Generation TKIs Research Articles

Real-world outcomes of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) treated with osimertinib (osi) vs. Afatinib or erlotinib

ObjectivesLimited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20. MethodsWe performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression. ResultsAmong 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004). ConclusionsIn a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC).

Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood-brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.

Flumatinib Versus Nilotinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Introduction Tyrosine kinase inhibitors (TKIs) have considerably improved the long-term clinical outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Most of these patients receive 1 st generation TKI imatinib as first-line therapy; however, an increasing number of patients are now receiving 2 nd generation TKIs as first-line therapy, because of the more potent BCR-ABL1 inhibition with proven efficacy in patients resistant or intolerant to imatinib. Flumatinib is a novel 2 nd generation BCR-ABL1 TKI with promising efficacy and manageable safety in newly diagnosed CML-CP. Compared to imatinib, patients treated with flumatinib have achieved significantly higher rates of 12-month major molecular response (MMR) and complete cytogenetic response were observed in patients with CML-CP and that too within a shorter time duration. Though there have been many studies comparing 2 nd generation TKIs vs imatinib in CML-CP, studies comparing clinical outcomes between different 2 nd generation TKIs are scarce. Here, we report the real-world effectiveness and safety of flumatinib and nilotinib in patients with newly diagnosed CML-CP. Methods In this study, adult patients (≥18 years old) with newly diagnosed Philadelphia chromosome-positive (Ph+) CML-CP who received either 300 mg nilotinib twice daily or 600 mg flumatinib once daily, were included, with a follow-up duration of roughly 3 years (NCT04739826). The primary endpoint was the rate of MMR at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]).The secondary endpoints were the rate of early molecular response (EMR) at 3 months (BCR-ABL1 IS ≤10%), the rate of molecular response at 6 months (BCR-ABL1 IS ≤ 1%) and safety (adverse events [AEs] reports in accordance to Common Terminology Criteria for Adverse Events, version 4.03). Results A total of 446 patients were enrolled in the study between November 2020 and August 2022, of which 150 and 296 patients were enrolled in nilotinib and flumatinib groups, respectively. The baseline characteristics were comparable between the two groups (Table 1). No significant difference in the rate of MMR was observed at 12 months between nilotinib and flumatinib (78% vs 80%; P=0.68) . Similarly, no significant difference was observed in the rate of EMR at 3 months (85% vs 89%; P=0.26) and the rate of optimal molecular response at 6 months (93% vs 92%; P=0.70; BCR-ABL1 is ≤1%) between the two groups. The overall safety profile was similar between the two groups. However, hyperbilirubinemia (47% vs 7%), increased ALT (33% vs 12%), increased AST (24% vs 9%), rash (30% vs 18%) and anemia (19% vs 10%) were more frequent in nilotinib group than flumatinib group, whereas diarrhea was lower in nilotinib than flumatinib (2.7% vs 8.8%). The incidence rate of grade 3-4 AEs were reported to be 13% in nilotinib group and 10% in flumatinib group. The safety of flumatinib was more favorable compared to nilotinib in terms of hepatic toxicities, skin toxicities, etc. (Figure 1). Conclusion The efficacy of flumatinib is comparable to nilotinib in Chinese patients with newly diagnosed Ph+ CML-CP. The overall incidences of grade 3-4 AEs were also accessible for the two drugs, nevertheless, a few AEs inclusively hepatic toxicity, anemia and skin toxicity were remarkably lower with flumatinib intervention.

Chronic Myeloid Leukemia Reduces Survival in Elderly Patients (age ≥ 75 years old): An International Multicenter Retrospective Study

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the life expectancy of individuals with chronic myeloid leukemia (CML), bringing it closer to that of the age-matched general population 1. However, clinical trial data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program indicates that only 3.8% of CML patients aged 75 or above participate in trials, despite this age group representing about 30% of CML patients 2. This study aims to assess the outcomes of elderly patients aged 75 years or older diagnosed with CML. Methods We conducted a retrospective study, using electronic medical records of consecutive CML patients aged ≥ 75 years, diagnosed between January 2002 and December 2021 at four hematological centers in Israel and Moffitt Cancer Center in Florida, United States (MCC). One-year and five-year overall survival (OS) rates were calculated for the whole cohort and for octogenarians (above 80 years). In addition, to assess if CML diagnosis affected life expectancy, we estimated the expected OS of the Israeli cohort based on life expectancy data from the central bureau of statistics (CBS). Kaplan-Meier curves were used to compare expected and observed median OS with the Log-rank analysis. Local Institutional Review Boards approved the study. Results A total of 123 patients (78 treated in MCC and 45 in Israel) aged ≥ 75 years were diagnosed with CML, with a median age of 79 (range: 75 - 100) years, and 55 patients (45%) were octogenarians. At the time of CML diagnosis 84% of had comorbidities, including cardiovascular risk factors in 90 patients (73%), while 50 patients (41%) had cardiovascular/cerebrovascular diseases. Most patients (93%) were diagnosed in chronic phase CML and high/intermediate EUTOS-LTS risk score (96%) treated with imatinib in the 1 st line treatment (69%). After a median duration of 15 (range:1-153) months on 1 st line treatment, 71 patients (58%) discontinued therapy primarily due to intolerance (n=51) while other causes included resistance (n=15), noncompliance/insurance issues (n=4) or progression to blast crisis (n=1). The 2 nd -line treatment included mainly 2 nd generation TKIs (n=53, 74%) (dasatinib-26, nilotinib -19 and bosutinib-8), while 9 patients received imatinib, 1 patient received nilotinib and imatinib, 5 patients received hydroxyurea and 3 patients were lost to follow-up. 35 patients (28%) reached 3 rd line of treatment (imatinib- 5, dasatinib- 3, bosutinib-12, nilotinib-5, ponatinib-2, asciminib-1, hydroxyurea -1, loss to follow up- 6) chiefly (28 patients) due to intolerance and others (7 patients) due to resistance. The best response assessed by RQ-PCR showed deep molecular response (DMR) in 50%, major molecular response (MMR) in 16%, and complete cytogenetic response (CCyR) in 11% of patients with a median time to maximal response of 19 (range: 0.5-111) months. Nevertheless, treatment-free remission (TFR) was rare (n=1). During a median follow-up of 45 (0.4-198) months, 55 (45%) patients died, with cardiovascular complications (n=9), disease progression (n=8), infection (n=7), and secondary malignancy (n=4) being the main known causes. The median OS for the whole cohort was 72.4 (53.1-91.7) months. Improved OS was documented in patients with an age adjusted charlson comorbidity index&amp;lt; 5 (vs. ≥5, p=0.007), those who achieved DMR (vs. no DMR, p=0.001) and median time to best response of 0-18 months (vs. ≥18, p=0.004). Moreover, OS was improved in patients who received 2 nd generation TKIs in 1 st line treatment, 91.1 (81.5-131) vs. 57.7 (35.4-79.9) months in those who received imatinib, (p=0.023). Older age did not affect OS; 1 and 5-year OS for the whole cohort was 86% and 29%, respectively, and 84.3% and 19.6% for the octogenarians, respectively (p=0.076). In the Israeli cohort, while the median expected OS was 103.7 (24-164.7) months, the median observed OS was only 54.77 (2.1-195) months (p=0.03). Conclusions Elderly CML patients were often diagnosed in chronic phase with high/intermediate risk scores. The majority received imatinib as 1 st line treatment and achieved CCyR and MMR, with half of patients achieving also DMR. Surprisingly, patients treated with imatinib had worse OS compared to those receiving 2nd generation TKIs as 1st line treatment. Furthermore, the Israeli cohort analysis supports reduced life expectancy in the very elderly patients with CML.

Lorlatinib as a first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer: Α cost-effectiveness analysis in Greece

ABSTRACT Objectives To evaluate the cost-effectiveness of lorlatinib compared to 1st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC). Methods A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients’ life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Results Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib. Conclusion Lorlatinib provides substantial clinical benefit and appears to be a cost – effective treatment option compared to 1st and 2nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece.

The Use of 2 nd Generation TKIs As First Line Therapy Does Not Prevent CML Related Deaths: Results of an Italian CML Campus Prospective Study in 1277 Patients Treated First Line with Imatinib or 2 nd Generation TKIs

Background: In the last decades prognosis and survival of chronic myeloid leukemia (CML) patients have dramatically improved, thanks to a wider therapeutic armamentarium. Molecular responses are the milestones that guide clinical decisions; however, some information is still lacking and what we know derives mainly from investigational trials: it is still unclear if real-life management could lead to comparable results. For this reason, a prospective observational study was conducted by a CML Italian network to analyze molecular responses in a real-life setting. Methods: A web-based database (www.epiclin.it/lmc) was used to collect clinical and biological data on newly diagnosed CML prospective consecutive patients enrolled in 24 Italian Hematology Centers from January 2013 onwards. Patients were treated according to the policy of the center and the molecular data were obtained by performing tests in accordance with the IS% parameters. Results: A total of 1277 patients were enrolled (Tab. 1) with a median follow up of 4,1 years. There was a significant difference in the median age of patients who started with imatinib (IMA) or 2 nd gen TKIs (II-TKI): 70 vs 52, respectively. The Overall Survival (OS) of the whole cohort at 5 years was 80% for the IMA and 94% for II-TKI treated patients respectively. Out of the total 86 deaths observed in the IMA treated cohort only 11 (12.7%) were due to CML related causes, whereas out of the 32 deaths observed in the II-TKI treated cohort 12 (37.5%) were due to CML. Out of the 607 patients who were on first line IMA, 422/607 (69%) did not switch therapy and have an OS of 81% at 5 years. One hundred and eighty-five out of 607 (31%) changed therapy and showed an OS of 80% at 5 years. Out of 670 patients who started with II-TKI, 492 (73%) continued the same treatment and 178/670 (27%) changed therapy, showing a 5-year OS of 96% and 89%, respectively. In summary, patients who remain in the same type of therapy in which they were initially started show a 5-year OS of 81% and 96% for IMA and II-TKI respectively and only 9 of the total 73 deaths observed in this group of 914 patients were CML related (8 of 58 II-TKI treated patients). Patients who switched to another therapy showed 80% and 89% 5-year OS on IMA and II-TKI group, respectively. Of the 45 deaths observed in this group of 363 patients, 14 were CML related (3 on IMA and 11 on II-TKI) (Tab. 2). In IMA treated patients, 5-year OS according to 6- and 12-months molecular response was worse for patients with BCR::ABL1 &amp;gt;1% compared to those with values between 1 and 0.1% and &amp;lt;0.1% BCR::ABL1 patients (looking at 12 months response, OS was 65% vs 85% vs 90%, Fig. 1A). At 24 months there was a statistical difference in OS between patients with BCR::ABL1 between 1 and 0.1% versus those &amp;lt;0.1% (OS at 3 years was 82% vs 92%) (Fig. 1B). Among II-TKI treated patients, no significant differences in OS were observed, but there was only a generic trend for those with deeper molecular responses between patients with BCR::ABL1 &amp;gt;0.1 versus patients with BCR::ABL1 &amp;lt; 0.1% at all timepoints; to note, the deaths are few and were observed within the first year, independently from the molecular response achieved: at 6 months, 10 deaths on 113 patients of which 7 CML related; at 12 months, 5 deaths on 48 patients of which 4 CML related. Row comparisons of OS were confirmed with multivariable Cox models including main prognostic factors. Conclusions: The real-life data collected by this observational study support the good prognosis of CML patients obtained in our days independently by the TKI used in first line. Indeed, most of the deaths observed are due to CML unrelated causes and the use of II-TKIs does not seem to prevent the CML related deaths, whose number is similar in both cohorts. The fact that the OS is similar in those who remain in IMA therapy versus to those who switch could also simply reflect the presence of unfavorable prognostic factors at diagnosis not controlled by IMA nor by II-TKIs. In this scenario, the observation that the achievement of &amp;lt;1% at 12 months and of MMR at 24 months in patients treated with imatinib is endowed with a statistically significant better OS could simply represent an association rather than a determining factor. Early NGS study would probably provide helpful information at this regard and for identifying patients that, even if treated first line with II-TKIs, could benefit of an early switch, since 11 of the 12 progressions were observed in this group.

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL and Blast Phase CML in Adults

Introduction:Oral ABL1 kinase inhibitors rapidly produce deep remissions in BCR::ABL1+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance. Asciminib (ASC), previously ABL001, is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric ABL1 inhibitor that binds to a site spatially distinct from ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR::ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and active in BCR::ABL1+ ALL and CML-LBC. Methods: This investigator initiated, phase I study (NCT03595917) of asciminib (ASC) in combination with DAS plus prednisone (pred) for BCR::ABL1+ ALL studied ASC in escalating doses in a 3+3 design with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); a 10 patient (pt) expansion cohort was then accrued. Secondary objectives define the depth and durability of responses. Pts with BCR::ABL1+ ALL or CML-LBC newly diagnosed ≥ 50 years (yrs), or unfit; or relapsed/refractory (no prior DAS or ASC) were eligible in dose escalation; all pts ≥18 yrs were eligible in dose expansion. Pts received DAS 140 mg/day(d) and pred 60 mg/m 2/d 1-24 (max 120 mg/d, tapered d 25-32) with escalating daily doses of ASC (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS and ASC were given in 28-d cycles indefinitely in setting of clinical benefit, with allogeneic stem cell transplant (SCT) consolidation after d85 per treating physician. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study was amended to assess DLT via CTCAEv5. Correlative science efforts seek to define biomarkers of response and resistance to dual ABL1 blockade. Results:The study enrolled 25 pts (48% female), with 14 in dose escalation (13 evaluable), and 11 in expansion (10 evaluable). Most (92%) had new ALL (p190: 15/23, p210: 8/23; 8% had CML-LBC. Median age was 65 yrs (range 33 - 85; 8 pts 70+). Median WBC was 15.1 K/μL (range 0.9 - 251.9 K/μL). No pt had CNS disease. DL1 and DL2 enrolled 3 pts each without DLT. Two of 3 pts at DL3 developed asymptomatic CTCAEv4 gr 3 amylase elevation during C1 meeting original DLT criteria. A 4 th pt enrolled on re-opened DL3 under an amendment defining asymptomatic CTCAEv4 gr 3 amylase/lipase elevations persisting ≤5d to not be a DLT. This pt experienced an asymptomatic CTCAEv4 gr 3 lipase elevation meeting DLT criteria. Thus, the study de-escalated to DL2, re-opening under an amendment assessing DLTs via CTCAEv5. Of note, all DLTs at DL3 would be gr &amp;lt;3 per CTCAEv5. Four more pts (3 evaluable) enrolled at DL2 without a DLT. Thus, ASC 80 mg/d was declared the RP2D, and 11 pts age ≥18 yrs enrolled in an expansion cohort, 10 of whom initiated study treatment. No pt had symptomatic pancreatitis. Rates of molecular response after 3 cycles among all evaluable patients were 58.3% (14/24) for MRD 3.0 and 25.0% (6/24) for MRD 4.0. Evaluable pts with new ALL treated at the RP2D achieved molecular response rates after 3 cycles of 78.6% (11/14) for MRD 3.0 and 42.9% (6/14) for MRD 4.0. Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 - MRD+, C45, C11, C11); 3 remain on study. Correlative science evaluation of serial pt biospecimens in pursuit of predictive biomarkers will be shared at the meeting. Conclusion: Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed. High rates of molecular response and bridging to transplant highlight encouraging preliminary activity. A phase II expansion cohort incorporating blinatumomab is now open.

Excellent Early and Major Molecular Responses Observed with Asciminib Treatment for CP-CML: Results from the ALLG CML13 Ascend-CML Study

ATP-competitive BCR::ABL1 inhibitors are effective in many patients with CP-CML patients. However, a significant minority experience treatment failure with currently available drugs due to resistance or toxicity. Asciminib, a first-in-class myristoyl site BCR::ABL1 inhibitor, is now indicated in many jurisdictions for CP-CML after ≥2 prior lines of treatment. The Australasian Leukaemia and Lymphoma Group (ALLG) CML13 ASCEND-CML trial assessed its tolerability and efficacy in the frontline setting, where data are scarce. ALLG CML13 is a prospective open-label phase II study that completed enrolment in Dec 2022 at 14 sites. Patients commenced asciminib 40mg twice a day (BID) at time of diagnosis, and were assessed according to optimal 2020 ELN targets ( BCR::ABL1 ≤10%, ≤1% &amp; ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients in Major Molecular Response (MMR; BCR::ABL1 ≤0.1%) at 12 months were switched to 80mg QD for ease of administration. Patients with treatment failure ( BCR::ABL1 &amp;gt;10% at 3 or 6 months; BCR::ABL1 &amp;gt;1% at 12 or 18 months) continued asciminib, with additional imatinib or dasatinib or nilotinib, according to physician preference. Patients with a suboptimal response at 6, 12, or 18 months, but without treatment failure, continued asciminib but with the dose doubled to 80mg BID. This is a pre-specified analysis of the co-primary end points: i) final analysis of Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 months) and ii) interim analysis of MMR by 12 months. By data cut-off in May 2023, 101 patients had median follow-up of 20 (0-29) months (including 1 patient who enrolled but never started therapy due to elevated lipase at baseline). Grade 3/4 adverse events (AEs) included neutropenia and thrombocytopenia, (reported in 6% and 5% of patients, respectively); increased lipase/amylase reported in 8% (clinical pancreatitis reported in 2%), anaemia (2%), infection (2%) and 1% each of increased AST/ALT, back, abdominal and chest pain from pulmonary embolism. The only treatment emergent vascular event was a stroke, reported in a male patient aged 73 with pre-existing diabetes and hypertension, after 20 months of asciminib. Fifteen patients discontinued asciminib: 6 due to AEs (2 with persistent cytopenia requiring an allograft, 3 with recurrent asymptomatic lipase elevation, 1 with pancreatitis); 3 lost to follow-up; and 6 due to resistant disease (1 confirmed loss of MMR at 9 months, without ABL1 mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T/V and P465S; 1 loss of MMR at 6 months with A337T mutation; 1 loss of MR2 with V506L; and 2 with failure to achieve EMR - below). No other transformation occurred. During the first 3 months of treatment, 85% of patients had an assigned dose density of &amp;gt;90%; 9% of patients dose reduced to &amp;lt;66%. EMR was achieved by 94/101 patients (93.1%; 96% CI 86-97%): 1 patient never started treatment, 1 patient missed this assessment, 3 patients had withdrawn by this timepoint, and 2 had BCR::ABL1 of 24% and 210%, respectively. Neither of the EMR failure patients had myristoyl site mutations; both were subsequently intolerant of combination TKI/asciminib therapy because of cytopenia and headaches, respectively and are now on dasatinib monotherapy. Six patients dose escalated and remain on asciminib 80mg BID: 3 after failing to achieve MMR by 12 months, &amp; 3 failing to achieve MR4 after 18 months; 2 have since achieved their targets. By 3 months, 48/101 (48%) patients achieved MMR and 12 (11.9%) achieved MR4. Considering only patients with &amp;gt;12 months of follow up, the interim rate of MMR by 12 months is 62/75 patients (82.7%; 98% CI 70-92%). With “off-protocol for any reason” as the competing risk, the cumulative incidences of MMR &amp; MR4.5 by 12 months were 81.1% &amp; 32.3% respectively (Figure). ASCEND is one of the first studies using frontline asciminib, with excellent achievement of EMR and MMR, and low transformation rate. Rates of MMR at 12 months are comparable to those reported with second generation TKIs, though achievement of deeper responses appears more rapid with asciminib. Treatment was well tolerated in general: majority of AEs were grade I/II events that did not result in treatment discontinuation, and only one vascular event was observed. Early achievement of MMR and MR4 may accelerate eligibility for, &amp; increased success of, treatment-free remission attempts.

A rare FBXO25–SEPT14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report

Abstract Objectives Exploring the pathogenesis of resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Case presentation This case report describes a rare fusion of FBXO25 and SEPT14 genes in a 58-year-old male patient with chronic myeloid leukemia. The patient had been treated with tyrosine kinase inhibitors for one year. After 6 months of imatinib treatment, the patient's symptoms improved significantly and the complete blood count returned to normal, but the optimal ratio of BCR::ABL transcripts to ABL transcripts is greater than 10 % indicating treatment failure. Then we switched to a second generation TKIs to continue treatment, During the Flumatinib treatment period, the patient developed severe bone marrow suppression and exhibited additional cytogenetic abnormalities involving chromosome aberration: 47, XY,+8[5]/47, idem, inv(Y)(p11.2q11.23)[15]. By adjusting the drug dose and elevating blood cells, the patient’s BCR::ABL P210/ABL was 2.56 % after six months of Flumatinib treatment. The patient’s BCR::ABL P210/ABL consistently remained above 1 % throughout the treatment, and additional cytogenetic abnormalities were present. Next-generation sequencing revealed the recombination of exon 4 of the FBXO25 and exon 10 of the SEPT14, and this mutation has not been previously reported. Conclusions Our findings suggest that the FBXO25-SEPT14 fusion may be associated with tyrosine kinase inhibitors resistance in chronic myeloid leukemia.

Is there a role for first generation TKIs in adjuvant setting of EGFR mutated early NSCLC?

Is there a role for first generation TKIs in adjuvant setting of EGFR mutated early NSCLC?

Dual kinase inhibitor for EGFR mutants and ErbB2 limit breast cancer

Mutations in the epidermal growth factor receptor (EGFR) have been found in more than 10% of non-small cell lung cancer (NSCLC) patients in North America. The vast majority of these differences are L858R point mutations in Exon 21. Currently, monoclonal antibodies directed against the extracellular domain of EGFR or small molecule/tyrosine kinase inhibitors (TKI) are the stalwarts of NSCLC therapy. Resistance, however, gradually develops because of the T790 mutation towards first and second generation TKIs. The third generation TKI AZD9291 (Osimertinib) has a high affinity for both activating and the acquired resistant mutation (T790 M) in EGFR, with a low affinity towards wild-type EGFR. Recent research, however, suggests that the EGFR (C797S) mutation in the tyrosine kinase domain is a likely cause of resistance to AZD9291. Another significant transformation mechanism associated with this resistance is erbB2 amplification. Our laboratory has developed a small kinase inhibitor, ER121 (MW: ∼500), that inhibits the erbB2/HER2 tyrosine kinases in addition to the EGFR C797S mutations. We have identified a TKI, ER121 targeting the mutant EGFR(T790 M). Using in vitro and in vivo models, examined the efficacy of ER121 on mutant EGFR cell lines. This has enabled us to establish that ER121 is well tolerated when administered orally and produces significant inhibitory activity against human cancers generated by mutant EGFR and amplified ErbB2.

Clinical significance of serum prohibitin in chronic myeloid leukemia patients on first-line tyrosine kinase inhibitors

Abstract Background Prohibitin is a widely expressed intracellular protein that is distributed in various compartments, where they exert different biological functions accordingly. Prohibitins have displayed both protumorigenic and antitumorigenic roles in cancer formation. Depending on the type of cancer and the localization of prohibitin, studies have shown that it exerts a different biological role. Aim This study aims to investigate prohibitin level in Egyptian patients with chronic myeloid leukemia (CML) and to evaluate its correlation with disease activity and response to first-line tyrosysine kinase inhibitor treatment. Patients and methods Prohibitin level was measured using enzyme-linked immunosorbent assay in 80 CML patients in the chronic phase. They were recruited from the clinical hematology division of Internal Medicine Department, Ain Shams University Hospitals. They were matched to 10 healthy volunteers as a control group. Results In our study, we have demonstrated that prohibitin levels were significantly higher in patients with CML than in the control participants (P=0.002). Prohibitin levels were significantly higher in CML patients with an active disease status (P=0.001). In addition, significantly higher levels of prohibitin in CML patients were associated with poor response to first generation TKIs (P=0.001). Receiver-operating characteristic curve was applied. A serum level of prohibitin higher than 289 is a good predictor for poor response to first generation TKIs as per response assessment by PCR for BCR-ABL (area under the curve=0.67, sensitivity and specificity 58.33 and 80.56, respectively). Conclusion Prohibitin is overexpressed in CML patients and has a possible impact on disease activity and response to treatment in CML patients that warrants further investigations.

Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum Albumin.

As third-generation tyrosine kinase inhibitors, furmonertinib and osimertinib exhibit better efficacy than first- and second-generation tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. However, radioactive pharmacokinetics studies showed that parent-related components remain in human plasma for at least 21 days after oral administration. Similar pharmacokinetic profiles were found in pyrotinib and neratinib, which have been identified to covalently bind with human serum albumin at Lys-190, leading to low extraction recovery in protein precipitation. However, the binding mechanism of furmonertinib and osimertinib in human plasma has not been confirmed. Comprehensive techniques were used to investigate the mechanism of this binding, including ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry and online/offline radioactivity profiling. SDS-PAGE and further autoradiography were also used to detect drug-protein adducts. We found that most furmonertinib exists in the human plasma following ex vivo incubation in the form of protein-drug adducts. Only lysine-furmonertinb adducts were found in pronase digests. A standard reference of lysine-furmonertinib was synthesized and confirmed by NMR. Through peptide mapping analysis, we confirmed that furmonertinib almost exclusively binds with human serum albumin (HSA) in plasma following ex vivo incubation, via Michael addition at Lys-195 and Lys-199, instead of Lys-190. Two peptides found to bond with furmonertinib were ASSAKQR and LKCASLQK. Osimertinib was also found to bond with Lys-195 and Lys-199 of HSA via peptide mapping analysis. SIGNIFICANCE STATEMENT: Here we report that furmonertinib and osimertinib can covalently bind with human serum albumin at the site of Lys-195 and Lys-199 instead of Lys-190, potentially leading to the long duration of drug-protein adducts in the human body.

CNS Outcomes in ALK Fusion Positive NSCLC Patients with BM Who Received Alectinib with or without Local Therapy

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) are common in patients (pts) with anaplastic lymphoma kinase (<i>ALK</i>) fusion positive non-small cell lung cancer (NSCLC). <i>ALK</i>-rearrangements are observed in approximately 5% of NSCLC patients. Alectinib is a highly selective, central nervous system (CNS)-penetrant tyrosine kinase inhibitor which may allow patients with BMs to defer local therapy (LT) such as surgery, stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). We characterized the CNS outcomes in pts with <i>ALK</i> fusion positive NSCLC BM treated with alectinib with or without LT. <h3>Materials/Methods</h3> We retrospectively reviewed <i>ALK</i> fusion-positive NSCLC pts with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. CNS response rates (RR) were assessed via modified Response Assessment in Neuro-Oncology (RANO)-BM criteria. Surgically resected lesions were excluded from this analysis. A complete response (CR) was defined as complete disappearance of the lesion and a partial response (PR) was defined as a >30% decrease in size relative to baseline. Intracranial progression (iPFS) was analyzed using the Kaplan-Meier (KM) method with log-rank test, with death factored in as a competing risk. <h3>Results</h3> We identified 39 pts with <i>ALK</i> fusion positive NSCLC who initiated alectinib at BM diagnosis: 27 pts received alectinib only and 12 pts received alectinib and upfront LT including surgical resection (<i>n</i> = 2, 17%), comprehensive surgical resection followed by SRS (<i>n</i> = 2, 17%), SRS 4 (<i>n</i> = 4, 33%) or WBRT (<i>n</i> = 4; 33%). Alectinib was first-line therapy for 26 (67%) pts and second-line therapy for 12 (31%) pts. Median follow-up from BM diagnosis was 50.6 months (IQR 33.3-56.7). Patients treated with alectinib and LT were more likely to have pre-treatment neurologic symptoms (83% vs 33%), larger median BM size (median 12 mm vs 5 mm), and BM > 1 cm in size (83% vs 30%) compared to pts who received alectinib only. Despite these negative factors, there were no differences between both groups with regards to iPFS (TKI only, HR 1.31, 95% CI 0.55-3.11; p=0.54). A total of 28 and 55 lesions were assessed for CNS RR in the alectinib + LT and alectinib only groups, respectively. At 6-months, the CNS RR were 46% (PR) and 54% (CR) vs. 19% (PR) and 74% (CR) in the alectinib + LT and alectinib only groups, respectively. <h3>Conclusion</h3> To our knowledge, this study represents the largest yet reported series of alectinib-treated NSCLC BM with detailed patient and lesion-level CNS-specific outcomes. Despite the fact that patients with <i>ALK</i> fusion positive NSCLC treated with alectinib + LT had larger BM and a greater likelihood of pre-treatment neurologic symptoms, the iPFS was similar between the patients treated with alectinib only and alectinib + LT. With newer generation TKIs which may have CNS penetrance, further prospective studies are required to identify which patients are most likely to benefit from the addition of LT to <i>ALK</i>-directed therapy.

996P Activity of OsimeRTInib in NSCLC with UNcommon EGFR Mutations: Retrospective observational multicenter study (ARTICUNO)

In 10-20% of patients (pts) with EGFR mutated NSCLC, an assorted group of uncommon mutations can be detected. These mutations confer variable sensitivity to 1st and 2nd generation TKIs, overall resulting in lower therapeutic activity. Data of Osimertinib (Osi), a 3rd generation TKI, are limited and strongly warranted.

The significance of micro-EGFR T790M mutation on EGFR-TKI efficacy in patients with NSCLC: The WJOG13119L study.

e21177 Background: The significance of micro-pretreatment EGFR T790M mutation on EGFR-tyrosine kinase inhibitor (TKI) efficacy in patients with non-small cell lung cancer (NSCLC) remains uncertain. In addition, there has been no method to examine the micro-T790M mutation after excluding formalin-fixed and paraffin-embedded (FFPE)-derived artificial mutations. Therefore, we used a novel method to examine the variant allele frequency (VAF) of T790M mutation in the FFPE samples after excluding the artificial mutations. Subsequently, we retrospectively investigated the association between micro-T790M mutations and time to treatment failure (TTF) in patients treated with 1st, 2nd, or 3rd generation (1G, 2G, 3G) EGFR-TKIs. Methods: We enrolled patients with NSCLC who harbored EGFR exon 19 deletion (Del19) or L858R without T790M mutation using conventional methods. Patients who received 1G or 2G EGFR-TKIs until June 2018 or 3G EGFR-TKI until June 2019 from 31 institutions were included. Droplet digital PCR was performed using pretreatment FFPE tumor samples. We defined cases as micro-T790M positive when the VAF of T790M was higher than that of F795F, owing to the FFPE-derived artificial mutations. The ratio of micro-T790M mutation was calculated as follows: {(VAF of T790M) – (VAF of F795F)} /VAF of (Del19 or L858R). The lowest value was set as 0. Results: A total of 110, 102, and 103 patients received 1G, 2G, and 3G EGFR-TKIs, respectively. Of these patients, 48.1%, 47.0%, and 47.6% were classified as micro-T790M positive, respectively. The ratios of micro-T790M mutation, represented as median (%) (interquartile range), in 1G, 2G, and 3G EGFR-TKI groups were 0.27 (0.12-0.87), 0.28 (0.13-0.47), and 0.42 (0.20-0.68), respectively. The VAF of T790M or F795F in all patients, represented as median (%) (interquartile range), was 0.26 (0.19-0.35) or 0.25 (0.19-0.33), respectively. The TTF was not significantly different between the T790M-positive and negative groups in analysis based on each generation TKIs. In the Del19 group, the TTF of the 1G EGFR-TKI was significantly shorter, while that of the 3G EGFR-TKI was significantly longer in the T790M-positive group than in the negative group ( p= 0.02, 0.04, respectively). In the T790M-positive group, the TTF of the 2G or 3G EGFR-TKI group was significantly longer than that of the 1G EGFR-TKI group ( p= 0.04, 0.01, respectively). This result was observed in the Del19 group but not in the L858 group. Furthermore, TTF did not significantly differ between the 1G, 2G, and 3G EGFR-TKIs in the T790M-negative group. Conclusions: This study showed that micro- EGFR T790M mutations influence the EGFR-TKI efficacy. Detection of micro-T790M mutations will facilitate selection of the optimal EGFR-TKI for patients with EGFR mutated NSCLC.

A Multi-Center, Open-Label, Randomized, Two-Arm Study, to Evaluate the Efficacy of Osimertinib with Early Intervention SRS Treatment Compared to the Continuation of Osimertinib Alone, in Patients with EGFR-Mutated NSCLC and Asymptomatic Brain Metastases

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) develop in 50-70% of patients with EGFR mutant NSCLC and are a main cause of morbidity and mortality. While radiation therapy (stereotactic radiosurgery (SRS) or whole brain) remains a viable treatment option for the treatment of BM, often Osimertinib monotherapy is the treatment of choice in cases of asymptomatic BM due to its improved pharmacokinetic profile and excellent CNS penetration compared to first generation TKIs. In the recently published FLAURA trial, 77% of patients with brain metastases demonstrated an objective response rate with Osimertinib, 18% having a complete response. Various studies, however, have highlighted the benefit of combining TKI and SRS treatment as opposed to each treatment alone. The goal of this Phase III trial is to assess whether early intervention with SRS (2 months post-treatment initiation of Osimertinib) to active brain metastases (as visualized by MRI at this time point) will better control disease that did not completely respond to Osimertinib and in turn will delay brain progression (CNS-PFS). <h3>Materials/Methods</h3> Eligible patients will undergo baseline brain MRI, CT, cognitive assessments and a QOL questionnaire. Patients will be treated with Osimertinib for 2 months (8 weeks). At 2 months, a second MRI will be performed. One-hundred and sixty two asymptomatic or mildly symptomatic patients with <20 visualized BM will be randomized in a 1:1 ratio between the control arm consisting of continued Osimertinib and the SRS arm consisting of Osimertinib + SRS to all residual brain lesions. Recommended SRS doses are 20 Gy in 1 fraction to metastases ≤ 1.5 cm and 27Gy in 3 fractions to larger metastases. The primary endpoint is CNS-PFS, assessed by RECIST criteria, and secondary endpoints include whole body PFS, cognitive function, QOL, time to whole-brain radiation, and overall survival. <h3>Results</h3> Accrual has begun at the main study center. <h3>Conclusion</h3> This study will determine if addition of SRS to residual brain metastases two months post-treatment initiation of Osimertinib for selected patients with asymptomatic brain metastases results in improved oncologic, cognitive and QOL outcomes.

Abstract P083: Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI

Abstract BACKGROUND Lung cancer is the most common cancer worldwide in males &amp; a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge. METHOD 20 patients of metastatic adenocarcinoma, confirmed with core biopsy &amp; IHC (EGFR positive) were offered Erlotinib initially. Osimertinib was offered to those who developed EGFR TKI resistance due to T790M mutation (10 cases). All 10 patients eventually developed resistance to Osimertinib. All patients were given 3 months drug free holiday &amp; then re-challenged with Erlotinib. RESULT 4 out of 10 (40%) patients responded to the therapy. 6 patients had progression &amp; were managed by systemic chemotherapy &amp; radiation. CONCLUSION Literature shows up to 50% metastatic adenocarcinoma, EGFR positive patients who had developed EGFR TKI resistance to 1st &amp; 3rd generation TKIs, responds to re-challenge with first generation TKI after a drug free holiday. In this series 40% patients responded. This approach should be tried &amp; non-responders can be offered systemic chemotherapy &amp; radiation. Citation Format: Suryakanta Acharya. Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P083.

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study