2nd Tyrosine Kinase Inhibitors Research Articles

Management of Patients with Treatment-Free Remission in Chronic Myeloid Leukemia

Background: Chronic myeloid leukemia (CML) is a relatively common BCR-ABL-positive chronic myeloproliferative neoplasm within the structure of morbidity by hematological malignancies with primary bone marrow (BM) involvement, being characterized in the advanced phases by a relapsing evolution, sizable disease burden, unfavorable socio-economic impact and poor prognosis. Tyrosine kinase inhibitors (TKIs) have improved fundamentally the treatment outcomes in CML, bringing the patients' life expectancy closer to that of the general population. Nevertheless, TKI discontinuation studies indicate discordance in the incidence of hematological and molecular relapses. Objectives: The aim of the study was to evaluate the short- and long-term outcomes of treatment discontinuation in CML patients with complete molecular response (CMR). Material and methods: This prospective study included 22 patients with chronic phase of CML, treated and followed up at the Oncologic Institute from Moldova between 2017-2022. The age range was 29-73 years (average age - 45.8 years). The male/female ratio was 1:1.2. The quantitative reverse transcription polymerase chain reaction (PCR) was performed in order to determine the expression of the BCR-ABL p210 and p190 transcripts. Five transcription products (b2a2, b3a2, b2a3, b3a3 si e1a2) were analyzed by the usage of the PCR test. The real-time quantitative PCR revealed the wide range of BCR-ABL p210 transcript: 21.84-100% IS. In 7 (31.8%) cases the initial rate of BCR-ABL p210-positive cells was less than 50%. Only 2 (9.0%) patients also proved to be positive for BCR-ABL p190 transcript. Results: CMR was obtained in 15 (68.2%) patients after imatinib therapy and in 7 (31.8%) patients after therapy with 2nd TKIs generation. The therapy with TKIs was stopped due to the different reasons in all patients after the achievement of CMR. Two (9.1%) patients discontinued the TKIs treatment due to the pregnancy. The molecular relapse occurred in 6 (27.3%) pts, including one pregnant female. There were no subsequent hematological relapses. All patients with molecular relapse had the initial BCR-ABL p210 transcript expression > 50%. One (4.5%) of them was positive for BCR-ABL p190 transcript at diagnosis. The CMR span ranged between 2.5-26 months in relapsed patients. The range of BCR-ABL p210 transcript in the relapsed cases was 0.002-0.56%. These patients attained the 2nd CMR after resuming the treatment with the same or higher TKIs generation. In 2 (9.0%) pregnant females the pregnancy resulted in the healthy newborns. One (4.5%) female with a history of lymphoblastic type of acute phase experienced the minor molecular relapse (BCR-ABL p210 transcript - 0.56%), and reobtained the CMR after restarting imatinib mesylate. The relapsed patients did not develop the 2nd molecular relapse. All patients are alive, with the ECOG-WHO score of 0-1. Conclusions: TKIs stopping proved to be a reliable management option in CML patients with chronic phase, CMR and low BCR-ABL p210 transcript expression at diagnosis. The stable 2nd CMR may be achieved after resuming the TKIs treatment at a higher dosage or generation in patients with minor molecular relapse. Pregnancy may not influence the molecular relapse rate after TKIs discontinuation and its curability.

Chinese Expert Consensus on Management of Special Adverse Effects 
Associated with Lorlatinib

间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性，并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好，其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等，多为轻至中度，通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC，开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况，预先告知患者可能经历的用药相关不良反应，并定期监测以实现药物临床获益的最大化。同时，多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。

Abstract 3346: BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC

Abstract Background: Activating mutations in EGFR, e.g., L858R (L) and Del19 (D), are observed in 14.1-32.3% of NSCLC worldwide and defines a druggable entity. Single agent EGFR TKI treatment was established in clinical trials. However, a treatment-emergent mutation of T790M (T) was identified as a major source of drug resistance. Irreversible 2nd and 3rd generation EGFR TKIs were shown effective. Mutant-specific inhibition by 3rd generation EGFR TKIs reduced adverse events such as skin toxicities. The emergence of a missense mutation at C797 (C), to which irreversible TKIs covalently bind, limited their efficacy. Patients harboring treatment-emergent C mutations are left with few therapeutic options. Despite anecdotal reports of efficacy from 1st generation TKIs, these complex molecular variants involving C797 are an increasing clinical concern. To prevent the emergence of drug-resistant subclones, a broad-spectrum EGFR TKI against both treatment-emergent and drug-naïve mutants is required. Such a 4th generation EGFR TKI must also enable monotherapy, allowing precise dose adjustment in case of toxicity. Method: Derived from BBT-176 which is under clinical evaluation (NCT04820023), we synthesized BBT-207 and other related molecules. Using Promega ADP-Glo™ kinase assay, we tested compounds against wild-type (WT) and mutated EGFR proteins. Ba/F3 cells harboring WT and mutated EGFR genes were created and cell viability was measured by CellTiter-Glo® and SpectraMax iD3®. In vivo anti-tumor activity was evaluated in Ba/F3 cell-derived xenograft models and an Osimertinib-resistant patient-derived xenograft model. Single dose pharmacokinetic (PK) study was performed in animals. Results: BBT-207 showed IC50 values < 10 nM against EGFR triple mutants (DTC and LTC) and comparable IC50 values against double mutants (DC and LC), while Osimertinib was ineffective in both groups. BBT-207 was also as active as Gefitinib to single mutants (D and L). Double mutants containing T790M (DT and LT) were inhibited effectively by BBT-207 and Osimertinib at similar concentrations, while not by Gefitinib. In in vivo models to which Osimertinib was inactive (LC and DTC), significant tumor growth inhibition was observed from BBT-207 alone, which was enhanced by the addition of Osimertinib. PK studies in mouse, rat, dog and monkey were consistent with high exposure and sustained drug concentrations above the IC50 values, with evidence of penetration into the central nervous system. Conclusion: BBT-207 is a reversible, mutant-specific, broad-spectrum TKI, active to clinically observed mutations of EGFR and is expected to be compatible with monotherapy of QD schedule in humans. BBT-207 is well-positioned to augment the treatment of EGFR mutated NSCLC, either for acquired drug resistance or in earlier line. Citation Format: Taiguang Jimmy Jin, Sang-Uk Kang, Chulwon Kim, Jehrod Brenneman, Mihee Song, Pavel Printsev, Bo-Bae Seo, Yong-Hee Lee, Sang-Yoon Lee. BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3346.

Uncommon single and compound EGFR mutations: clinical outcomes of a heterogeneous subgroup of NSCLC

Molecular characterization of non-small-cell lung cancer (NSCLC) is essential to define the correct therapeutic algorithm in metastatic disease. Approximately 90% of epidermal growth factor receptor (EGFR) mutations are usually associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The remaining 10% defines a small, extremely heterogeneous subgroup of mutations, with a varied profile of sensitivity and response to target therapies.This retrospective observational study includes 47 patients affected by metastatic NSCLC harboring uncommon EGFR mutations (single or compound mutation). Patients were treated with EGFR-targeting TKIs or platinum-based chemotherapy as first-line treatment.Median OS resulted longer in the compound mutation group when compared to single rare mutations (33.6 vs 12 months; P = 0.473); a similar result was observed for PFS (16 vs 7.6 months; P = 0.281), although statistical significance was not reached. ORR, PFS and OS resulted similar for patients treated with first-line EGFR TKIs or chemotherapy. No difference in terms of PFS and OS was found according to the TKI administered.Compound mutations seem to be a good prognostic indicator for OS; they are also predictive of response to 1st and 2nd generation EGFR TKIs, as well as exon 19 insertions and mutations in codon 719 of exon 18. For mutations in exon 18 (not in codon 719) and exon 20 insertions, chemotherapy seems the most effective available option. The addition of immunotherapy to chemotherapy could change this approach in the next future.

Long-Term Outcome of CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors in the Second Line: A Single Center Experience

Background: Since the introduction of tyrosine kinase inhibitors (TKI), most patients (pts) with chronic myeloid leukemia (CML) have a favorable outcome with their initial therapy. However, some pts experience resistance or intolerance. Second generation TKI dasatinib, nilotinib and bosutinib are effective (and approved) for pts with failure to one prior TKI. In the absence of specific mutations or patient comorbidities driving the selection of a specific TKI, selecting the next TKI remains at the physician discretion, especially in the lack of randomized data comparing 2nd generation TKI.Methods: We analyzed the outcomes of 621 consecutive patients with CML treated at a single institution with 2nd generation TKI in the 2nd line following failure of frontline TKI. For this analysis we focused on the 572 pts that received dasatinib, nilotinib or bosutinib as 2nd line TKI (not including 49 pts treated with ponatinib, imatinib or investigational TKI).Results: The median age at diagnosis was 47 years (range, 12-86) and 49% were male. 516 pts received TKI as frontline treatment and 105 had other therapies (interferon, chemotherapy) prior to TKI. Pts were switched to a 2nd generation TKI for resistance (n=337; 54%) or intolerance (n= 279; 45%). The median time from diagnosis to start of 2nd line TKI was 32 mo (0 to 206 mo). Dasatinib, nilotinib and bosutinib were used as 2nd line TKI in 338 (54%), 194 (31%), and 40 (6%) pts, respectively. Overall, out of 572 pts who received one of these three TKIs, 401 had cytogenetic evaluation of which 323 (81%) achieved major cytogenetic response (34 (8%) partial (PCyR) and 289 (72%) complete (CCyR)). Out of 428 who had a molecular evaluation, 75% achieved molecular response (94 (18%) MMR, 52 (6%) MR4, 217 (51%) MR4.5). The rates of major cytogenetic response (MCyR) were, with dasatinib 85% (76% CCyR), nilotinib 76% (70% CCyR), and bosutinib 67% (50% CCyR) (p=0.015). Rates of molecular response (MMR or better) were with dasatinib 72% (55% MR4.5), nilotinib 65% (46% MR4.5), and bosutinib 55% (39% MR4.5), (p=0.07). At a median follow-up from diagnosis of 96 mo (range, 4-283), 39 (7%) pts transformed either to accelerated (n=26, 5%) or to blast phase (n=13, 2%) while on 2nd line TKI. Median overall survival (OS) and transformation-free survival (TFS) were not reached and the median event-free survival (EFS) was 121 mo. Seven-year probabilities of OS, TFS and EFS were 66%, 91% and 55%, respectively. Higher OS, TFS, and EFS were found in patients who received frontline TKI (7-yr 70%, 92% and 59%, respectively) vs those who failed another treatment prior to any TKI (49%, 83%, and 38%, respectively) (p<0.001, p=0.005, p<0.001, respectively) and in patients who switched to second line TKI due to intolerance (79%, 95% and 74%) vs resistance (58%, 87%, and 42%) (p<0.001, p=0.002, p<0.001, respectively). No difference in OS, TFS and EFS was found when comparing dasatinib, nilotinib and bosutinib in all pts (p=0.651, p=0.673, p=0.057). There were trends for better OS and EFS with dasatinib than nilotinib in patients who received their first TKI after failing another treatment (p= 0.034, p=0.009). Dasatinib had also better EFS than Nilotinib in patients who switched to 2nd line for resistance (p=0.007). 49 (9%) pts discontinued their 2nd TKI, including 18 (3%) due to intolerance, 9 (2%) due to transplant, 6 (1%) due to resistance, and 5 (1%) due to sustained MR4.5. Of these 5 pts with elective treatment discontinuation, all have remained treatment-free a median of 20 mo after treatment discontinuation. 248 (43%) switched to third line TKI due to resistance (n=110, 44%) or intolerance (n=128, 52%). 51 (9%) pts acquired mutations following first-line TKI with T315I and G250E being the most common (n=10, 19%, and n=7, 13%, respectively), and 70 (12%) after their 2nd TKI with T315I and F317L being the most common (n=16, 22%, and n=9, 12%, respectively).Conclusion: This analysis shows that dasatinib, nilotinib and bosutinib remain largely effective in inducing cytogenetic and molecular response when used as a 2nd line TKI with similar OS, TFS and EFS in the overall pts population. A multivariate analysis to identify predictors of long-term outcome, including specific TKI as a variable, is ongoing. DisclosuresKantarjian:Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. DiNardo:Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Daver:Bristol-Myers Squibb Company: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Pemmaraju:Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding. Burger:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding.

Optimal Timing of Allogeneic Stem Cell Transplantation (Allo-SCT) for Chronic Myeloid Leukemia (CML) Patients in the Tyrosine Kinase Inhibitor (TKI) Era

Introduction: TKIs have transformed the clinical history of chronic phase (CP) CML, largely replacing allo-SCT as the preferred first line treatment due to high efficacy and favorable safety profile. However some patients (pts) do not achieve an adequate response, develop resistance and/or transform to accelerated phase (AP) or blast phase (BP) CML. Response rates and duration are generally inferior beyond 2nd TKI. Allo-SCT remains an important consideration for pts with TKI failure, but outcomes are worse in advance stage CML. Thus, timing of allo-SCT in the setting of suitable HLA-matched donor for CML pt with multiple failed TKIs is important to optimize outcome.Methods: The aim of this study is to estimate residual life expectancy (RLE) for pts ages 18-65 with CP CML at initial diagnosis based on timing of allo-SCT in various settings: allo-SCT at CP1 CML, at CP2+ (after transformation to AP or BP), at AP, or at BP, or continuation of 2nd or 3rd TKI at CP1 CML, CP2+, AP or BP. The non-transplant cohort was extracted from MD Anderson (MDACC) Leukemia Department database, and the allo-SCT from Center for International Blood and Marrow Transplant Research (CIBMTR). MDACC cohort included patients initiating TKI between 1/1/2001-12/31/2013 and switched TKI due to failure as defined by European Leukemia Net (ELN) criteria; pts who underwent allo-SCT were excluded. CIBMTR cohort included pts diagnosed with CML between 1/1/2001-12/31/2013 and underwent HLA sibling matched (MRD) or unrelated donor (MUD) SCT. RLE was restricted to 10 yrs. Death due to any cause is considered an event.Results: A total of 1361 pts were included for analysis: 138 in MDACC cohort and 1223 in CIBMTR cohort. In the MDACC cohort, 77 (56%) were male and median age was 46 years (yr) (range 18.5-64.4). In the CIBMTR cohort, 703 (57%) were male and median age was 39 yrs (range 18.2-64.8). In CP1 CML multivariate analysis (MVA) which included age (younger or older than 50 yrs) demonstrated an overall mortality hazard ratio (HR) for allo-SCT compared to no SCT of 2.4 [95% CI in () hereafter, (1.2-4.9; p=0.02)] with HR for MRD SCT of 1.9 (0.9-3.8, p=0.1) and HR for MUD SCT 3.3 (1.6-6.7, p=0.001), Table 1 and Figure 1. Mean RLE was 7.1 yrs (6.8-7.5) if patients underwent allo-SCT in CP1 CML vs. 8.5 yrs (7.6-9.5) if they did not, Table 2. Patients on their 1st TKI had mean RLE of 7.0 yrs (6.6-7.5) if they underwent allo-SCT vs. 8.6 yrs (7.6-9.7) if they did not. HR for CP1 CML on their 1st TKI was 2.6 (1.1-6.0; p=0.02) for allo-SCT vs. TKI continuation. HR was 2.3 (1.0-5.3, p=0.055) and 3.0 (1.3-6.9; p=0.01) for MRD and MUD SCT, respectively. Similarly, mean RLE was 6.8 yrs (5.6-8.3) for CP1 CML pts on 2nd TKI if they underwent allo-SCT vs. 8.5 yrs (6.6-10) with TKI continuation. For CP1 CML pts on 2nd TKI, HR for allo-SCT was 2.1 (0.5-9.2; p=0.3). For CP2+ CML pts, HR was 2.0 (0.8-4.9, p=0.13) for allo-SCT on MVA. HR was 1.8 (0.7-4.6, p=0.19) and 2.2 (0.9-5.4; p=0.10) for MRD and MUD SCT, respectively. Mean RLE was 4.7 (4.1-5.3) yrs for pts undergoing allo-SCT in CP2+ CML vs. 7.4 (5.6-9.7) yrs with TKI continuation. HR was 1.1 for allo-SCT at AP (0.6-2.1; p=0.8). Mean RLE was 5.3 (4.5-6.3) yrs for AP patients undergoing allo-SCT vs. 5.6 yrs (4.0-8.2) with TKI continuation. For those in BP, a trend towards higher survival with allo-SCT compared to no SCT was noted on MVA; HR 0.7 (0.5-1.1; p=0.099). HR=0.8 (0.5-1.3); p=0.33 for MRD SCT and HR=0.7 (0.4-1.0); p=0.08 for MUD SCT when compared to no SCT. Mean RLE was 2.6 (1.8-3.8) yrs in the pts who underwent allo-SCT in BP vs. 1.5 (0.9-2.8) yrs for those who continued their TKI.Conclusion: Allo-SCT appeared to shorten survival for patients with CP1 CML but there was a trend towards benefit of SCT for those who progressed to BP CML. For CP2+ CML pts, allo-SCT trended towards worse survival. The role of allo-SCT in AP is less clear and should be determined on a case by case basis, dependent on mutation status, comorbidities, and the remaining TKI options available. However, given that this is not a clinical trial, it remains possible that patients referred for SCT may have had more aggressive disease so our results should be interpreted with caution due to the observational nature of the study and the small cohort of non-transplant pts. Considering the retrospective nature of this analysis, prospective randomized trials would be required to more formally define the optimal timing of SCT in different scenarios.^contributed equally [Display omitted] DisclosuresLee:Pimera Inc: Consultancy; Daiichi Sankyo: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Eutropics Pharmaceuticals: Research Funding; Takeda: Consultancy. Jabbour:Bristol-Myers Squibb: Consultancy. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; Lilly Oncology: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Blueprint Medicines Corp: Research Funding; Astrazeneca: Research Funding; Seattle Genetics: Research Funding; Blueprint Medicines Corp: Research Funding; Incyte: Research Funding; Astrazeneca: Research Funding; Pfizer: Research Funding; CTI BioPharma Corp: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Galena BioPharma: Research Funding; Galena BioPharma: Research Funding; Roche: Research Funding; CTI BioPharma Corp: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding. Kantarjian:Amgen: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding. Cortes:Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding.

Observational Study of CML Italian Patients Who Discontinued TKIs

Background: Different studies analysed the outcome of patients (pts) who discontinued tyrosine kinase inhibitors (TKIs) reporting a median treatment-free remission (TFR) rate of 55%. On these bases it is judged safe to discontinue treatment in experimental contexts.Aims: Aim of our study was to evaluate TFR in the setting of Italian pts .Material and Methods: We designed a retrospective observational study of Italian pts with chronic phase CML who discontinued TKI treatment in deep molecular response (DMR). All Hematological Centers who are part of the GIMEMA group were invited to participate to this retrospective study and 32 centers had cases and participated to the study.Results: We collected a total of 293 pts. Median age was 59 years; 59%, 30% and 11% of pts were low, intermediate and high Sokal score respectively. 72% of pts were on treatment with imatinib, 28.% with either nilotinib (n=58), dasatinib (n=23) or bosutinib (n=1) at the time of discontinuation. 55% of pts discontinued in first line, 40% in second line, 5% in third line. Median duration of treatment with the last TKI was 77 months (mos, IQR 54;111) median time to deep molecular response (DMR, i.e. undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 46 mos (IQR 30;73), median duration of DMR was 46 mos (IQR 31;74) before stop. Duration of treatment with TKIs and duration of DMR were shorter with 2nd gen TKIs than with imatinib (p<0.001). At 3 mos of last TKI most of the pts were in optimal response: 34% of pts were already in MR3, 25% in PCyR and/or had a transcript < 10%, 40% were in CCyR and/or had a transcript < 1%. Only 1% of the whole population had no response. Definition of response at discontinuation was: undetectable for 16%, MR4 for 35%, MR 4.5 for 31%, and MR5 for 18% of pts. Only 12% of the Italian pts discontinued in a prospective interventional study. In the other cases pts discontinued per clinical practice and reasons for stopping treatment were: toxicity for 20% of pts, pregnancy for 6% pts and shared decision between treating physician and patient upon pts request for 62% of cases. After a median follow-up of 34 mos (Min-Max 12-161) estimated TFR was 62% (95% CI 56;68). At 12 mos estimated TFR was 68% (95% CI 62;74) for imatinib, 73% (95% CI 64;83) for 2nd gen TKIs. There was no statistically significant difference (see CI) between TFR at 12 mos with imatinib and with 2nd gen TKIs. Overall 115 pts (39%) restarted treatment. Reasons for restarting were: loss of MR4 for 19%, loss of MR3 for 69%, loss of CCyR for 9%, other reasons for 3% of pts. Overall median time to restart treatment was 6 mos (IQR 4;11). Although 75% of pts restarted treatment by the first year, last pt was reported to restart treatment after 105 mos. Median time from loss of response to restart-treatment was 1 mo (IQR 0;2). No progressions occurred. Nine deaths were reported but none of them was disease related. Pts who had to restart therapy were treated with imatinib (77), nilotinib (22), dasatinib (9), bosutinib (3) or ponatinib (1). Interestingly most of the pts who stopped imatinib restarted imatinib after relapse and most of the pts who were on 2nd gen TKIs stayed with 2nd gen TKIs. 24 pts who lost MR4 (including 4 who lost MMR) did not restart treatment and were still off therapy after a median time of 12 mos. Almost all the pts retreated regained at least MR3. 73 pts regained the MR criteria for a second discontinuation attempt. We assessed age, sex, Sokal score, type of transcript, previous IFN therapy, duration of TKI therapy, response at 3 mos, time to DMR, DMR duration, line of therapy at stop, depth of MR, reasons for stop as potential prognostic factors for TFR, but no statistically significant association were found, with the exception of age: a decreased risk of relapse in older vs younger ptsConclusion: Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and 2nd gen TKIs is feasible and safe in the clinical practice. DisclosuresFava:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rege-Carmbrin:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gugliotta:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Abruzzese:Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Orlandi:Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pregno:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Crugnola:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Bocchia:Celgene: Other: Travel grant; Novartis: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Galimberti:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau. Iurlo:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:TEVA: Speakers Bureau. Cavazzini:Novartis: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy. Giai:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Musto:BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; janssen: Honoraria. Specchia:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Pane:Novartis: Honoraria, Speakers Bureau. Baccarani:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Saglio:Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

First-Line Dasatinib in BCR-ABL1+ Chronic Myeloid Leukemia in Early Chronic Phase: A Gimema Prospective Multicentric Observational Study

Background: Dasatinib (DAS) is a 2nd generation (2nd gen) tyrosine kinase inhibitor (TKI) approved for 1st line treatment of chronic myeloid leukemia (CML) patients based on DASISION study results. Most data on 2nd generation TKIs are from company-sponsored studies, but the patient selection and the high rate of patient switching to other treatments may jeopardize data interpretation. Interestingly, despite significant differences in terms of cytogenetic and molecular response, 2nd gen TKIs did not produce relevant advantages in terms of overall survival (OS). A post-marketing surveillance in large independent trials is extremely important to confirm efficacy and the safety data.Aims: To describe, in the clinical practice, the response to DAS and the events leading to permanent treatment discontinuation.Methods: An italian multicentric prospective observational study of CML patients treated frontline with DAS has been conducted by the GIMEMA CML Working Party. DAS was given at the discretion of investigators, according to prescribing information, without any exclusion criteria, apart from age (<18 years old) and prior treatment with TKIs or interferon. Molecular response was assessed in standardized molecular laboratories (Labnet network): major molecular response (MR3.0 or MMR), BCR-ABL1 < 0.1% IS; MR4.0, BCR-ABL1 < 0.01% IS or undetectable disease with ≥10,000 ABL1 copies; MR4.5, BCR-ABL1 < 0.0032% IS or undetectable disease with ≥32,000 ABL1 copies. Progression was defined as transformation to advanced (accelerated or blast) phase, according to ELN criteria.Results: 147 CML patients in early chronic phase have been enrolled in 27 italian hematologic centers. The median age was 57 years (65 years or older: 34% of patients). High risk patients according to Sokal, Euro and EUTOS score were 28%, 11%, and 13%, respectively. Median follow-up: 12 months. At 3 months, 88% of patients had BCR-ABL1 transcript levels < 10% IS (at the same timeopoint, < 1% in 66% of patients). At 6 months, 81% of patients had BCR-ABL transcript levels < 1%. The MMR rates at 6 and 12 months were 53% and 72%, respectively. The proportion of patients achieving a MR4 or a MR4.5 at least once was 35% and 16%, respectively. At the last contact, the patients still on treatment with DAS were 88%, while 12% permanently interrupted the study drug. The reasons for study discontinuation were: 1% progression in advanced phase, 2% failure, 1% unrelated death, 1% lost to follow-up, 7% adverse event (1% hematologic toxicity, 4% pleural effusion, 1% tachyarrythmia, 1% other non-hematologic adverse event). No pulmonary hypertension or cardiovascular ischemic adverse events were reported. The probability of OS and progression-free survival at 1 year was 98% and 99%, respectively.Conclusion: The median age of patients receiving DAS in our observational trial was close to the median age reported in population-based CML registries, with one third of patients at least 65 years old; consequently, we may argue that, outside of clinical trials, the decision to treat or not to treat patients with DAS is probably not influenced by age. The proportion of high risk patients, as expected, was higher than reported by population-based CML registries. High molecular response rates were observed and the most frequent reason of permanent treatment discontinuation was the occurrence of adverse events (in particular, pleural effusion). DisclosuresCastagnetti:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Breccia:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy. Iurlo:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Stagno:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Abruzzese:Novartis: Consultancy; Incyte: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Crugnola:Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria. Specchia:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tiribelli:Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonifacio:Incyte: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Galieni:Abbvie: Other: Advisory Board; Takeda: Other: Advisory Board. Soverini:Incyte Biosciences: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Foà:Roche: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Martinelli:ARIAD/INCYTE: Consultancy; ROCHE: Consultancy; JOHNSON & JOHNSON: Consultancy; CELGENE: Consultancy; PFIZER: Consultancy; AMGEN: Consultancy. Saglio:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Pane:Novartis: Honoraria, Speakers Bureau. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Rosti:Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Molecular Responses after Switching from a Standard-Dose Twice-Daily Nilotinib Regimen to a Reduced-Dose Once-Daily Schedule in Patients with Chronic Myeloid Leukemia: A Real Life Observational Study (NILO-RED)

IntroductionStandard dosing regimen for the BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib in chronic myeloid leukemia (CML) is 300mg twice daily (BID) in the frontline setting and 400mg BID in the 2nd line setting or beyond. Patients (pts) are instructed to fast within 2 hours before and 1 hour after medication intake due to significant high-fat food effects on drug bioavailability. On-label dose adjustments to a lower-dose once-daily (QD) regimen are recommended solely in case of significant toxicity.Study goalThe primary aim of our observational two-center study was to ask whether nilotinib-treated adult CML pts were able to maintain major molecular responses (MMR) within 1 year after conversion to a more convenient nilotinib QD regimen at reduced doses, regardless of reasons for tapering nilotinib. Pts with minor transcripts or a history of blast crisis or allogeneic stem cell transplantation were excluded.PatientsEighty one pts in chronic phase were identified and included and results from the first 67 pts with a follow-up of at least 12 months after the switch to the once-daily dose-reduced nilotinib regimen are presented. Median age at study entry was 52 years (range: 19-82). There were 25 males (37.3%) and the Sokal score was low, intermediate, high or unknown in 43.3%, 37.3%, 13.4% and 6% of pts, respectively. All pts had major-type BCR-ABL1 transcripts. Nilotinib was started as 1st line TKI at 300mg BID in 68.6% of pts and as 2nd or subsequent line TKI at 400 or 300 mg BID in 31.4% of pts due to intolerance, warning, resistance or absence of a deep molecular response on prior therapy. Median duration of nilotinib prior switching to a reduced QD dosing was 29 months (range: 1-94) and median duration of MMR was 25 months (range: 3-212). Primary reason for the switch to a reduced QD nilotinib dosing was non-serious adverse events in 37.3% of pts and improvement in pts convenience in 62.7% of pts. Nilotinib was reduced down to 450mg QD, 400mg QD or 300mg QD in 86.6%, 10.4% and 3% of pts, respectively. A 2nd dose reduction from 450mg to 300mg QD was performed in 30 pts after a median time of 18 months (range: 4-37). The median duration of low-dose nilotinib QD was 24 months (5-54). No severe tolerance issues were encountered and no ischemic cardiovascular events occurred. Eleven pts stopped nilotinib due to treatment-free remission attempt (n=10) or persistent adverse event (n=1). All pts were alive at last follow-up.Evolution of molecular responsesAt baseline, the number of pts in MMR, MR4 and ≥MR4.5 was 9 (13.4%), 17 (25.4%) and 41 (61.2%), respectively and 32 pts (47.8%) had undetectable BCR-ABL1 transcripts. Median BCR-ABL1/ABL1 % IS was 0.006% (range: 0.0007-0.063) and median ABL1 copy number in pts with undetectable transcripts was 87259 (range: 36018-921339). Only 2 pts treated with 1st line nilotinib lost MMR 4 and 6 months after QD dose reduction of nilotinib with BCR-ABL1/ABL1 % IS at 0.13 and 0.11%, respectively. Both pts spontaneously regained MMR 4 months later without any treatment modification. Kaplan-Meier analysis of survival without unconfirmed MMR loss was 97% (95% CI: 92.9-100) at 12 months and analysis by molecular response category showed that none of the pts who were at least in MR4 at baseline lost MMR (Figure 1). At last follow-up on low-dose QD nilotinib, the number of pts in MMR, MR4 and ≥MR4.5 was 4 (6.3%), 11 (16.4%) and 52 (77.6%), respectively and 37 pts had undetectable transcripts (55.2%). Median BCR-ABL1/ABL1 % IS was 0.0035% (range: 0.00025-0.058) and median ABL1 copy number in pts with undetectable transcripts was 96000 (range: 23285-472000).Ten pts in long-lasting deep molecular response stopped nilotinib without further treatment after a median duration of TKI and of nilotinib of 60 months (range: 50-149) and 56 months (range: 42-87), respectively. Their follow-up after nilotinib discontinuation was 18 months (range: 5-33). Only 1 of them lost MMR and restarted therapy 5 months later while the others remained treatment-free.ConclusionSwitching to a nilotinib QD regimen at reduced doses as maintenance therapy after achievement of a MMR on standard-dose nilotinib BID schedule is feasible and safe in chronic phase CML pts regardless of prior treatment history and does not compromise the anti-leukemic efficacy of nilotinib. Our results may pave the way for clinical trials aiming at systematic avoidance of overtreatment and improvement of pts convenience in treatment with nilotinib. [Display omitted] DisclosuresRea:Pfizer: Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Honoraria. Cayuela:BMS: Honoraria; Novartis: Honoraria. Etienne:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Research Funding.

Response and Outcomes of Third-Line Tyrosine Kinase Inhibitor Therapy on Patients with Chronic Phase Chronic Myeloid Leukemia

Introduction: Patients with chronic phase chronic myeloid leukemia (CML) who fail to respond to first- and second-line tyrosine kinase inhibitor (TKI) therapy may be treated with third-line TKIs or undergo allogeneic hematopoietic stem cell transplant (alloHSCT). However, data demonstrating the efficacy of third-line TKI therapy is limited other than those coming from industry-sponsored studies for individual drugs.Objective: evaluate the efficacy of various third-line TKIs and identify factors predicting outcomes and response in patients with chronic phase CMLMethods: A retrospective study was conducted on 185 patients with chronic phase CML with failure to first- or second-line TKIs. Demographic factors and clinical parameters were noted along with TKI therapies. Treatment response and outcomes, including cytogenetic response, molecular response, overall survival (OS), event-free survival (EFS) and transformation-free survival (TFS) were measured. Events were defined by death on third-line TKI therapy, loss of MCyR, loss of CHR, increased WBC, or progression to AP/BC; whichever occurred first.Results: The median age of patients was 55.0 years (range: 19-92 years), and the majority were female (n=97; 52%). Patients received the following TKIs: bosutinib (n=13, 7%); dasatinib (n=64, 35%); imatinib (n=19, 10%); nilotinib (n=67, 36%); and ponatinib (n=22, 12%). Patients received third-line TKI for a median of 18.07 months (5.40 - 93.60), and 78 (42.16%) remain on their third-line TKI. The 25% percentile of OS for all treatments combined was 3.2 years (95% CI, 2.1-6.3) At the final data cut-off, 75% of patients on third-line TKIs were alive (47 deaths). At 5 years, median EFS was 55.1 months, median TFS was not reached.Third-generation ponatinib was associated with significantly better OS compared with imatinib (HR, 0.248; 95% CI, 0.067-0.917; p=0.037). Compared with imatinib, patients treated with bosutinib also had better survival, and this association approached significance (HR, 0.147; 95% CI, 0.017-1.240; p=0.078). There was no difference by TKI in either TFS (p=0.134), or OS (p=0.315).At baseline, 39 patients (32.77%) had CCyR and 76 (63.86%) did not, while at best response 71 patients (59.66%) had CCyR, 48 (40.33%) did not have CCyR, and the rest were excluded due to missing data. 8% also achieved major molecular response (MMR, based on international scale) as best response.On univariate Cox regression analysis, the following factors were significantly associated with improved OS: age, best cytogenetics (CCyR vs not CCyR), best molecular response (MMR vs. not MMR), reason for TKI switch (resistance vs. intolerance to 2nd line TKI), baseline cytogenetics, baseline molecular response status, and stem cell transplantation. Baseline mutation status was not associated with OS (HR, 1.137; 95% CI, 0.438-2.948; p=0.792). Multivariate analysis identified the following as significant predictors of improved OS: age, gender, best molecular response, reason for TKI switch, stem cell transplant, and third-line treatment with ponatinib or bosutinib versus imatinib (Table 1).Conclusion: In the largest cohort of chronic phase CML patients on third-line TKI therapy to date, we identified predictors of clinical outcomes in the context of this setting. In addition to confirming previous findings that third-line TKI therapy may prolong OS and EFS, we found that ponatinib is associated with significantly better OS than any other TKI used as third-line therapy. [Display omitted] DisclosuresKantarjian:Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding. Jain:Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Wierda:Juno: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Kite: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding. Pemmaraju:Cellectis: Research Funding; Stemline: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria. Thompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daver:Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Immunogen: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Honoraria, Research Funding; Kiromic: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Primary and secondary resistance mechanisms in first, second and third generation tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer patients.

e21142 Background: Different molecular mechanisms of on target and off target primary and secondary resistance have been observed in EGFR mutant NSCLC patients after first(1st), second(2nd) and third (3rd) generation of tyrosine kinase inhibitors(TKIs). Next generation sequencing(NGS) offers a comprehensive method of detecting these mechanisms to decide next line of treatment. Methods: We retrospectively analyzed 430 samples of NSCLC for primary and secondary resistance to 1st, 2nd and 3rd TKIs. NGS was performed using thermofischer Ion Torrent Oncomine Focus 52 gene Assay. These cases were divided into 4 groups.1)Primary resistance to first and second generation TKIs 2)Primary resistance to 3rd generation TKI 3)Secondary resistance to 1st and 2nd generation TKI 4) Secondary resistance to 3rd generation TKI.Last group was further subgrouped into A when 3rd generation TKI was offered as second line after 1st or 2nd generation TKIs on detection of T790M and subgroup B when it was given as first line. Results: Group1 had 13 cases. There were 2 cases of complex EGFR exon 19 mutation p.Glu746_Leu747delinsValPro, 4 cases of EGFR exon 20 insertion, 1 case of dual EGFR L833V &amp; H835L mutation, 2 cases with EGFR amplification with EGFR exon 19 del and PIK3CA C420_P421del along with EGFR exon 19 del. Four cases had no additional abnormality. Group 2 had 5 cases:1 case had L858R and E709A dual mutation, 2 cases had KRAS G13C and KRAS G12V along with EGFR exon 19 del. One case had EGFR amplification and one case had MET amplification along with EGFR exon 19 del respectively.Group 3 had 34 cases including 10 cases of EGFR L858R and 24 cases of exon 19 deletion.T790M mutation was detected in 8 patients, MET amplification in 7 cases,one case had both T790M and MET amplification. One case lost the primary EGFR exon 19 del. Others mutations detected were KRAS G13C, PIK3CA H1047R, TP53 R213Q and TP53 C242fs. Group3 had 15 cases with 7 cases in subgroup A and 9 cases in subgroup B. In subgroup A T790M mutation was lost in 6 out of 7 cases.One case which lost T790M developed ALK translocation.One case of EGFR exon 19 del retained EGFR T790M with EGFR C797S in cis allele. Other mutations detected were PIK3CA E542K and KRAS G12C. In subgroup B one case showed EGFR C797S(both cis and trans) besides the primary EGFR exon 19 del. One case showed BRAF G469A along with EGFR exon 19 del. Other mutations detected were CTNNB1 D32N, KRAS G12V, and PIK3CA E542K. Conclusions: Primary and secondary acquired resistance is unavoidable in EGFR mutant advanced NSCLC on any generation of TKIs. NGS offers an advantage in diagnosing mechanism of resistance for further choice of therapy.

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer.

PurposeEpidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.Materials and MethodsWe identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.ResultsIn cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.ConclusionOur study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

Contemporary Practice Patterns of Tyrosine Kinase Inhibitor Use Among Older Patients with Chronic Myeloid Leukemia in the United States

Introduction: BCR-ABL1-directed tyrosine kinase inhibitor (TKI) therapy is the standard of care for patients (pts) with chronic-phase chronic myeloid leukemia (CML). Several TKI agents are available and approved for use in the frontline (1L) setting, specifically imatinib and the second-generation TKIs dasatinib, nilotinib, bosutinib. No prospective study has compared the efficacy of the second-generation TKIs, so the choice of 1L TKI may be tailored to disease risk as well as patient characteristics such as age and comorbidity. As many CML pts are older, they have a greater burden of comorbidities that may be relevant to the initial TKI choice and sequence of additional TKI lines of therapy (LOT). We sought to describe the patterns of TKI use in older CML pts in the United States. We expected imatinib to be the most common 1L TKI for older pts, but that switching to another TKI within 12 months of diagnosis would be common. Methods: We assembled a population-based cohort of older CML pts diagnosed during 2007-15 and included in the Surveillance, Epidemiology, and End Results (SEER) database who: 1) were age 66-99 years at diagnosis, 2) had continuous Medicare Parts A/B and D coverage from 1 year and 3 months, respectively, before diagnosis to end of follow-up and 3) did not receive a TKI within 3 months before diagnosis. Pts were followed from diagnosis to change in Medicare status, death, or 12/31/2016, whichever came first. We identified 5 available TKIs (imbatinib, bosutinib, dasatinib, nilotinib, and ponatinib) for the treatment of CML from diagnosis to the end of follow-up. A switch from one TKI to another was defined as a new TKI LOT. Results: We identified 828 pts with newly-diagnosed CML initiating a TKI. The median time from diagnosis to TKI initiation was 45 (IQR 29-81.5) days and median follow-up for the cohort was 2.2 years. The median age of pts was 75 (interquartile range [IQR] 70-81) years; 50.8% were female and 88.2% were white. A total of 241 (29.1%) TKI users also received hydroxyurea after diagnosis. The proportion of pts ever receiving a TKI increased over time from 50.0% among pts diagnosed in 2007 to 69.5% among pts diagnosed in 2015 (Figure 1). TKI users received up to 5 available TKIs, with 66.1%, 24.4% and 7.7% pts having ever used 1, 2 and 3 TKIs, respectively. Only 15 (1.8%) pts used &amp;gt;4 different TKIs. Imatinib was the most common ever-used TKI (72.6%) followed by dasatinib (38.3%) and nilotinib (28.1%); bosutinib, the latest available during the study timeframe, was used in only 38 (4.6%) pts. Only 16 pts (1.9%) ever-used ponatinib with nearly all pts using it as &amp;gt;2nd LOT. Imatinib (65.3%) was the most used 1L TKI. With increasing availability and use of dasatinib and nilotinib during the study period, the use of imatinib as 1L decreased during 2009-2015 (Figure 1). The median duration of the 1L treatment was 17.8 (IQR 4.5-37.8) months. At 360 days after TKI initiation, among 689 alive pts, 507 (73.6%) were still on the 1L TKI and 129 (18.7%) already switched to another TKI LOT. Among 281 TKI users who eventually switched to another TKI LOT, only 35 (12.5%) pts had received ≥4 LOT with a maximum of 7 LOT as pts may return to a previously abandoned TKI as a subsequent LOT. Median time on post-1L TKI LOT progressively decreased with each additional TKI LOT (10.5, 8.0, and 4.5 months for 2nd, 3rd, and 4th LOT, respectively). The most common 2nd LOT TKI was dasatinib (38.4%) and nilotinib (32.0%). However, imatinib (30.9%) was the most common choice as 3rd LOT among 110 pts receiving &amp;gt;3 TKI LOT (Table 1). Of the 110 pts that switched from 1L imatinib therapy, 31 (28.2%) eventually returned to imatinib with nearly all returning to it as the 3rd TKI LOT. Only 4.2% and 2.7% of pts treated with 1L dasatinib and nilotinib returned to it after 2nd TKI LOT. Conclusions: We report a large, contemporary analysis of TKI use in older CML pts which showed imatinib to be the preferred 1L TKI with a majority of patients remianing on it after 1 year of treatment. Despite the associated pulmonary toxicity and vaso-occlusive complications of dasatinib and nilotinib, respetively, these TKIs were used in a substantial proportion of older pts with the number of users increasing over time. One-third of 1L TKI users switched to another TKI LOT with one-quarter of pts switching from 1L imatinib eventually returning to imatinib, suggesting that the toxicity of imatinib is likely tolerable among those older CML pts. This work was supported by the Frederick A. DeLuca Foundation. Disclosures Wang: Celgene/BMS: Research Funding. Zeidan:Leukemia and Lymphoma Society: Other; CCITLA: Other; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding. Huntington:DTRM: Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; Novartis: Consultancy; AbbVie: Consultancy; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Davidoff:Celgene: Research Funding. Ma:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Podoltsev:Samus Therapeutics: Research Funding; Kartos Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Astellas Pharma: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding.

Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

Progression free survival (PFS) in Asian vs non-Asian patients (pts) with EGFR mutant non-small cell lung cancer (NSCLC) receiving osimertinib.

e21679 Background: Third generation EGFR tyrosine kinase inhibitor (TKI) osimertinib demonstrated superior PFS and OS compared to earlier generation TKIs in pts with EGFR+ NSCLC. These pts are disproportionately Asian, female, and never-smokers. Contradictory data has been reported regarding the PFS and OS to osimertinib in Asian pts as compared to 1st and 2nd generation EGFR TKI. These inconsistencies warrant further investigation. The purpose of this study is to evaluate the PFS in Asian vs non-Asian pts with EGFR+ NSCLC receiving osimertinib. Methods: We conducted a single institution IRB approved retrospective study of pts with EGFR+ NSCLC. PFS was evaluated in pts treated from 1/2013 – 12/2019. Disease and treatment characteristics were summarized using frequency distributions and Kaplan-Meier curves for comparison of subgroups. Results: Of 190 EGFR+ pts: 52 (27%) Asian, 108 (57%) Caucasian, 125 (66%) female, 172 (91%) advanced disease, 107 (56%) never-smokers. Baseline characteristics in Asian and non-Asian pts were similar in regards to de-novo stage IV disease (71% vs 65%, p = 0.80), brain metastases (42% vs 54%, p = 0.48), and differed with regards to ever-smoking (29% vs 56%, p = 0.04). Treatment: 126/172 (73%) pts with advanced disease received TKI across all lines of therapy; 92/126 received osimertinib (22 (24%) 1st line; 45 (49%) 2nd line; 18 (19%) 3rd line; 7 (8%) ≥4th line). There were insufficient number of pts who received osimertinib in the 1st line to comment on differences in PFS between Asian and non-Asian pts. In the 2nd line, 19 Asian pts and 26 non-Asian pts received osimertinib, with no observed difference in PFS (median 15.4 v 13.8 months, p = 0.20). Moreover, Asian pts who received osimertinib as second line therapy had superior PFS (median 15.4 vs 9.6 months, p &lt; 0.01) compared to Asian pts who received earlier generation TKIs, likely due to T790M resistance. Conclusions: Among second line advanced EGFR+ NSCLC, we did not observe a difference in PFS between Asian and non-Asian pts treated with osimertinib. Median PFS in Asian pts treated with osimertinib was longer compared to those treated with 1st or 2nd generation TKIs in the 2nd line setting. Our study highlights the the role of ethnic background in response to EGFR therapies and may warrant further study.

A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.

5065 Background: SRT is increasingly considered to delay the need to change systemic therapy in metastatic cancer patients who develop oligoprogression. This prospective phase II study evaluated the use of SRT in the setting of mRCC patients who developed oligoprogression while on 1st or 2nd line TKI therapy. Methods: IMDC favourable or intermediate risk mRCC patients (pts) who had previous stability or response on ≥ 3 months of TKI therapy were eligible if they developed radiographic progression of ≤ 5 metastases. The oligoprogressive tumours were treated with SRT while other metastases which were stable or responding to TKI therapy were left alone. TKI therapy was temporarily stopped during SRT, and the same TKI drug then resumed. Endpoints included local control of the irradiated lesions, progression free survival (PFS), overall survival (OS), and cumulative incidence of changing systemic therapy after study entry. Results: 37 pts (median age 63, IMDC favourable 12, intermediate 25) with 57 oligoprogressive tumours were enrolled. 35 pts were on sunitinib and 2 on pazopanib. Median duration of TKI therapy prior to study entry was 18.6 months. 4 pts had IL-2 therapy prior to a 2nd line TKI. 21 pts had a solitary oligoprogressive tumour, while 17 pts had 2-3 oligoprogressive tumours treated with SRT. Median biological effective dose (BED10) was 72 Gy, corresponding to an SRT dose of 40 Gy in 5 fractions. Irradiated tumour sites were the following: 21 lung/pleural, 15 bone, 7 lymph node, 4 adrenal, 4 liver, 3 brain, 2 spleen, and 1 pancreas. At a median followup of 11.6 (1.8-53.5) months the median PFS from study entry was 9.6 months (95%CI 7.4-20.5) with the vast majority of progression occurring outside of the irradiated areas. The 2-year local control of the irradiated tumours was 96%. The 2-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at 1 year and 75% at 2 years, with a median time to a change in systemic therapy of 12.6 months. There were no grade 3-5 SRT related toxicities. Conclusions: To our knowledge, this is the first prospective evaluation of the use of SRT for oligoprogressive metastatic cancer. Local control of irradiated oligoprogressive mRCC tumours was high. After delivering SRT, mRCC patients did not need a change in their systemic therapy for a median of 1 year, effectively increasing the PFS of their TKI therapy. This novel approach should be studied in patients with oligoprogression on immunotherapy. Clinical trial information: NCT02019576 .

Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients.

9514 Background: Treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations in an independent cohort of a multi-cohort, multi-center Phase 2 study ( ZENITH20-1). Methods: ZENITH20-1 study enrolled pts with advanced NSCLC with an EGFR exon 20 insertion identified on local tissue testing who had received at least one prior line of therapy. Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated centrally by RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Efficacy was also evaluated by specific exon 20 insertions and prior lines of therapy. Results: 115 patients with a median age of 61 years (33-83) were enrolled. Patients had a median of 2 prior lines of therapy (range, 1-9.) The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. The ORR in the as-treated population was 14.8% (95% CI 8.9 - 22.6%), and the DCR was 68.7% (95% CI 59.4 - 77.0%) with a median DoR of 7.4 months. 65% patients had tumor size reductions and the median PFS was 4.2 months. In the evaluable population (n = 88), the ORR was 19.3% and the unconfirmed ORR was 25%. Responses were predominantly observed in insertions between residues M766 to D770 of exon 20 (8/44; 18.2%). Responses were observed in patients with 2 lines (14%); ≥3 lines of therapy (16.2%). The most common treatment-related Grade ≥3 AEs were rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis was 4%, however some cases may have been confounded by prior checkpoint inhibitors as first line treatment. Conclusions: Although the ORR primary endpoint was not met, poziotinib induced tumor reduction in the majority of patients with durable responses, including the heavily pre-treated population. Responses were more common in patients with insertions between M766 to D770 of EGFR exon 20. The safety profile was overall consistent with other 2nd generation EGFR TKIs. Evaluation of these subgroups with refined dosing and improved toxicity management to maintain continuous treatment is warranted to assess the potential of poziotinib in Exon20 related tumors. Clinical trial information: NCT03318939 .

A phase III, open-label, randomized study of atezolizumab in combination with carboplatin + paclitaxel + bevacizumab compared with pemetrexed + cisplatin or carboplatin with stage IV non-squamous non-small cell lung cancer (NSCLC) with activating EGFR mutation or ALK translocation (ATLAS Trial).

TPS9636 Background: In patients with activating EGFR mutations and ALK fusion, target specific tyrosine kinase inhibitor (TKI) showed significant survival improvement compared to the cytotoxic chemotherapy. However, the questions remain which combination strategy will be the best option for the patients who have failed from TKI. Especially, the role of an immune checkpoint inhibitor (ICI) in this population is still unclear. This study is designed and conducted based on the recent subgroup analyses from the IMpower 150 study which showed the positive clinical outcomes of atezolizumab combined with VEGF inhibitor and conventional cytotoxic chemotherapy in EGFR mutation and ALK translocation. Methods: This study is the phase III, open-label, multicenter study of atezolizumab in combination with bevacizumab + carboplatin + paclitaxel (ABCP, Arm A) compared with pemetrexed + cisplatin or carboplatin (Arm B). The study population will be randomized to either Arm A (n = 152) or Arm B (n = 72) based on two stratification factors, EGFR vs. ALK and presence of brain metastases. In Arm A, patients will be treated with 4 or 6 cycles of ABCP followed by maintenance atezolizumab and bevacizumab every three weeks. In Arm B, pemetrexed maintenance therapy will be applied every three weeks after 4 or 6 cycles of pemetrexed + cisplatin or carboplatin. As key inclusion criteria, the patients must be diagnosed with stage IV non-squamous non-small cell lung cancer with either activating EGFR mutation or ALK translocation. All the patients need to be cytotoxic chemotherapy naïve and must have experienced disease progression to treatment with at least one EGFR or ALK TKI. If the patients have T790M mutation after 1st or 2nd generation EGFR TKI, second line 3rd generation EGFR TKI treatment is mandatory. The number of T790M positive patients is restricted to under 30% of the entire study population. The primary endpoint is progression-free survival and the major secondary endpoints are overall survival, objective response rate and duration of response. A total of 228 subjects will be enrolled to detect a hazard ratio of 0.67. The first subject received treatment in Aug. 2019 and 19 patients receive the treatment. This study is opened in 3 sites and expected to be opened at 18 sites in South Korea. The time point for the primary analyses is Q3. 2022. Clinical trial information: NCT03991403 .

Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1

Background: Pretreatment status assessment at diagnosis in patients with chronic myeloid leukemia in chronic phase (CML-CP) is more important for successful treatment in the tyrosine kinase inhibitors (TKIs) era. For instance, the Charlson comorbidity index (CCI) score is considered the useful tool for predicting overall survival (OS) in patients with CML treated with imatinib (IM) (Saussele S et al., 2015). However, the effect of CCI in patients with CML treated with second-generation TKI (2nd TKI) and clinical practice setting was unknown. This study aimed to evaluate the effect of pretreatment statuses, including CCI, on OS of participants of the New TARGET observational study 1 conducted by the Japanese Society of Hematology (JSH). Methods: Patients newly diagnosed with CML-CP were registered to the New TARGET observational study 1 from April 2010 to March 2013. They were treated with TKIs (IM, nilotinib [NIL], or dasatinib [DAS]) after registration. Exclusion criteria were defined as follows: (1) accelerated phase/blast crisis (AP/BC) CML and (2) pretreatment with interferon-alfa, any TKIs, or hydroxyurea for more than 3 months, or allogeneic hematopoietic stem cell transplantation before registration. Other details of the protocol were previously reported (Kizaki et al., 2019). Patients were classified into CCI risk groups of 2, 3, and ≥4 for analysis. The New TARGET observational study 1 was supported by research fundings from Novartis Pharmaceuticals and Bristol-Myers Squibb to JSH. This subgroup analysis was approved by the institutional review board of the Hamamatsu University School of Medicine. The chi-square test was used to compare clinical characteristics for categoricaldata and the Wilcoxon rank-sum test for continuous data. OS was calculated using the Kaplan-Meier method and compared by the log-rank test. Gray's test was used to compare cumulative incidence curves. Cox proportional hazard analyses were performed to determine prognostic indicators of OS. The Wald test was used to assess the prognostic significance of a candidate variable. Statistical analyses were performed using EZR, a graphical user interface for R (Kanda Y, 2013). Results: Among 506 enrolled patients, 475 with a median age of 56 years were assessable. The median follow-up period was 5.4 years. In total, 103 patients (21.7%) had various types of comorbidities, with diabetes mellitus, mild liver disease, peripheral vascular disease, myocardial infarction, renal disease, and peptic ulcer disease (7.3%, 4.1%, 3.2%, 2.6%, 2.2%, and 2.2%, respectively) as the most common. The lowest CCI score was 2 owing to CML. CCI scores were stratified as follows: 2, 372 patients (78%); 3, 74 patients (16%); and ≥4, 29 patients (6%). Higher CCI scores were significantly associated with older age (P &lt;.001). Overall, 151 patients were treated with IM, 175 with NIL, and 149 with DAS. Patients with higher CCI scores tended to be treated with IM. Differences in cumulative incidence of complete cytogenetic response, major molecular response, and AP/BC were not statistically significant in the observational period according to CCI scores (P = 0.46, P = 0.58, and P = 0.63, respectively). No differences in the treatment response among the CCI risk scores were found in the IM and 2nd TKI cohorts. The OS of patients with CCI scores of 2, 3, and ≥4 were 94.3%, 89.3%, and 73.9%, respectively (P &lt;.001). Similar results for OS were observed in IM and 2nd TKI cohorts. In the multivariate analysis including the CCI, performance status (PS), the presence of additional chromosomal abnormalities (ACAs), EUTOS long-term survival score (ELTS), age (≥65 years), and the choice of initial TKI treatment (IM vs. 2nd TKIs), the CCI score of ≥4 and PS of ≥2 were identified as adverse prognostic factors for OS (Wald test, P &lt;.01 and P = 0.02). Hazard ratios for the CCI score of ≥4 (vs. score 2) and PS of ≥2 (vs. PS 0) were 5.94 (95% confidence interval [CI]: 1.94-18.2; P &lt;.01) and 6.01 (95% CI: 1.67-21.6; P &lt;.01), respectively. ACAs, ELTS, and older age did not significantly affect OS in this cohort including patients treated with 2nd TKI. Conclusion: Our results demonstrated that comorbidities and poor PS at diagnosis were important predictive factors for OS, regardless of the type of TKI in patients with CML-CP. The risk-adopted management based on comorbidities and PS may be important to further improve the clinical outcomes of CML-CP. Disclosures ONO: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Kyowa Hakko Kirin: Research Funding; ONO Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Merck Sharp &amp; Dohme: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Takahashi:Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Asahi Kasei Pharma: Research Funding; Chug Pharmaceuticals: Research Funding. Kizaki:Kyowa Kirin: Research Funding; Chugai Pharm: Research Funding; Novartis: Speakers Bureau; Ono Pharm: Research Funding, Speakers Bureau; Takeda Pharm: Research Funding, Speakers Bureau; Janssen Pharm: Speakers Bureau; Sumitomo Dainippon Pharm: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Research Funding. Kawaguchi:Alexion: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Suzuki:Merck Sharp &amp; Dohme: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Eisai: Honoraria; Janssen: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Meiji Seika: Honoraria; Kyowa Hakko Kirin: Honoraria; AbbVie: Honoraria; Novartis: Honoraria. Yamamoto:Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Gilead Sciences: Research Funding; Otsuka: Honoraria; Novartis: Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Solasia Pharma: Research Funding; SymBio: Research Funding; MSD: Consultancy, Honoraria; Janssen: Honoraria; Sumitomo Dainippon: Honoraria; ARIAD: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Incyte: Research Funding; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

The TKI-Free Duration after a First Discontinuation Attempt That Failed in CP CML Patients Is a Predictive Factor of TKI-Free Remission after a Second Attempt

Legros: Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Etienne:BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria. Guerci:INCYTE: Consultancy, Honoraria. Huguet:Incyte Biosciences: Honoraria; Novartis: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Coiteux:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.