Second-generation TKI Research Articles

Abstract 5204: Exploring the therapeutic potential of EGFR retreatment: A comprehensive analysis of T790m(+) conversion and prognosis in lung cancer patients

Abstract Background: T790M acquired resistance occurs in 30-40% of cases after first- or second-generation EGFR TKI treatment. However, some patients who did not develop T790M mutation are converted to T790M positive through EGFR TKI retreatment. We conducted a Phase II prospective study analyzing T790m (+) conversion and prognosis in patients who were not induced T790M mutation at 2nd biopsy and were re-treated with first-generation EGFR-TKI as the third-line or later therapy. Methods: We re-administered first-generation EGFR-TKI to 63 patients (gefitinib n=34 or erlotinib n=29) who had previously been treated with first- or second- generation EGFR TKIs and cytotoxic chemotherapy because they were T790M-negative at the 2nd biopsy. Results: Among the 63 patients, a new T790m (+) mutation was identified in 20 patients (32%) with EGFR TKI retreatment. The first EGFR TKI treatment period and EGFR TKI retreatment period were significantly longer in the T790m (+) group than in the T790m (-) group (P-value=0.026, P-value=0.029, respectively). The best response to retreatment was also favorable in the T790m (+) group (P-value=0.038). The median overall survival (OS) in the T790m (+) group was 29.3 months, which was significantly better than the 6.0 months observed in the T790m (-) group (P-value<0.001). In an additional NGS analysis conducted on stored plasma samples from the 24 patients who were negative for T790M in the tumor tissue before retreatment, T790M was detected in five patients. These patients, who were subsequently treated with a third EGFR TKI, demonstrated very favorable overall survival (OS). Conclusions: EGFR retreatment could induce T790m (+) conversion in approximately one-third of cases, and these patients exhibited favorable prognosis. Through NGS analysis using plasma samples, approximately 20% cases of T790m mutation, which were not detected through routine PCR tests at the tumor tissue, could be identified. Retreatment-EGFR TKI and NGS analysis through blood samples could improve patient prognosis through the additional discovery of T790m (+) mutation. Citation Format: Joong Jin Ahn, Jae Cheol Lee, Chang Min Choi, In Ae Kim, Kye Young Lee, Jeong Eun Lee, Seung Hoon Jang, Seong Hoon Yoon, In Jae Oh, Sang Hoon Lee, Eun Young Kim, Juwhan Choi, Sung Yong Lee. Exploring the therapeutic potential of EGFR retreatment: A comprehensive analysis of T790m(+) conversion and prognosis in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5204.

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed BCR::ABL1-Positive Acute Lymphoblastic Leukemia in Adults: Updated Results from RJ-ALL2020.2A Trial

Background The introduction of the second-generation TKIs further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib is a novel second-generation TKI approved in China in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Herein, we report the updated results of the RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in adult BCR::ABL1+ ALL last year. The enrollment will be completed at the end of Aug. 2023. Methods In this prospective phase II study, patient (pt) eligibility mainly includes: 18≤age＜65 years; newly diagnosed BCR::ABL+ ALL; with adequate organ function. Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly. Allo-HSCT is recommended for all eligible pts. Blinatumomab is allowed to administer for MRD clearance before allo-HSCT. All pts receive central nervous system (CNS) prophylaxis once achieving remission. The choice of subsequent salvage treatments is based on the discretion of physicians. Multiparameter flow cytometry (minimal residual disease[MRD]<10 -4) and RT-qPCR (BCR-ABL1 transcript<10 -5) are used to monitor MRD. The primary endpoints are MRD clearance, PFS, and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results From Dec. 2020 to Jun. 2023, 81 adult pts with de novo BCR::ABL1+ ALL were enrolled. Seventy-eight pts were included in the efficacy and safety assessment (3 were excluded due to the short duration of treatment), and 76 were available for survival analysis (2 withdrew). Median age was 42 years (range, 18-63). Median WBC count at diagnosis was 38.7×10 9/L (0.6-675.3). Four pts had primary CNS leukemia (Table 1). Among 78 pts, 75 (96.2%) achieved CR/CRi at the end of induction, and 78 (100%) achieved CR/CRi at any time. No early death occurred during the induction course. MRD flow negative rates were 67.1% (51/76) and 79.7% (55/69), while the CMR rates were 31.1% (23/74) and 52.2% (36/69) at the end of induction and 3 months, respectively. With a median follow-up time of 16.2 months (range, 1.8-29.2), the estimated 2-year PFS and OS rates were 64.8% and 81.3% (Figure 1). Among the 69 survived pts, 61 were in continuous remission, and 8 were relapsed (4 had CNS involvement). Among 7 deaths, 6 died of disease progression (4 had CNS involvement), and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD flow negativity (PFS: p=0.091, OS: p=0.005) or CMR (PFS: p=0.055; OS: p=0.033) at 3 months. With a median time of 6.4 months (range, 1.6-10.3) from diagnosis, 46 pts (median age of 39 years [range, 20-60]) received allo-HSCT with 45 pts in CR1. The MRD flow negativity and CMR rates were 82.2% (37/45) and 70.5% (31/44) before HSCT, respectively. PFS and OS significantly improved in patients who underwent HSCT (PFS: p<0.001, OS: p=0.012). In multivariate analysis for PFS and OS, MRD flow negativity at 3 months (PFS: HR: 0.129, p=0.016; OS: HR: 0.151, p=0.029) and allo-HSCT (PFS: HR: 0.247, p=0.036; OS: HR: 0.176, p=0.042) still had a significant effect on PFS and OS as protective factors. When including CMR as a variable, CMR at 3 months (PFS: HR: 0.221, p=0.02; OS: HR: 0.115, p=0.054) and allo-HSCT (PFS: HR: 0.169, p=0.01; OS: HR: 0.139, p=0.021) had the similar impact on survival. Among 75 pts evaluable for ABL1 mutations, 24 (32%) pts were mutated, and T315I was the most frequently identified (75%). Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.01). Meanwhile, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were mostly G1-2, which were reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to chemotherapy. No permanent discontinuation or death related to flumatinib was observed. Conclusion This prospective study further confirmed the efficacy and safety of the promising second-generation TKI flumatinib combined with chemotherapy in newly-diagnosed Chinese adult pts with BCR::ABL1+ ALL. Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Comparison of Characteristics of Chronic Myeloid Leukemia Combined with Different Degrees of Myelofibrosis : A Real-World Multicenter Retrospective Study from China

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by excessive proliferation of myeloid cells, which belongs to the group of myeloproliferative neoplasms (MPNs). Myelofibrosis (MF) is a significant prognostic indicator of CML, and its discovery at the time of diagnosis aids in decisions regarding the patient's course of treatment, according to a descriptive cross-sectional study. Nevertheless, the influence of MF is not clear. Our study is to investigate clinical characteristics and prognosis of CML pantients with different degrees of myelofibrosis, exploring the influence of MF. We retrospectively analyzed 1757 CML patients with bone marrow biopsy results and compared the characteristics of CML combined with different degrees of MF in 44 Chinese institutions from January 2010 to October 2022(ChiCTR2200061208). A total of 1757 CML patients with MF, including 1090 males (62.0%) and 667 females (38.0%) with a median age of 49 (6-92) years. 1757 CML patients were treated with TKIs, as shown in the picture ( Figure A).The median WBC count was 119.8×10 9/L (0.1-910.8×10 9/L) in peripheral blood at diagnosis, the median HB level was 111.5 g/L (12.6-181 g/L), the median PLT count was 512.1×10 9/L (5-4384×10 9/L), the median EOS% was 3.3% (0.0-31.1%), the median BAS% was 4.3% (0.0-19.0%), the median spleen size was 4.10 cm (0.0-26.0 cm). Patients with MF were older (p<0.001); had higher leukocyte counts (p<0.001) and platelet counts (p<0.001); were more prone to anemia (p<0.001), acidophilia (p<0.001), alkalophilia (p<0.001), and splenomegaly (p<0.001); and a higher proportion of peripheral blood blast cells (p<0.001). There was no significant difference between the two groups in the male to female ratio. Patients without MF were more likely to reach 3-month EMR (p<0.001), 6-month BCR::ABL IS ≤ 1% (p<0.001), and 12-month MMR (p<0.001). The proportion of medium / high-risk patients with MF according to the Sokal score (p<0.001), Hasford score (p<0.001), ELTS score (p<0.001) and EUTOS score (p=0.002) was significantly increased ( Figure B). CML patients with MF had lower OS and PFS than patients without MF (p=0.007, p=0.006, Figure D, E). CML patients with MF were more prone to treatment failure with imatinib as the first-line treatment (p<0.001, Figure F). There was no statistically significant difference in treatment failure between first-generation TKI (1G-TKI) and second-generation TKI (2G-TKI) (p=0.222, Figure G).With increasing degree of MF, CML patients had higher leukocyte counts were more susceptible to anemia and splenomegaly, and had more peripheral blood blast cells. However, there was no significant difference in sex ratio, age, platelets, eosinophils, and basophils. CML patients without MF were more likely to achieve 3-month EMR, 6-month BCR::ABL IS ≤ 1%, and 12-month MMR. As the degree of MF increased, the proportion of intermediate / high risk patients according to Sokal score, Hasford score, and ELTS score increased significantly ( Figure C), OS and PFS of CML patients decreased (p<0.001, p<0.001, Figure H, I) and the failure rate of first-line treatment increased (p<0.001, p<0.001, Figure J, K). In conclusion, we performed 1757 CML patients with MF and compared the characteristics of CML combined with different degrees of MF. As the degree of MF increased, the proportion of intermediate / high risk patients according to Sokal score, Hasford score, and ELTS score increased, the efficacy of TKIs was lower, the prognosis of patients was worse. So MF is an independent risk factor affecting the prognosis of patients with CML. Acknowledgement: This research was funded by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09. *Correspondence to: Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003,Zhejiang, Peoples R China.E-mail: househuang@zju.edu.cn

Analysis of the pharmacotherapeutic effectiveness of the tyrosine kinase inhibitors therapy in patients with Chronic Myeloid Leukemia in a single hematology center in Plovdiv, Bulgaria

Aim. The aim of this study is to evaluate treatment retrospectively, response to the therapy and outcomes in patients with chronic myeloid leukemia (CML) and to what extent the European recommendations of LeukemiaNET (ELN) are followed at the Hematology Clinic, University Hospital “St. Georgi”, MU Plovdiv. Methods. All patients with Ph+, BCR-ABL1+ CML who were treated and observed between 01.01.2018 and 12.31.2022 at the clinic were included in the study and were analyzed retrospectively. Results. One hundred and eighty-eight patients with a mean age of 61.26 (21–91) years were analyzed. 151 (80.3%) were in chronic phase (CP), 27 (14.4%) in accelerating one and 10 (5.3%) in blast crisis. The actual overall survival rate was 79.26%, while for CP it is very high – 86.75%, and the mortality rate is 20.74%. All patients received some form of tyrosine kinase inhibitors therapy (TKIs-therapy). The first line TKI was imatinib in 120 patients (64%), and 68 (36%) received a second-generation TKI. Treatment response was monitored with TKIs by RT-qPCR. Conclusion.CML patients treated in the hematology clinic receive standard care in accordance with ELN and BMSH recommendations. Overall survival (OS) in routine care is comparable to published data from international studies. Molecular monitoring provides a good basis for disease control in CP. There are unmet needs in the treatment of patients in advanced stages.

Italian Physicians' Perceptions about the Role of Asciminib in Later Lines Chronic Myeloid Leukemia in Clinical Practice: A GIMEMA Survey.

Unmet needs remain in later lines chronic myeloid leukemia (CML): the response rate and the overall survival of resistant patients in the chronic phase who changed a second-generation TKI in the second line with another TKI with similar action are usually poor, while the off-target toxicities and the potential development of mutations increase. The recent approval of asciminib, a STAMP inhibitor, in the third line, has the potential to soon change the therapeutic algorithm for this subset of patients. Here, we report the results of a GIMEMA survey assessing the number of patients currently treated in the third line in Italy, the current approach in later lines by Italian physicians, and the future role of this drug according to the reason to switch to asciminib (resistance and/or intolerance), as well as the perceptions about the future position of this agent.

Upfront Use of First-/Second-Generation EGFR-TKI Followed by Osimertinib Shows Better Prognosis than Upfront Osimertinib Therapy in Japanese Patients with Non-small-cell Lung Cancer with Exon 19 Deletion: A Single-Center Retrospective Study.

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.

Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n= 257) and OPTIC (n= 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Outcomes of Patients with EGFR-Mutant Advanced NSCLC in a Developing Country in Southeast Asia.

BackgroundAlthough first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment.MethodsThis multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included.ResultsOf 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation – 54.1%, second generation – 25.6% and third-generation – 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after first- or second-generation EGFR TKI were started on a third-generation EGFR TKI.ConclusionIn the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients.

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Managing TKI Resistance: New Options

ATP-competitive TKIs have transformed CML from a fatal disease to one associated with a near-to-normal life expectancy, providing achievement of optimal therapeutic responses. However, some patients experience resistance, a situation of high clinical concern, as genetic instability is associated with lack or loss of response exposes to CML progression. Resistance to imatinib occurs in 10–15% and to second-generation TKI in <10% of patients in the first-line setting.

Chidamide, a Novel Histone Deacetylase Inhibitor, Combined with Imatinib Induces Synthetic Lethality in Drug-Resistant Chronic Myeloid Leukemia

Background and ObjectiveTyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC) remain formidable challenges for chronic myeloid leukemia (CML). The second-generation TKI have been shown to overcome Imatinib-resistance in CML, but limited effect in CML cells harboring the T315I mutation and leukemia stem cells (LSC). Histone deacetylase inhibitors (HDACi) have shown promise as a therapy for TKI-resistance cells and CML-LSC. Chidamide (CS055/HBI-8000), a novel orally active HDACi, has been approved for treatment of T-cell lymphomas in multiple clinical trials, whereas its effect on CML patients has not been characterized. Here we investigated the effects of Chidamide alone and in combination with Imatinib(IM), on isogenic TKI-sensitive and -resistant CML cell lines, as well as BC-CML stem/progenitor cells.Methods and ResultsWe chosen CML cell lines (KBM5 cells and KBM5-T315I cells) and primary cells from 7 BC-CML patients and 5 healthy volunteers as experimental subject. We found that treatment with Chidamide alone inhibited cell proliferation, induced cell cycle G0/G1 arrest and apoptosis in Bcr-Abl expressing KBM5 cells by FCM. Co-treatment with Chidamide and Imatinib synergistically killed TKI-resistant CML cell line KBM5-T315I, and caused more reduction in phosphorylation of Bcr-Abl, STAT5 and CRKL by Western-blot, as compared with treatment with either agent alone (P <.05). Additionally, β-catenin is overexpressed in BC-CML stem/progenitor cells and can be induced by BM stromal cells, suggesting that β-catenin contributes to intrinsic and extrinsic Bcr-Abl kinase-independent TKI-resistance in CML. The co-treatment was also associated with a greater decrease in the protein levels of β-catenin, C-myc and Survivin, increase in the acetylation of Histone H3 and activation of Caspase-3/-9. Importantly, combination of Chidamide and Imatinib significantly down-regulated Bcr-Abl levels and induced apoptosis of CD34+ leukemia stem/progenitor cells derived from BC-CML patients with or without Bcr-Abl kinase mutations, but exhibited minimal toxicity to normal CD34+ progenitor cells.ConclusionCombined treatment with Chidamide and Imatinib exerts a superior anti-leukemia activity on CML cells including T315I mutation-harboring cell line, as well as BC-CML stem/progenitor cells. Our findings suggest potential benefit of the combination to overcome Bcr-Abl kinase-dependent and -independent TKI-resistance in CML, which may be a promising strategy to TKI-resistant BC-CML patients. DisclosuresNo relevant conflicts of interest to declare.

Molecular characteristics of EGFR exon 20 uncommon R776H mutation and response to osimertinib in NSCLC patients.

e21001 Background: EGFR R776H is an uncommon exon 20 mutation in non-small cell lung cancer (NSCLC) patients. This mutation was first reported in samples after first generation EGFR TKI treatment as an acquired resistant mutation to first generation of EGFR-TKI. We further analyzed the molecular characteristics of patients with EGFR R776H mutation and its correlation with EGFR TKI therapy. Methods: In this study, a total of 16131 NSCLC patients from multiple centers with NGS data were retrospectively analyzed to study the molecular characteristics and clinical outcomes of patients with EGFR R776H mutation. Results: 44 of the 16131 patients (0.27%) had EGFR R776H mutation, and 28 of them (63.6%) were treatment-naïve while performing the mutation test. TP53 was the most common concomitant mutation in both treatment-naïve (57.1%) and treated (81.3%) patients. EGFR R776H mutation was found to coexist with multiple types EGFR mutation. The common mutations were EGFR L858R (54%) and EGFR G719A/S (25%), but It almost never coexists with 19del (2%). The coexist of EGFR R776H mutation was similar in both treatment-naïve and treated patients. In 16 of treated patients, all had received first - or second-generation EGFR TKI treatment, and the median progression-free survival (PFS) was 9 months. Interestingly, four of them found the presence of not only EGFR R776H but also EGFR T790M. It may be that EGFR R776H and T790M appear together in drug resistance, or it may be that EGFR R776H and EGFR sensitive mutation are not in the same cell clone. Two patients with EGFR R776H received treatment of Osimertinib and achieved partial response. The PFS of two patients in Osimertinib were 11 and 10 months, respectively. Moreover, EGFR C797S mutation was detected in two patients after resistant to Osimertinib. Conclusions: Presence of EGFR R776H mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that Osimertinib could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients with EGFR R776H.

Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive metastatic non-small-cell lung cancer (NSCLC). EGFR mutations are relatively common in Asian patients with NSCLC, and there is an increasing number of studies supporting the effectiveness of the second-generation TKI afatinib in routine clinical practice in Asia. This article reviews these real-world studies investigating afatinib as first-line treatment for EGFR mutation-positive NSCLC in Asian patients. Evidence from real-world studies with afatinib in this patient population supports findings from randomized controlled trials (RCTs) showing that afatinib is associated with more favorable outcomes compared with the first-generation EGFR TKIs. The effectiveness of afatinib has also been shown in real-world studies in Asian patients with poor prognostic factors, who are often under-represented or excluded from RCTs, such as those with uncommon EGFR mutations, brain metastases, or poor performance status, and elderly patients. The tolerability profile of afatinib in the real-world setting reflects that seen in RCTs, with no new safety signals reported in real-world studies in Asian patients with EGFR mutation-positive NSCLC. Dose-modification strategies also seem to be effective in the real world, with results of the RealGido study, which included 44% Asian patients, confirming findings from prospective clinical trials showing that tolerability-guided afatinib dose modifications can reduce the incidence of adverse events without adversely affecting clinical outcomes. While further research, including clinical trial data, is needed, real-world data have also demonstrated the feasibility of sequential afatinib followed by the third-generation TKI osimertinib in T790M-positive EGFR mutation-positive patients, which showed longer overall survival. Together, these real-world results demonstrate the real-world clinical effectiveness of afatinib as first-line treatment for patients with EGFR mutation-positive NSCLC.

Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Exploratory Study to Evaluate the Efficacy and Safety of HAD-B1 for Dose-Finding in EGFR Mutation Positive and Locally Advanced or Metastatic NSCLC Subjects Who Need Afatinib Therapy.

Afatinib is a target anticancer drug of the second-generation EGFR TKI type, showing an advantage in treatment effect compared to conventional chemotherapy. However, patients on EGFR-TKI drugs also usually progress after 9 to 13 months according to secondary resistance. HAD-B1 is composed of drugs that are effective against lung cancer. This study is an exploratory study to evaluate the efficacy and safety between dosage groups by conducting a clinical trial in subjects requiring afatinib drug treatment in non-small cell lung cancer with EGFR mutation positive to determine the optimal dosage for HAD-B1 administration. At the final visit compared to before administration, each change in the disease control rate was measured according to the HAD-B1 doses of the test group 1 (972 mg), the test group 2 (1944 mg), and the control group. The efficacy and safety of HAD-B1 were compared and evaluated through sub-evaluation variables. As a result of the study, there was no statistically significant difference in the disease control rate at 12 weeks after dosing, but complete and partial remission were evaluated as 1 patient each in the test group 1, and none in the other groups. There was no statistically significant difference between groups in the sub-evaluation variable. In addition, there was no problem of safety from taking the test drug. However, the initially planned number of subjects was 66, but the number of enrolled subjects was only 14, which may limit the results of this study.

CML-083: Prognostic Factors of Durable Treatment-Free Remission in CML Patients Based on the Prospective Study RU-SKI

Aim To define the prognostic factors for molecular relapse-free survival (MRFS) after TKI discontinuation in the Russian CML population. Methods The base for the analysis was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in patients (pts) with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic-phase, TKI therapy for at least three years and a stable DMR (BCR-ABL Results Three-year MRFS rate was 51%. Baseline pts characteristics: male - 50%; median (Me) age at TKI cessation 46 years (range, 22 to 80); Me duration of TKI therapy 8.3 years (range, 3 to 16.2); Me duration of DMR 3.2 years (range, 2 to 10.7). Therapy before treatment cessation: imatinib in 67 (68.4%) pts, second-generation (2G) TKI in 31 (31.6%) pts. Me follow-up time after TKI cessation was 40 mo (range, 28 to 57). Probability of MRFS (1st stop) was 53% after 36 mo of follow-up. Length of DMR, duration of therapy and depth of molecular response were found to be significant factors with p ≤ 0.05. We have found that the duration of TKI therapy, and not the duration of DMR, has an independent prognostic value for the Russian CML population due to the lack of molecular monitoring data at early stages of the disease. No difference in 36 months MRFS was observed in 1st-line imatinib (55%) compared with 1st-line 2G TKI (70%; p=0.26) and 2nd-line 2G TKI (39%; p=0,09) groups. However, significantly shorter treatment duration was observed in pts treated with 1st-line 2G TKI (Me=41.5 mo) vs imatinib (Me=96.4 mo), p Conclusion Longer treatment duration and depth of DMR before cancellation at least MR 4.5 are associated with durable TFR. Our study showed that the MRFS rate is not significantly improved with the use of 1st-line 2G TKI in comparison with 1st-line imatinib.

1395P Who will maintain as long-term responders more than 3 years with first- or second-generation EGFR TKI among EGFR mutant NSCLC?

1395P Who will maintain as long-term responders more than 3 years with first- or second-generation EGFR TKI among EGFR mutant NSCLC?

CML-411: Treatment-Free Remission in Patients with Chronic Myeloid Leukemia (CML): A Real-World Cohort of Patients in Colombia

Context Long-term TKI treatment is related to notable adverse events, quality-of-life impact, and significant costs to health systems. TFR has been shown to be safe in multiple clinical trials, so it has become a new goal for CML management, although information about TFR in Colombia is scarce. Objective Our aim is to show the outcomes of TFR in Colombia. Design The Colombian Association of Hematology and Oncology (ACHO)'s hematological disease registry (RENEHOC) is a multicenter study that has collected information in 14 centers with Institutional Ethics Committee approval. This report represents a sub-analysis of the patients in the registry in whom discontinuation was performed. Setting RENEHOC is a nationwide, multicenter registry on hematologic malignancies that captures information from academic and general community centers. Since 2019, it has been collecting information on CML. Patients or other participants A total of 357 CML adult patients treated in the last 20 years have been registered until now on RENEHOC. Twenty patients were considered candidates for TFR; in 14 of them, TKI have been discontinued. Interventions Treatment was according to investigator preferences. Ten patients received Imatinib as first-line and ten received second-generation TKI. Four required a second line (Nilotinib); three due to intolerance. Nine patients discontinued in a standardized TFR program, three with the intention to seek a pregnancy, one for toxicity (pleural effusion), and one for personal reasons. Main outcome measures The main outcome measured is survival without TKI re-initiation. Results The mean age was 56 yrs. (25–92), 11 were women, and 19 were in the chronic phase. On average, they received 9.3 years of TKI (3.2–14) and were in RMM for 6.9 years before TFR. At a median follow-up of 15.2 months (range 1–44.5), 12 patients remain TKI-free; the patients that re-initiated TKI regained 4.5 MMR. Five patients developed withdrawal syndrome. Conclusions The TFR is a real goal for a selected group of patients with CML. This report represents real-world data in Colombia, showing its feasibility and safety under well-controlled settings. Funding ACHO has received grants for RENEHOC project from Takeda, Abbvie, Amgen, Dr. Reddy's.

Curative Efficacy of First Generation TKI in the Treatment of CML-CP Combined with vPh and Analysis of Its Genetic Characteristics

To investigate the curative efficacy of first generation TKI in the treatment of CML-CP combined with vPh and genetic characteristics. 60 patients with CML-CP combined with vPh from January 2010 to May 2017 in the First Affiliated Hospital of Kunming Medical University were chosen as CML-CP-vPh group, and 107 patients with CML-CP combined with typical Ph chromosome at the same time were chosen as control group. The patients in two groups were treated with imatinib; The curative efficacy, karyotype and FISH signal type were compared between 2 groups, and the factors influencing long-term survival of patients were analyzed by Cox risk model. There was no significant difference in the demographic and hematological baseline data between 2 groups (P＞0.05), and there was no significant difference in the incidence of drug-resistance between 2 groups (P＞0.05). The incidence of primary drug-resistance and primary hematological drug-resistance in the CML-CP-vPh group were significantly higher than that in control group (P＜0.05). There was no significant difference in the accumulative CCyR rate, accumulative MMR rate, OS and EFS between 2 groups (P＞0.05). Multivariate Cox model analysis showed that vPh not correlated with OS and EFS of patients with CML-CP (P＞0.05). The factors influencing OS in CML-vPh patients included high risk of Sokal scores, peripheral blood basophils proportion ≥10%, BCR-ABLIS in 3 months after treatment＜10%, achieviag CCyR in 6 months after treatment and achieviag MMR in 12 months after treatment (P＜0.05). The factors influencing EFS included BCR-ABLIS＜10% in 3 months after treatment and achieving MMR in 12 months after treatment (P＜0.05). The regions with high frequency of heterotopic involvement included 12q1, 12q2 [9 cases (15.00%)] and 1p3 [8 cases (13.33%)]. The percentage of 2G2R1Y, 1G1R2F, 1G2R1Y, 2G1R1Y and 1G1R1Y in FISH signal types were 73.33%, 10.00%, 1.67%, 1.67% and 1.67% respectively. Patients with CML-CP combined with vPh possess higher primary drug-resistance rate and primary hematological drug-resistance rate for the first generation TKI, while second-generation TKI can efficiently improve long-term survival, its efficacy is similar to efficacy for patients with typical Ph chromosomes. CML-CP combined with vPh does not display special demographic and hematological characteristics. The main involved regions of heterotopic variants include 12q1, 12q2 and 1p3, while 2G2R1Y type is the most common type of FISH signal.

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n=203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.

Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）在治疗癌症的同时仍面临不可避免的耐药。通过研究EGFR-TKI发生耐药的机制从而发现一些新的分子标志物和药物靶点，促进了第三代TKIs的发展并针对耐药提出合理化建议。经临床验证，T790M是一个可用于判断预后的生物学标志物，可导致第一代和第二代TKIs的难治性。对于T790M阴性的患者，尽管靶向治疗和检查点阻断治疗结合可能提供有希望的替代方案，细胞毒性药物序贯EGFR-TKI治疗仍是疾病进展后可接受的标准治疗方式。在T790M阳性患者中，第三代EGFR-TKI药物奥希替尼在随机临床试验中优于铂类二联化疗和第一代EGFR-TKI。文章综述了近年来有关奥希替尼在非小细胞肺癌患者获得性耐药机制及治疗的主要文献，并展望了未来可能的研究方向。