Second-generation Tyrosine Kinase Inhibitor Therapy Research Articles

A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy

AbstractAlthough tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI–therapy failure in people with chronic-phase CML.

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

Therapeutic options for chronic myeloid leukemia following the failure of second-generation tyrosine kinase inhibitor therapy.

The management of chronic myeloid leukemia in the chronic phase (CML-CP) has witnessed significant advancements since the identification of a common chromosomal translocation anomaly involving chromosomes 9 and 22, which results in the formation of the Philadelphia chromosome driven by the BCR-ABL1 fusion protein. This discovery paved the way for the development of tyrosine kinase inhibitors (TKIs) that target the adenosine triphosphate (ATP) binding site of ABL1 through the BCR-ABL-1 fusion protein. Following the approval of Imatinib by the Food and Drug Administration (FDA) as the first TKI for CML treatment in 2001, the median overall survival (OS) for chronic phase CML (CML-CP) has significantly improved, approaching that of the general population. However, achieving this milestone crucially depends on reaching certain treatment response milestones. Since the introduction of imatinib, five additional TKIs have been approved for CML-CP treatment. Despite the availability of these treatments, many patients may experience treatment failure and require multiple lines of therapy due to factors such as the emergence of resistance, such as mutations in the ATP binding site of ABL, or intolerance to therapy. This review will primarily focus on exploring treatment options for patients who fail second-generation TKI therapy due to true resistance.

Comparison of Efficacy and Safety of Imatinib and Dasatinib in the Treatment of Chronic-phase Chronic Myeloid Leukemia

Chronic-phase chronic myeloid leukemia (CML-CP) treatment has significantly improved in recent years. The generational development of small molecule tyrosine kinase inhibitors (TKIs) such as Imatinib and Dasatinib, has revolutionized the treatment of CML. Their mechanisms and efficacy have been clear, but there is no literature review to summarize or comprehensively compare their efficacy and safety. Studies have revealed that second-generation TKI therapy yields noticeably greater response rates than imatinib and there is no marked difference in treatment-related adverse events between the two therapies. According to this direction, A double-therapies analysis was performed to assess the efficacy and tolerability of various front-line treatments for individuals with CML-CP. Both direct and indirect comparisons between the various treatment choices were taken into account in this general analysis. The author took Imatinib and Dasatinib as the main comparison objects and provide a comprehensive assessment of the two available therapies for CML-CP. By comparing the efficacy outcomes and adverse effects (AEs), the study was aimed to identify the treatment options that are both highly effective and well-tolerated for patients in general.

Clinical management of second-generation tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase, focusing on age and dose effects.

ABL1-tyrosine kinase inhibitors (TKIs) are an established treatment choice for patients with chronic myeloid leukemia in the chronic phase (CML-CP). However, effects of TKI dose modification have not been well investigated. In this study, we retrospectively analyzed 178 patients with newly diagnosed CML-CP who were treated with dasatinib or nilotinib, focusing on age and dose effects. Efficacy as measured by cumulative major molecular response (MMR) and molecular response 4.5 rates did not differ significantly between the younger group and elderly group. Elderly patients who started nilotinib at a reduced dose had similar or better efficacy outcomes (including cumulative MMR and continuation ratios) than other groups, and elderly patients who started dasatinib at a reduced dose had the lowest MMR ratio and longest MMR duration. Effects of dose modification based on age and TKI selection can be attributed to flexible management of TKI therapy in real-world practice, but further studies are required to validate the findings of this study.

Prognostic Model of Transformation to Blast Phase in Patients with Chronic Myeloid Leukemia

Background: Since the advent of Tyrosine kinase inhibitor (TKI) therapy, the survival of patients with chronic myeloid leukemia (CML) is approaching to that of general population. The European LeukemiaNet recommends monitoring reverse transcriptase quantitative PCR for the guidance of molecular response. However, the rare incidence of progression to blast phase may occur during frontline TKI therapy. The aim of this study is to identify prognostic factors for the progression to blast phase during frontline TKI therapy and to develop a nomogram to calculate the risk of transformation at 1 year. Methods: We analyzed 347 patients with newly diagnosed CML in chronic phase (CP) and accelerated phase (AP) who were treated with frontline TKI therapy (standard-dose imatinib, 73 patients; dasatinib, 144 patients; and nilotinib, 130 patients) from July 2000 to September 2014. The presence of comorbidity was assessed by the Adult Comorbidity Evaluation-27. Given the rare incidence of transformation to blast phase and equivalent efficacy of second-generation TKIs between dasatinib and nilotinib, we compared the cumulative incidence of transformation to blast phase between imatinib 400 mg/day and second-generation TKI therapy. We performed univariate and multivariate competing risk regression to identify prognostic factors for cumulative incidence of transformation to blast phase with treatment failure (intolerance, resistance, and/or others) during frontline TKI therapy as a competing events. Multiple imputation was performed for missing variables to reduce bias. Nomogram was developed to estimate 1-year cumulative incidence of transformation to blast phase. Results: The median age at the start of TKI therapy was 49 years (range, 15.1-86.4) with a median follow-up of 146 months (range, 5.3-253.9) (standard-dose imatinib, 231 months; dasatinib 137 months; nilotinib 138 months) (Table 1). Overall, the incidence of transformation to blast phase was observed in 8 patients during frontline TKI therapy; 4 patients received imatinib; and 4 patients received second-generation TKIs (1 patient, dasatinib; 3 patients, nilotinib). Competing risk regression identified percentage of blasts in peripheral blood and bone marrow, and standard-dose imatinib therapy as prognostic factors for transformation to blast phase during frontline TKI therapy. The 1-year cumulative incidence of transformation rates were 4% and 1% in the imatinib and second-generation TKI groups, respectively; the 5-year cumulative incidence rates were 5% and 1%, respectively (P=0.043 by Gray's test). The nomogram was developed for the risk calculations for 1-year transformation to blast phase (Figure 1). Conclusion: The incidence of transformation to blast phase is rare in the era of TKI therapy. The nomogram helps physicians select optimal TKI therapy to prevent the transformation to blast phase. Given the dismal outcome of patients who progressed to blast phase, we propose frontline second-generation TKI therapy in patients with estimated 1-year cumulative incidence of transformation above 5% or higher. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Predictive Scoring System for Therapy Failure in Persons with Chronic Myeloid Leukemia Receiving Initial a Second-Generation Tyrosine Kinase Inhibitor Therapy

Purposes Develop and validate a predictive scoring system for therapy failure in persons with chronic phase chronic myeloid leukemia (CML) receiving initial a second-generation tyrosine kinase inhibitor (2G-TKI). Methods Data from 329 consecutive subjects with CML receiving initial 2G-TKI therapy at one centre (Beijing, China) in a training dataset were interrogated to develop a predictive model which was then validated in 1,083 subjects from 65 other centers in China. Therapy-failure was defined using the 2020 ELN criteria including progression to accelerated or blast phases or CML-related death. Fine-Gray model was used for uni- and multi-variable analyses (UVA and MVA) to identify co-variates significantly-associated with therapy-failure. Akaike information criterion (AIC) was used to select prognostic co-variate and determine the best model. 1000 bootstrap re-samplings, Fine-Gray test, the minimal p-value approach, Bonferroni correction and kernel density estimator were used to determine optimal cut-offs to classify subjects into risk cohorts. Time-dependent receiver-operator characteristic curves (ROC) were used to estimate prediction accuracy and calibration plots used to determine concordance between predicted and observed cumulative incidences. Decision curve analysis (DCA) was used to calculate the net benefit using the model. Results In the training dataset, 279 subjects (85%) initially received nilotinib; and 50 (15%), dasatinib. Median 2G-TKI therapy-duration was 36 months (interquartile range [IQR], 24-68 months). 75 subjects (23%) had therapy-failure at a median of 9 months (IQR 3-12 months) after therapy start. In MVA, increasing splenomegaly and a higher percentage blood blasts were significantly-associated with the higher cumulative incidences of therapy-failure. We used these data to develop a predictive scoring system: "2G-TKI failure risk score= 0.6405×[(spleen size below the costal margin in cm + 0.2)/10] + 0.1348×(blood blasts + 0.2)" which divided subjects into low- (score ≤ 0.3021; n = 89; 31%), intermediate- (0.3021 < score < 1.4508; n = 155; 54%) and high-risk (score ≥ 1.4508; n = 43; 15%) cohorts with 5-year cumulative incidences of therapy-failure of 3% (95% Confidence Interval [CI], 0, 5%), 26% (20, 32%) and 72% (56, 88%; p-value for trend < 0.001; Figure 1A). Hazard ratios (HRs) for therapy-failure (low-risk cohort as reference) were 4.8 (1.7, 13.6; p = 0.002) and 16.5 (5.7, 47.6; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the external validation dataset, subjects were classified into the low- (n = 433; 40%), intermediate- (n = 583; 54%) and high-risk (n = 67; 6%) cohorts using our scoring system. 5-year cumulative incidences of therapy failure were 8% (3, 13%), 18% (12, 25%) and 44% (29, 60%; p for trend < 0.001; Figure 1B). HRs (low-risk cohort as reference) were 2.7 (1.9, 3.6; p < 0.001) and 10.6 (5.8, 15.4; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the training dataset cohort time-dependent AUROC curves for therapy-failure at 1-, 3-, and 5-years in the model were 0.73-0.82 and 0.68-0.75 in the validation dataset. Calibration plots for the 1-, 3- and 5-years cumulative incidences of therapy-failure indicated good concordance between predicted and observed outcomes. DCA curves indicated net benefit from using the predictive scoring system in clinical settings. Conclusions We developed and externally validated a therapy-failure scoring system in persons with chronic phase CML receiving initial 2G-TKI. The model had high AUROCs and performed well in calibration plots and DCAs. Our model may help physicians decide appropriateness of initial the 2G-TKI therapy including possible selection of appropriate haematopoietic cell transplant candidates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study

IntroductionBefotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. MethodsThis was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. ResultsA total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75–100 mg), respectively. At data cutoff (August 15, 2021), independent review committee–assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%–72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%–61.5%) in cohort A and 65.9% (95% CI: 60.1%–71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6–12.5) months in cohort A and 12.5 (95% CI: 11.1–13.8) months in cohort B. The median independent review committee–assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0–not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%–55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%–78.2%) and 55.9% (95% CI: 37.9%–72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6–NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8–NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. ConclusionsBefotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Analysis the influence factors of treatment free remission outcome with chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitors

Objective: To explore the related factors affecting the outcome of treatment free remission (TFR) in patients with chronic myeloid leukemia (CML). Methods: Clinical data of CML patients with automatic discontinuation of tyrosine kinase inhibitor (TKI) from the CML cooperative organization of Henan province between June 2, 2013 to March 27, 2021 and the follow-up time was ≥ 6 months were retrospectively analyzed. Log-rank test was used for univariate analysis and Cox proportional risk regression model was used for multivariate analysis. Results: A total of 135 patients were enrolled, and 69 patients (51.1%) were femal and 66 patients (48.9%)were male. Median age was[M(Q1,Q3)] 49 years (38, 58)at discontinuation.Before discontinuation, 72 patients (53.3%) were on treatment with second-generation TKI, 63 patients (46.7%) were on treatment with IM, 17patients (12.6%) had a history of TKI reduction/withdrawal;median duration of treatment was months 84 (68, 108) for all patients;median time of TKI treatment to DMR was months 12(8, 26);median duration of DMR was months 65 (54, 84), and 9 patients (6.7%) had unsustained DMR.The median follow-up time was months 16(6-96), 35 patients (25.9%) lost MMR at a median months 3(1-22), overall estimated TFR was 74.1%.The univariate analysis results showed that:second-generation TKI was used, the time of TKI treatment to DMR was ≤12 months, DMR duration time ≥48 months, had sustained DMR, without TKI reduction/withdrawal history were favorable factors affecting of TFR in patients with TKI discontinuation (all P<0.05).The TFR rate of the second-generation TKI therapy group was significantly higher than the IM therapy group (81.9% vs 65.1%, P=0.019).The multivariate analysis results showed that second-generation TKI treatment[RR=0.451, 95%CI (0.227-0.896), P=0.023] and had sustained DMR [RR=0.120, 95%CI (0.053-0.271), P<0.001] were the protective factors of TFR in patients with TKI discontinuation. Conclusions: Treated with second-generation TKI and had sustained DMR are the protective factors of TFR in patients with TKI discontinuation.The CML patients who had sustained DMR more≥48 months before TKI discontinuation showed a better TFR.

Efficacy of Aumolertinib (HS-10296) in Patients With Advanced EGFR T790M+ NSCLC: Updated Post-National Medical Products Administration Approval Results From the APOLLO Registrational Trial

IntroductionAumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation. MethodsPatients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review. ResultsA total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6–74.6). The disease control rate was 93.4% (95% CI: 89.6–96.2). The median duration of response was 15.1 months (95% CI: 12.5–16.6). The median progression-free survival was 12.4 months (95% CI: 9.7–15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5–80.3) and 91.3% (95% CI: 72.0–98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6–not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study. ConclusionsAumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People’s Republic of China for patients positive for EGFR T790M NSCLC.

Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients.

Background:Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations.Methods:Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR).Results:Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80.Conclusions:We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

Impact of Molecular Response at Specific Timepoints in Patients with Newly Diagnosed Chronic Myeloid Leukemia Treated with Second Generation Tyrosine Kinase Inhibitors

Impact of Molecular Response at Specific Timepoints in Patients with Newly Diagnosed Chronic Myeloid Leukemia Treated with Second Generation Tyrosine Kinase Inhibitors

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

Cytogenetic and Molecular Response with First- and Second-Generation Tyrosine Kinase Inhibitor (TKI) Therapy in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Introduction: SIMPLICITY (NCT01244750) is an ongoing observational study of patients (pts) with CP-CML receiving first-line (1L) imatinib (IM), dasatinib (DAS), or nilotinib (NIL) in routine clinical practice in Europe and the United States (US). The study aimed to assess the effectiveness and safety of TKIs for pts with CP-CML outside the clinical trial setting. Here, we analyze the clinical outcomes (complete cytogenetic response [CCyR] and major molecular response [MMR]) associated with the CML risk level in SIMPLICITY pts with CP-CML receiving first-generation (1G: IM) or second-generation (2G: DAS/NIL) TKI therapy. Methods: Clinical outcomes after 1L TKI initiation were assessed by CyR (karyotype analysis or fluorescence in situ hybridization) and polymerase chain reaction MR tests. Proportions of pts achieving CCyR and MMR are presented for those with at least one recorded response test during 1L TKI therapy. Outcomes were stratified by CML risk level (Hasford scoring; low [≤780] and intermediate/high risk [≥781]), and the differences between 1L 1G and 2G TKI cohorts analyzed. Statistical comparisons for continuous variables were made using t-tests and the Mann-Whitney U test, and chi-square test for categorical variables. Multivariate logistic regression models, adjusted for age, gender, region, risk level (low vs intermediate/high), and baseline (BL) comorbidities, were used to determine if generation of TKI therapy (1G/2G) was associated with clinical response (CCyR or MMR) after start of 1L TKI. Performance and timing of CyR and MR tests were at the discretion of oncologists, limiting the analysis of outcomes and comparisons of CCyR and MMR rates. Results: There were 1,241 pts (IM: n=416; DAS: n=417; NIL: n=408) at database lock (October 2018); only 391 (31.5%) pts with CP-CML receiving 1L TKI were identified to have the elements needed for a Hasford risk assessment documented at diagnosis (IM: n=140; DAS: n=119; NIL: n=132). CML risk assessment (Hasford score) was significantly more common in Europe (68.7% vs 11.7% in the US, p&lt;0.0001). No significant difference in risk score was observed across the different 1L TKI groups (p=0.7012). Of the 130 (33.2%) pts with recorded CyR test results, no significant differences in BL demographics were observed except for median age at start of 1L TKI and BL cardiovascular and gastrointestinal (GI) comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved CCyR compared with 1G TKI in both low (88.1% vs 79.2%) and intermediate/high (73.0% vs 44.4%) CML risk categories, with statistical significance reached in the intermediate/high-risk group (p=0.0209). Multivariate logistic regression analysis (Figure 1) showed that pts were approximately 3 times more likely to achieve CCyR if receiving 2G TKIs (odds ratio [95% confidence interval]: 2.93 [1.21, 7.13] vs 1G, p=0.0177). Other predictors of CCyR were low baseline CML risk (5.75 [2.00, 16.50] vs intermediate/high CML risk, p=0.0011) and treatment at European centers (2.72 [1.03, 7.18] vs US centers, p=0.0431). MR test results were recorded in 358 (91.6%) pts; median number of MR tests was significantly higher in Europe (8 vs 5 in the US, p&lt;0.0001). No significant differences in pt demographics were observed except for age at start of 1L TKI and BL GI comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved MMR compared with 1G TKI in the low (82.0%vs 74.6%) and intermediate/high (87.0% vs 72.4%) CML risk groups, with significance reached in the latter cohort (p=0.0185). Multivariate logistic regression analysis showed that TKI generation was the sole predictor of MMR achievement; pts were approximately twice as likely to achieve MMR with 2G TKIs as with 1G TKI (OR: 2.13 [1.23, 3.70], p=0.0070) (Figure 1). Conclusions: Despite treatment guidelines recommending 2G TKI therapy for pts with higher CML risk, our analysis of SIMPLICITY pts showed no differences in 2G versus 1G TKI use in low and intermediate/high risk groups. Here, the use of 2G TKIs, compared with 1G TKI, was a significant predictor for achieving either CCyR or MMR, thereby validating the clinical response benefits of 2G TKIs regardless of BL CML risk. These findings emphasize the importance of adhering to treatment guidelines when making decisions on the generation of TKI, first (IM) or second (DAS/NIL), to be used in the 1L treatment of pts with CP-CML, particularly in higher risk pts. Disclosures Cortes: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment, Equity Ownership. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Novartis Oncology: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy.

The Relationship between Molecular Response of BCR-ABL1 Transcripts within 6 Months and Deep Molecular Response at 18 Months to Dasatinib Treatment for Newly Diagnosed Patients with CML-CP

BACKGROUND: The overall survival of patients with newly diagnosed chronic myeloid leukemia (CML) has improved significantly since the introduction of tyrosine kinase inhibitors (TKIs), and recently, some patients with CML who achieve stable deep molecular response (DMR) to TKI therapy could safely suspend treatment. In addition to European LeukemiaNet criteria (ELN), the European Society for Medical Oncology (ESMO) proposed that less than 0.01% of BCR-ABL1 transcript (MR4.0) on the International Scale (IS) after 18 months is optimal for patients to achieve treatment-free remission. Branford et al. indicated that major molecular response (MMR; less than or equal to 0.1% of BCR-ABL1 IS ; MR3.0) at three months predicts stable undetectable BCR-ABL1 transcript levels during imatinib treatment. However, second-generation TKIs induce more rapid and deeper responses at early time points compared to imatinib; however, whether early molecular response predicts MR4.0 by 18 months to second-generation TKI therapy, remains unclear. AIMS: We retrospectively analyzed BCR-ABL1 transcript levels in patients with CML in chronic phase (CML-CP) at 3, 6, 12, and 18 months after initiating dasatinib treatment to identify molecular milestones that would predict MR4.0 by 18 months. METHODS: Fifty-nine newly diagnosed patients with CML-CP were included in this study. The median age was 61 years (18-81 years), 72% of whom were males, and patients older than 65 years comprised 31% of the overall enrollment. Eighty-six percent of them had low and intermediate Sokal scores. Patients received 100 mg of dasatinib once daily. Dose interruption or reduction was allowed if drug-related grade 3 non-hematological toxicity or grade 3 or worse hematological toxicity occurred.BCR-ABL1/ ABL ratio IS (BCR-ABL1 IS) was performed at approximately 3-month intervals. To assess the kinetics of response, we calculated halving time (HT) of BCR-ABL1 IS. HT-BCR-ABL1 was calculated as described by Branford et al. We used a receiver-operating characteristic (ROC) curve to identify the cut-offs in transcript levels at three and six months. Mann-Whitney test was used to determine statistical significance. Categorical variables were compared using Fisher's exact test. Factors were subjected to multivariate analysis using Cox regression; differences with p&lt;0.05 were considered statistically significant. RESULTS: The median BCR-ABL1 IS level before therapy was 82.1% (range 13.5-157.9 %). The estimated MMR by 12 months and MR4.0 by 18 months were 86.4% and 50.8%, respectively. We analyzed each into a cohort that achieved MR4.0 by 18 months (MR4.0 cohort) and a cohort that did not achieve MR4.0 (non-MR4.0 cohort). The BCR-ABL1 IS level in each cohort is indicated in the Table. Median HT-BCR-ABL1 IS 0-3 months was 10.8 days (6.5-71.3 days) in MR4.0 cohort, and 13.0 days (8.5- 169.6 days, p&lt;0.05) in non-MR4.0 cohort, whereas that of 3-6 months was 24.4 days (6.5-228.9 days) in MR4.0 cohort and 47.3 days (18.0- 154.9 days, p&lt;0.01) in non-MR4.0 cohort. The shape of BCR-ABL1 IS descent was biphasic in MR4.0 cohort. The cut-off values of BCR-ABL1 IS at 3 months and 6 months for prediction of MR4.0 by 18 months were 0.122% (specificity 0.964, sensitivity 0.586, AUC 0.784) and 0.048% (0.852, 0.833, 0.909), respectively. We determined the optimal threshold for predicting MR4.0 by 18 months using these parameters. Some of them (BCR-ABL1 IS 3 months ≤0.122%,BCR-ABL1 IS 6 months ≤ 0.048%, BCR-ABL1 IS 6 months ≤1%: ELN optimal criteria) were identified as predictive cut-off values for MR4.0 by 18 months in univariate analysis (BCR-ABL1 IS 3 months ≤0.122%; 94.4% vs. 30.7%, p&lt;0.01, BCR-ABL1 IS 6 months ≤ 0.048%; 85.7% VS. 20.7%, p&lt;0.01 and BCR-ABL1 IS 6 months &lt;1.0%; 58.8% vs. 0%, p&lt;0.01). However, BCR-ABL1 IS 3 months ≤ 10% (ELN optimal criteria at three months) was not identified as predictive cut-off value for MR4.0 (54.7% vs. 20%, N.S.). Multivariate analysis indicated that BCR-ABL1 IS 6 months ≤ 0.048% was a significant independent factor for achievement of MR4.0 by 18 months (hazard ratio 0.05, p&lt;0.01). CONCLUSION: Even though dasatinib is highly-priced, dasatinib treatment results in higher rates of molecular responses in newly diagnosed patients with CML-CP. Assessment of molecular reduction within six months has become an important landmark to predict MR4.0 by 18 months during dasatinib treatment for patients with the aim to achieve treatment-free remission. Disclosures Oyake: Astellas: Speakers Bureau; Celgene: Honoraria; Chugai: Honoraria; Kyowa-Hakko Kirin: Honoraria. Ito:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Ono: Honoraria.

Intrapatient Molecular and Histologic Heterogeneity After First-generation or Second-generation TKI Therapy of NSCLC Patients: Potential Clinical Impact on Subsequent third-generation TKI Treatment.

The discovery of tyrosine kinase inhibitors (TKI) has remarkably improved the clinical course of patients with non-small cell lung cancer driven by Epidermal Growth Factor Receptor (EGFR) mutations. However, virtually in all cases, the disease resurfaces in a TKI-resistant form that is mainly linked to an acquired EGFR-T790M mutation, a MET amplification, or small cell lung cancer (SCLC) transformation. Third-generation TKIs are able to block tumor growth through an irreversible binding to the T790M-mutated receptor. Such new treatments require the diagnostic analysis of new pathologic tissue or a liquid biopsy to detect the presence of the T790M mutation. Pre-TKI and post-TKI biopsies from 27 patients with an activating EGFR mutation were collected and analyzed for EGFR-T790M mutation, MET amplification, and SCLC transformation. The T790M mutation was found in 16 patients (59%) whereas MET gene amplification was found in 2 (10.5%) of 19 evaluated cases. The histologic transformation from adenocarcinoma (ADC) to SCLC was identified in 3 patients (11%). In one of them reversal from SCLC back to adenocarcinoma was observed. One patient had the T790M mutation concordantly detected in 2 synchronous lesions whereas another patient showed T790M positivity only in one of 2 specimens. In 4 patients longitudinal biopsies revealed T790M gains and losses not always according to biological expectations. Intrapatient molecular or histologic heterogeneity may be frequently found during routine treatment of non-small cell lung cancer patients. This biological aspect may have profound repercussions on subsequent therapeutic decisions, and therefore requires in-depth investigation.

Single center, open and prospective evaluation of genomic sequencing on cerebro-spinal fluid, brain metastatic lesions and plasma from patients in non-small cell lung cancer with brain metastasis.

e13578 Background: Leptomeningeal metastases are observed in 9.4% non–small Cell Lung Cancer (NSCLC) patients with EGFR mutations. Depending on patient specific gene mutations, tumor cells may also have different proliferative activity, leading to differential metastatic potential. However, the clinical significance of observed gene mutation differences between CSF, plasma, primary pulmonary tumor and metastatic brain tumor samples remains unclear and should be further explored. Methods: From Apr. 2018 to Jan. 2019, plasma and CSF paired samples were drawn from consented NSCLC patients with diagnosed brain metastasis. Of these 21, brain lesion samples were obtained from 5 patients. All the samples were tested by next-generation sequencing. Patients were treated based on the detection results. Results: For this cohort, the detection rate of EGFR mutations in CSF cfDNA versus plasma cfDNA/CTC was 57.1% and 23.8% respectively (p &lt; 0.05). For patients who had not received tyrosine kinase inhibitor (TKI) therapy, the CSF cfDNA EGFR mutation results were consistent with results for plasma, brain lesion and primary tumor samples. Conversely, for patients who had received TKI therapy, EGFR mutations detected in CSF were consistent with those from brain samples, but different from those observed in plasma or primary tumor samples. A high response rate (ORR, 70%; DCR, 90%) was observed in patients with EGFR positive detected in CSF after treatment with second orthird-generation TKI. Among the EGFR mutations detected in CSF, the EGFR uncommon mutation frequency was 58.3%(7/12), including G7I9A/L861Q/L703P/R776H/G575R/T790M 85.7% (6/7) of these occurred in LM patients. One patient who progressed from BM to LM had an uncommon mutation in the CSF sample. Among these five patients with EGFR G719A or L861Q positive and T790M negative, 4 patients had PR and 1 patient had SD after the second-generation TKI therapy. Conclusions: Differences in EGFR gene mutations were observed between CSF, plasma, primary pulmonary lesion and brain tissue samples in NSCLC patients with diagnosed brain metastasis after TKI therapy. The reasons for this discrepancy remain to be understood. Nevertheless, CSF may be a useful prognostic tool for patient monitoring and metastasis risk evaluation. The detection of uncommon EGFR mutations may increase the risk of LM in NSCLC patients. Clinical trial information: ChiCTR1800017499.

Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non–Small-Cell Lung Cancer

BackgroundStandard therapy of advanced non–small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear. Patients and MethodsA total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing. ResultsWe detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations. ConclusionInformation about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations.

Targeted therapies: Remembrance of things past - discontinuation of second-generation TKI therapy for CML.

Data from the recent Stop 2G-TKI study confirm that around 60% of patients with chronic myeloid leukaemia who discontinue second-generation BCR–ABL1 tyrosine-kinase inhibitor (TKI) therapy after a sustained deep molecular response remain in remission for longer than 1 year. Importantly, the interim findings suggest that prior response to first-line TKI treatment might predict relapse risk after treatment discontinuation.

Safety and Efficacy of Nilotinib (NIL) in Patients (Pts) with Chronic Phase (CP) or Accelerated Phase (AP) Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib Mesylate (IM): Results from the Multicenter, Observational NOVEL Study in Taiwan

▪Background: The selective tyrosine kinase inhibitor (TKI) NIL is approved for the treatment of IM resistant CML-CP or CML-AP pts globally, including Taiwan. A non-interventional, multi-center observational study of N ilotinib in pts with CP or AP Philadelphia chrOmosome positiVe (Ph+) chronic myElogenous Leukemia (NOVEL) was conducted to assess the safety and efficacy of NIL in Taiwanese patients with IM intolerance or resistance.Methods: NOVEL was an open-label, single arm, study conducted across 12 centers in Taiwan for a period of up to 2 years (y). Adult CML-CP or CML-AP pts with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to ≥1 prior CML therapy were enrolled. Also, IM resistant or intolerant pts with prior second-generation TKI therapy could be included. The primary objective was to collect long-term safety data in pts treated with NIL 400 mg twice daily. Efficacy data were collected as secondary objectives.Results: A total of 85 pts including CML-CP (n = 76) pts and CML-AP (n = 9) were enrolled. Median age was 47 y (range, 21-85); 56.5% were males. At baseline, median duration of CML diagnosis was 20.3 (range: 1.4-287.7) months (mo). In 7 pts, confirmed BCR-ABL mutations (E450G, E543A, F317L, F486S, G250E, M244V, M351T) were found, 26 (30.6%) did not have mutations, and 52 (61.2%) did not perform BCR-ABL mutation analysis. All pts (100%) had been treated with prior IM, while 19 pts (22.4%) pts had also received dasatinib; 61 (71.8%) pts had complete hematologic response (CHR) prior to NIL initiation.Of the 85 pts, 54 (63.5%) completed the study while 31 (36.5%) discontinued due to unsatisfactory therapeutic effect (n = 14), consent withdrawal (n = 5), adverse events (n = 4), deaths (n = 3), pregnancy (n = 1), administrative problems (n = 1), unknown (n = 1), and other reasons (n = 2).A total of 1166 AEs were reported by 80 (94.1%) pts, of which 70 (6%) AEs in 28 (32.9%) pts were serious. Of the total AEs, 336 (28.8%) drug-related AEs were reported in 60 (70.6%) pts with the majority (87.5%) being Grade 1 or 2. Of the total drug-related AEs, 85 (25.3%) were hematological and 251 (74.7%) were non-hematological. Common hematological AEs (≥5 % of pts) were thrombocytopenia (n=18; 21.18%) and anemia (n=12; 14.1%). Frequent non-hematological AEs (≥5 % of pts) were increased alanine amino-transferase ([ALT], n = 18; 21.2%), pruritus (n = 15; 17.7%), increased bilirubin (n=12; 14.1%), rash (n = 10; 11.8%), increased aspartate transaminase ([AST], n = 7; 8.2%, and increased lipase (n = 5; 5.9%). Seven deaths were reported during the study and follow-up period, respectively due to cardiopulmonary failure (suspected to be related to study-drug), acute myelogenous leukemia, accident, exacerbation of chronic obstructive pulmonary disease, subarachnoid hemorrhage, pneumonia, and sepsis. Of the 19 pts, who switched to NIL due to known AEs with IM, AEs resolved in 16 (84.2%) pts (Table).Cumulative CHR, major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABLIS <0.01%) and MR4.5 (BCR-ABLIS <0.0032%) rates are presented in figure. Almost 50% of pts achieved MMR by 18 mo. In pts with confirmed BCR-ABL mutations, the median time to CHR and MMR were 11.9 mo and 37.0 mo compared to 2.3 mo and 16.9 mo in other pts, respectively. In pts without CHR at baseline, median time to CHR and MMR was 3.1 mo and 15.4 mo, respectively. Statistically significant benefit on overall survival (OS) and progression-free survival (PFS) was seen in pts with CML-CP versus pts with CML-AP at screening. Median OS and PFS were not reached for CML-CP pts. In CML-AP pts, median OS was 42.3 mo (95% Confidence interval [CI], 4.4-42.3), and median PFS was 42.3 mo (95% CI, 3.3-42.3).Conclusions: The NOVEL study demonstrates that treatment with NIL was effective in achieving cytogenetic and molecular responses in pts resistant or intolerant to IM in the real world setting. The response outcomes appeared to be influenced by BCR-ABL mutation status and CHR status at baseline, while OS and PFS were influenced by disease status (CML-CP or CML-AP) at screening. Safety profile of NIL was consistent with earlier reports. A number of AEs had lower incidences, with no incidence of peripheral arterial occlusive disorder (PAOD) reported, reflecting appropriate disease management among clinicians in Taiwan. More than 80% of AEs due to IM were resolved after switching to NIL. [Display omitted] [Display omitted] DisclosuresTang:Novartis: Consultancy, Honoraria. Chang:Novartis: Honoraria. Hseih:Novartis: Employment. Lin:Novartis: Employment. Darko:Novartis: Employment. Cheng-Shyong:Novartis: Honoraria, Speakers Bureau.