (Oncology). Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

The third generation TKI (osimertinib) according to AURA III trial results achieved longer PFS compared to standard platinum based chemotherapy in patient's resistant to 1-2 generation TKIs due to T790M mutation (8.5 vs 4.2 months). The evolution of resistance profile during thins therapy can be analyzed based on ctDNA. In this study patients with metastatic EGFR mutated NSCLC, with a confirmed disease progression during treatment with 1/2 generation TKIs, T790M positive which included patients received osimertinib 80 mg daily. Before the treatment and then every 2 months, whole blood was taken, for qualitative assessment of ctDNA dynamics by RT-PCR. The aim of the study was to assess the relationship between the disappearance of T790M + ctDNA and the time to progression on osimertinib. From August 2016 to December 2018 22 patients with T790M positive progression were identified. 18/22 (81.9%) were women, 4/22 (18.1%) - men. The mean age was 61.2 years (50-75). Only 1/22 had a smoking history >30 pack/years. Primary activating mutations in EGFR gene were ex19del, L858R and G719S + S768I in 16, 5 and 1 patients respectively. Median PFS on the first line TKI was 21.7 months (CI 95%, 10.8 – 53.3). In 59.1% (13/22) progressive disease was characterized by the appearance of new metastases and in 40.9% (9/22) by the growth of previously identified metastases. 22 patients were evaluable for response. PR and SD were achieved in 11/20 (50%) and 10/20 (45/5%) respectively. Median PFS was in a whole group 16.7 months (CI 95%, 11.4 - 22.0). T790M in ctDNA was negative after 2 months of osimertinib treatment in 12/22 patients. Median PFS was 18.9 months (CI 95%, 14.8–19.7) in patients with undetectable T790M in ctDNA after 2 month of therapy compared to 8.0 months (CI 95%, 4.2 – 11.8) in patients remaining ctDNA T790M positive. No clinical factors were associated with the disappearance of ctDNA by statistical analysis. The disappearance of T790M + ctDNA after 2 months osimertinib therapy is predictive of greater PFS in patients with EGFR mutation positive NSCLC, receving of 2nd line.

Abstract Background For many years, researchers have tried to find more effective ways to find out if a person has cancer, and find it at an early stage, when it is most curable. One idea that is gaining popularity is called liquid biopsy. Methods From 2016 to 2018 we studied 1050 patients with non-small-cell lung cancer (NSCLC). Before the treatment and then every 2 months after, whole blood was taken for qualitative assessment of ctDNA dynamics by RT-PCR. The aim of the study was to assess the relationship between the presence of mEGFR ctDNA in tumor tissue and blood plasma. Results The study involved 1050 patients, of which 462 cases were represented by adenocarcinoma of NSCLC. EGFR mutations were detected in 145/462 targeted agents (31.38%). The molecular genetic profile ctDNA was represented by the following mutations for women 33/59 (55.9%): ex19del - 20 (60.6%), L858R - 13 (39.4%); for men 13/19 (68.42%). No association was found in the detectability of the mutation with sex, age, localization of metastases, or stage. Among patients with stage III only the L858 mutation (3/3) was found. The T790m resistance mutation was detected in the primary plasma sample in 8/79 cases (10.1%). After 2 months of gefitinib, EGFR-mutation-positive ctDNA were detected in blood plasma in 23.3% of cases (13/56). Of the 42 patients in whom the ctDNA was detected before treatment, after 2 months of therapy it was detectedin only 6/42. Thus, the disappearance of the mutation was observed in 85.71% (36/42). Median progression-free survival for patients who retained ctDNA after 2 months was 16.25 months (Cl 95% 11.24 - 19.94), and for patients in whom the mutation disappeared after 2 months it was 21.10 (Cl 19.21 - 22.98). The results of the study showed that blood plasma analysis is an appropriate the method of EGFR mutation detection: sensitivity 59.2%, specificity 98.8%, prognostic positive result 91.3%, prognostic negative result 91.6%. Conclusions The integration and liquid biopsy might complement the gold standard tissue testing and is a promising candidate for studying NSCLC. ctDNA assay might be applied in identifying actionable genomic alterations, dynamically monitoring response and resistance to targeted agents, prescreening early-stage lung cancer, and tracking the spatiotemporal evolution of lung cancer. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Introduction: FTD/TPI, also known as TAS-102, is a novel chemotherapy approved in patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. This study evaluates the efficacy and safety of FTD/TPI in the Russian population. Methods: This confirmatory open-label study was conducted in 2 Russian centers. The main inclusion criteria were patients who received at least 2 prior regimens of standard chemotherapies for metastatic colorectal adenocarcinoma. The primary endpoint was progression-free survival (PFS) rate at 2 months. Secondary objectives included median PFS, disease control rate (DCR) and safety. The cut-off date of this analysis was February 15, 2019. Clinical trial identification: NCT03274882. Results: A total of 26 pts were enrolled with a median age of 60.5 years (range 30 to 78 years), 19 pts (73%) were female, 4 and 22 pts had an ECOG PS of 0 and 1, respectively. All patients had received prior chemotherapy regimens containing a fluoropyrimidine, oxaliplatin, and irinotecan; 21 pts (81%) received an anti-VEGF drug, 6 pts received an anti-EGFR drug, and 2 pts (7.7%) received regorafenib. At the cut-off date, the patients received FTD/TPI for a median of 4 cycles (range, 1 to 21) and 11 pts were treated for 6 months or more. In the full analysis set (25 pts), the PFS rate at 2 months was 52% and the median PFS was 4 months (95% CI, 1.8-7.4 months). The DCR was 60%. Drugrelated adverse events (AEs) reported (≥ 5 pts) were neutropenia, diarrhoea, decreased appetite, nausea, anemia, and fatigue. Most drug-related AEs (74.3%) were grade 1-2; the most common grade 3-4 drugrelated AE was neutropenia. 3 pts reported grade 3 febrile neutropenia. Conclusion: In Russian patients with refractory metastatic colorectal cancer, FTD/TPI showed efficacy and safety profiles in line with the data observed in the RECOURSE trial.

Introduction: Trifluridine/tipiracil, also known as TAS-102, is a novel chemotherapy approved in patients with mCRC refractory to, or not candidates for standard therapies. A phase I/II study evaluated the combination of trifluridine/tipiracil and bevacizumab in mCRC patients who were refractory to standard therapies and showed encouraging antitumor activity with manageable toxicity (C-TASK FORCE) (Kuboki Y et al. Lancet Oncology, 2017). These promising results led to the initiation of a global non-comparative phase 2 study, TASCO1, to evaluate the efficacy and safety of trifluridine/tipiracil + bevacizumab (TT-B) and capecitabine + bevacizumab (C-B) in first-line unresectable mCRC patients who are non-eligible for standard first-line therapy. Methods: First-line mCRC-patients not candidate for intensive oxaliplatin- or irinotecan-based chemotherapy and without chance for curative resection according to the investigator's judgment were randomized (in a 1:1 ratio; stratified by RAS status, ECOG performance status and country) to receive trifluridine/tipiracil (35 mg/m2 given orally bid on days 1–5 and 8–12 in a 28-day cycle) plus bevacizumab (5 mg/kg on days 1 and 15 of a 28-day treatment cycle) or capecitabine (1250 or 1000 mg/m²/dose bid on days 1-14 in a 21-day) plus bevacizumab (7.5 mg/kg on day 1 in a 21-day treatment cycle). The primary endpoint was progression-free survival, the secondary endpoints included overall survival, safety and quality of life assessed by EORTC QLQ-C30 and QLQ-CR29 questionnaires. Results: Between Apr 29, 2016 and Mar 29, 2017, 154 patients were randomized and 153 pts were treated with TT-B (n=77) or C-B (n=76). The median PFS was 9.2 months in the TT-B group, 7.8 months in the C-B group. When considering only severe (Grade ≥3) events, a ≥5% difference in incidence between arms was reported for seven Preferred Terms of neutropenia (46.8% with TT-B vs. 5.2% with C-B), neutrophil count decrease (18.2% vs. 1.3%), white blood cell count decrease (10.4% vs. 1.3%), anemia (10.4% vs. 0%), hypertension (13% vs 5.3%), palmar-plantar erythrodysaesthesia syndrome (0% with TT-B vs. 11.8% with C-B) and diarrhea (1.3% vs. 7.9%). Serious events of febrile neutropenia were reported for 3.9% of patients in the TT-B arm, identical to the rate observed in the C-B arm. Further analyses on Quality of Life and biomarkers are on-going and will be presented later. Conclusion: The promising activity of TT-B observed in the C-TASK Force trial was confirmed in the TASCO1 phase 2 trial in 1st line mCRC patients non-eligible for intensive therapy. The opportunity to conduct a global confirmatory phase 3 trial versus C-B is currently being evaluated.