Failure Of Tyrosine Kinase Inhibitors Research Articles

PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPC could be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNP gene encoding PrPC is associated with EMT. By manipulating the levels of PrPC in different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPC is mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPC operates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPC levels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNP levels increase with TKI resistance and that reducing PRNP expression sensitizes cells to osimertinib. Finally, we found that plasma PrPC levels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPC as a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPC levels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.

Management of Chronic Myeloid Leukemia that is Intolerant or Resistant to Front-Line Treatment

With advances in treatment for chronic myeloid leukemia (CML), the natural history of chronic phase (CP) CML has changed, with most individuals expected to live a normal life expectancy. The goal of therapy for most is to achieve a long-term deep molecular response (DMR) with the potential for medication discontinuation and treatment-free remission (TFR).1 Currently, six oral therapies have been approved for CP-CML in Canada: (1) imatinib, a first-generation tyrosine kinase inhibitor (TKI); (2) dasatinib, (3) nilotinib, and (4) bosutinib, the second-generation TKIs (2G-TKIs); (5) ponantinib, a third-generation TKI; and (6) asciminib, specifically targeting the ABL Myristoyl pocket (STAMP) inhibitor. Classically, treatment for CP-CML has consisted of front-line imatinib and switching to a 2G-TKI upon treatment resistance or intolerance. Increasingly, patients are being prescribed an upfront 2G-TKI with the goal of achieving quicker and deeper molecular remissions and a TFR.2 Challenges arise in CML when treatment with either two TKIs (imatinib + 2G-TKI) or one 2G-TKI fails, given the lack of evidence to inform clinical decision-making at this juncture. This paper aims to define TKI failure and help guide the selection of second-line treatment after failure of front-line therapy.

A retrospective study of tislelizumab combined with bevacizumab, pemetrexed, and carboplatin in driver-gene mutated advanced non-squamous non-small cell lung cancer after tyrosine kinase inhibitors failure.

e20620 Background: Overcoming resistance to tumor targeted therapies is a major challenge in the management of driver-gene mutated non-small cell lung cancer (NSCLC). Recent clinical trials suggested that the combination approach of immunotherapy, bevacizumab and platinum-based chemotherapy was effective for driver-gene mutated NSCLC after tyrosine kinase inhibitors (TKIs) failure. Our retrospective study was aimed to examine the efficacy and safety of tislelizumab (TIS) combined with bevacizumab plus chemotherapy for advanced driver-gene mutated non-squamous NSCLC (nsq NSCLC) who had failed to TKIs therapies. Methods: We retrospectively collected medical records of driver-gene mutations advanced nsq NSCLC who had failed to TKIs therapies in the Affiliated Hospital of Zunyi Medical University and Second Affiliated Hospital of Zunyi Medical University from January 2021 to December 2023. The participants were sorted into two groups. Pts in TBCP group received TIS combined with bevacizumab, carboplatin and pemetrexed (BCP) for six cycles, followed by TIS with pemetrexed as maintenance therapy. Pts in BCP group received BCP regimen for six cycles, followed by pemetrexed as maintenance therapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: A total of 12 pts were enrolled (6 pts in TBCP group and 6 pts in BCP group). In TBCP group, there was one patient with EGFR exon 19del, KRAS, BRAF V600 mutation and RET fusion, respectively. 2 pts harbored EGFR exon 21 L858R mutations. In BCP group, 4 pts harbored EGFR exon 19del, 1 patient with exon 21 L858R, and 1 patinet with BRAF V600 mutation. All pts were failed to previous TKI therapy. 3 pts (50%) had progression after two systemic treatment lines in ABCP group. 4 pts(66.7%) had progressive disease after at least two systemic regimen. As of 6 February 2024 (median follow-up, 18.6 months), significantly longer PFS was observed in TBCP group compared with BCP group (HR = 0.269 [95% CI: 0.068-1.065], p = 0.0080). Median PFS was 14.20 months (95% CI: 0.5010-5.379) and 8.65 months (95% CI: 0.1859-1.996) in TBCP group and BCP group, respectively. A higher ORR assessed was observed with TBCP group (66.7%) compared with BCP group (33.3%). The DCR were both 100% in two groups. Median OS was not reached. Grade 3-4 TRAEs occurred in 1 and 2 pts in TBCP group and BCP group, respectively. Conclusions: TIS combined with bevacizumab, carboplatin and pemetrexed has shown a promising anti-tumor efficacy with manageable safety profile for TKI failure driver-gene mutations advanced nsq NSCLC. However, these findings still need to be further confirmed by prospective clinical trials with larger sample sizes.

Abstract CT055: Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation

Abstract In the multicenter, dose-escalation and dose-expansion phase 1 clinical trial (NCT05767866), we evaluated safety and tolerability of YK-029A in various EGFR mutated non-small-cell lung cancer (NSCLC). We have reported efficacy of YK-029A in untreated NSCLC with EGFR ex20ins mutation[1]. This time we report efficacy of YK-029A in patients with acquired EGFR T790M mutation after failure of first or second generation EGFR tyrosine kinase inhibitors (TKIs). Method: This dose-escalation and dose-expansion phase 1 trial recruited previously treated NSCLC patients with EGFR T790M mutation or patients with EGFR ex20ins or EGFR rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or EGFR rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. Efficacy of YK-029A in EGFR T790M mutated NSCLC was assessed by the investigators. Results: A total of 114 patients were recruited into the study. Safety profile of the first 108 patients was reported previously[1]. By the cut-off date on Sep 12, 2023, 38 patients harbored EGFR T790M mutation were included in efficacy analysis. All these patients were previously treated with first or second generation EGFR-TKIs. The objective response rate (ORR; RECIST 1.1) was 65.8% (95%CI: 48.6%-80.4%) and disease control rate (DCR) was 84.2% (95%CI: 68.7%-94.0%). With a median follow-up time of 8.2 months,the median progression free survival (PFS) was 11.0 months (95%CI: 7.75-NR). The median overall survival (OS) was not reached. Among the 8 patients with measurable brain metastases, intracranial ORR was 75% (95%CI: 35.6%-95.6%) . Conclusions: YK-029A has promising activity in previously treated NSCLC patients harboring EGFR T790M mutation. Reference[1] DUAN J, WU L, YANG K, et al. Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial [J]. J Thorac Oncol, 2023. Citation Format: Rui Wan, Yi Fung Chau, Jun Zhao, Zhe Liu, Mingfang Zhao, Yanqiu Zhao, Xiumei Dai, Yueyin Pan, Zhihong Zhang, Yu Yao, Kunyu Yang, Lin Wu, Yanyan Xie, Bi Chen, Yixuan Yang, Yongqi Guo, Jie Wang, Jianchun Duan. Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT055.

The Role of Molecular or Cytogenetic Response as a Favorable Prognostic Factor Before Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of this study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD. Median survival was 11 years, with a 1-year OS of 70% (57.8 to 79.3) and a 5-year OS of 57.7% (45.1 to 68.5). The estimated 5-year OS was not different for CP1 (60%) versus advanced stages (45%); P = .60. The degree of response immediately before transplantation was directly associated with worse outcomes [HR 5.89 (1.19-29.16); P = .03] for patients with only a hematological response compared with patients with a cytogenetic or molecular response. This study corroborates the potential of HSCT in the scenario of therapeutic failure and highlights the role of molecular or cytogenetic response as a potential target to be achieved before transplantation.

Abstract 987: Novel ALK mutations in EML4::ALK+ NSCLC resistant to TKIs identified by liquid biopsy

Abstract The identification of Anaplastic Lymphoma Kinase (ALK) chromosomal translocations led to the development of effective targeted therapies in a subset of Non-Small Cell Lung Cancer (NSCLC) patients. Several drugs are currently in clinical practice for advanced ALK+ NSCLC. However, resistance remains a challenge in these patients. The possibility to analyze circulating tumor DNA (ctDNA) with non-invasive methods can greatly improve prognostic capabilities, by allowing early detection of relapse and of drug-resistant mutations from peripheral blood. We report a series of 15 consecutive relapsed NSCLC patients (12 ALK+, 3 ROS1+) treated at the Fondazione IRCCS-San Gerardo dei Tintori (Monza, Italy) that were investigated by liquid biopsy at tyrosine kinase inhibitor (TKI) failure, through amplicon deep sequencing of the ALK/ROS1 kinase domains. Median DNA yield was 4.8 ng per ml of plasma and mean fragment size was 176 bp. Mutational hotspot coding regions of ALK and ROS1 genes were amplified by high-fidelity PCR and sequenced. Mean coverage of called variants was 24,687x. The threshold for mutation calling was set at 0.6%, after correcting for mapping quality, minimum coverage, and strand bias. Analysis of background signal on healthy control DNA identified 0.0024 mismatches per mapped base. Overall, plasma ctDNA analysis detected an ALK mutation in 7/18 relapse samples from 7/15 patients. No ROS1 mutations were found in ROS1 fusion-positive patients. Among 12 patients carrying an EML4::ALK fusion, 10 variants potentially driving resistance were found. Along with mutations that were previously identified (L1196M/G1202R, E1154K, F1174L), novel ALK variants were detected such as L1198R, T1211I, C1235R, C1237Y, L1196P. Mutations were characterized for sensitivity to ALK inhibitors in a BaF3-EML4::ALK cell model, using cell proliferation assays and western blotting to evaluate the effects on ALK phosphorylation. C1237Y and L1196P mutants appeared to resist all TKIs; hence, we further tested their sensitivity to novel investigational drugs, zotizalkib and repotrectinib. Both mutants demonstrated resistance, suggesting that these two mutations confer broad resistance to TKIs. Molecular modelling of C1237Y and L1196P mutants was run to elucidate the mechanisms of resistance. The ADP-C1237Y complex showed a much smaller root-mean-square deviation than ADP-WT, indicating a higher affinity/activity of the mutant. L1196 interacts hydrophobically with a methyl group of lorlatinib, P1196 is predicted to lose such interaction, while ATP binding is not affected. The presence of C1237Y and L1196P variants, is a relevant finding due to their resistance, even after the exposure to the fourth-generation inhibitor zotizalkib. The clonal selection of these mutations, made by second/third generation ALK TKIs may lead to a complete refractory status, which would then render TKIs useless in a sequential therapeutic strategy. Citation Format: Federica Malighetti, Matteo Villa, Elisa Sala, Geeta Sharma, Giulia Arosio, Maria Gemelli, Chiara Manfroni, Diletta Fontana, Nicoletta Cordani, Raffaella Meneveri, Alfonso Zambon, Rocco Piazza, Fabio Pagni, Diego Cortinovis, Luca Mologni. Novel ALK mutations in EML4::ALK+ NSCLC resistant to TKIs identified by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 987.

Safety and efficacy of SNK01 (autologous natural killer cells) in combination with cytotoxic chemotherapy and/or cetuximab after failure of prior tyrosine kinase inhibitor in non-small cell lung cancer: non-clinical mouse model and phase I/IIa clinical study

BackgroundChoosing treatments for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with osimertinib resistance is challenging. We evaluated the safety and efficacy of SNK01 (autologous natural killer...

Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Abstract C025: Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI

Abstract Background: There is a high unmet need for an effective therapy for the treatment of non-small cell lung cancer (NSCLC) following osimertinib or other 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure, especially when resistance is driven by the occurrence of the C797S mutation. BBT-207 is a fourth-generation EGFR inhibitor. Preclinically BBT-207 has shown activity against treatment-emergent complex EGFR mutations containing T790M and/or C797S as well as drug-naïve mutants providing a possibility to overcome resistance to prior TKIs. Activity to intracranial lesions is also anticipated from animal models. Methods: Study BBT207-ONC-001 is an open-label, phase 1/2 study evaluating safety, tolerability, pharmacokinetic profile, pharmacodynamic characterization, and preliminary antitumor activity of BBT-207 monotherapy in approximately 92 patients with EGFR-mutant NSCLC. It consists of 3 phases: Phase 1a (dose escalation), phase 1b (recommended phase 2 dose selection), and phase 2 (dose expansion). Key eligibility criteria include patients ≥18 years of age with advanced stage and refractory NSCLC with an activating EGFR mutation, documented partial response, complete response, or durable stable disease after treatment of an EGFR TKI, and previous treatment with all standard therapeutic options and at least one third-generation EGFR TKI. There is no limit on the number of previous treatments received. Phase 1a requires confirmation that the tumor harbors a classical EGFR mutation (19Del or L858R), and phase 1b and phase 2 require confirmation that the tumor or the blood harbors complex EGFR mutations containing C797S. Patients with asymptomatic brain metastases who are on stable dose of corticosteroid are eligible. Primary endpoints are to determine recommended dose range (RDR) which is defined between the minimal reproducibly active dose, and the maximum tolerated dose or maximum administered dose and to characterize the overall safety and tolerability of BBT-207 (phase 1a); to determine the recommended phase 2 dose (phase 1b); to evaluate preliminary antitumor activity with objective response rate (phase 2). Phase 1a dose escalation will be guided by Bayesian logistic regression model. The safety monitoring committee will determine RDR and two recommended dose levels (RDs) within the RDR to be explored in phase 1b. In phase 1b, up to 20 patients will be randomized to each of the two RDs. At the end of phase 1b, a futility test will be performed in the dose level to be treated with the RP2D using Bayesian analysis. Phase 2 will be a non-randomized, open-label phase with up to 20 patients. Patients may receive treatment until disease progression or unacceptable toxicity. Treatment continuation beyond progression will be allowed if potential benefits are justified. Investigational new drug application was cleared by the U.S. FDA. Patient enrollment will begin in approximately August 2023 in the U.S. and Republic of Korea. Clinical trial information: NCT05920135. Citation Format: NaEun Jeon, Alexander Spira, Douglas Orr, Lyudmila Bazhenova, Misako Nagasaka, Jin Seok Ahn, Dong-Wan Kim, Yu Jung Kim, Jimin Cho, Agnes Jung, Eunsoo Jung, Chul-Won Kim, Taiguang Jin, Yong-Hee Lee, Sang-Yoon Lee. Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C025.

Mutation of Epigenetic Regulators at Diagnosis Is an Independent Predictor of Tyrosine Kinase Inhibitor Treatment Failure: A Report from the Residiag Study

Introduction Additional mutations at chronic myeloid leukemia (CML) diagnosis have been shown to variably affect tyrosine kinase inhibitor (TKI) response and were inconstantly detected at loss of response. Contradictory observations may have resulted from difficulties in reliably inferring CML clonal architecture from mutations quantified by NGS, BCR::ABL1 by qRT-PCR, ABL1-TK by RNA-Seq. The RESIDIAG study was designed to identify at diagnosis molecular markers predictive of TKI treatment failure and analyze the clonal dynamics using asymmetric capture sequencing (aCAP-Seq). Methods DNA samples from 60 TKI responders (median follow-up: 7.1 years) were sequenced at diagnosis by aCAP-Seq, allowing quantification and breakpoint sequencing of genomic BCR::ABL1 fusion together with 43 myeloid genes, including ABL1 with a limit of detection of ~0.1% for BCR::ABL1 and 0.5-1% for SNVs and Indels. In parallel, CML patients who experienced treatment failure (ELN 2020) were sequentially analyzed at diagnosis and at failure (n=53), at diagnosis only (n=1), and at failure only (n=3). Small deletions and BCR::ABL1 breakpoints were analyzed to search for microhomology-mediated end-joining (MMEJ) repair signatures. Mutation analysis followed strict medical standards. Results The proportion of patients receiving imatinib at diagnosis wasn't statistically different (p=0.08; Pearson's Chi-square test) between responders (70%) and the failure group (56%). At diagnosis, the number of mutations was higher (p<0.001, t-test with Welch correction) in the failure group (0.9±0.1) as compared with responders (0.18± 0.05). ASXL1, DNMT3A, and TET2 were more frequently mutated at diagnosis in the failure group (38.6%, p<0.001; 10.5%, p=0.01, and 4.3%, p=0.025 respectively; Pearson's Chi²test) as compared with responders (6.7%, 0% and 0% respectively) and the presence of a mutation in one of these genes was highly associated with a reduced failure-free survival (p<0.001, Log-ranked test, Figure 1). An MMEJ signature at BCR::ABL1 breakpoints was more frequent (p=0.014, Pearson's Chi² test) in the failure group (29.1%) than in the responder group (9.1%). and was significantly associated with the ELTS score (p=0.005, Pearson's Chi² test) but not the Sokal score (p=0.017, Pearson's Chi² test). At first failure, 69% of patients had additional mutations in ASXL1 (39%), ABL1-TK (38%), DNMT3A (18%), or TET2 (15%), while other genes were rarely (<5%) mutated. ASXL1 mutations found at diagnosis were still detectable in 18/22 patients at failure and VAF suggested that double mutant BCR::ABL1/ ASXL1 clones were driving TKI failure with or without BCR:: ABL1 tyrosine kinase domain mutation (TKD). ASXL1 mutations disappearing upon treatment were mostly at low frequency <5% at diagnosis and thus possibly not clonally related to CML. Furthermore, a stepwise selection of variables followed by multivariate analysis with the Fine-Gray model identified the age of patients (sdHR [95% C.I.] = 0.99 [0.97-1.00]; p=0.08) and the presence of a mutation in epigenetics regulators at diagnosis as factors affecting the onset of TKD mutations (sdHR = 3.01 [1.76-5.15]; p<0.001). Intriguingly, co-occurring mutations in DNMT3A and TET2 were found in five patients at TKI failure. Their allelic frequency kinetics suggested that these belonged to the same clone driving CML relapse in 4/5 CML patients, while one patient also had a TKD mutation likely involved in CML relapse. Finally, multivariate COX regression analysis identified two independent predictors of TKI failure at diagnosis: a high-risk ELTS score (p=0.001; hazard ratio=3.42 [1.62-7.22] with low-risk as baseline) and a mutation in ASXL1, DNMT3A or TET2 (p=0.002; hazard ratio=2.87 [1.49-5.51]). Conclusion Altogether these results strongly point to the contribution of epigenetic regulator mutations in the emergence of TKI failure in CML and warrant further biological studies to better understand the underlying mechanisms

The Updated Results of Asciminib Managed-Access Program (MAP) in Patients with Chronic Myeloid Leukemia in Russia

Background: Therapy choice in chronic myeloid leukemia (CML) patients (pts) with ≥2 lines of tyrosine kinase inhibitors (TKIs) failure or in pts with T315I mutationis a relevant problem. Efficacy and good tolerability of a first-in-class BCR::ABL1 allosteric inhibitor Asciminib (ASC) in chronic phase (CP) CML pts were confirmed in clinical trials. The out-study world data of ASC use in Managed Access Program (MAP) is of particular interest. Aim: to report the updated results of the ASC use within MAP in 3 clinical centers of Russia. Methods : Adult (≥18 years) CML pts with the lack of efficacy or intolerance to ≥2 lines of TKIs or T315I-positive pts after ≥1 prior TKI were included into a MAP. Inclusion criteria for our analysis were: CML-CP, ASC therapy for >3 months (mo). Two dosing regimen were used: 40 mg BID in BCR::ABL1 T315I-negative pts (40BID group) and 200 mg BID in BCR::ABL1 T315I-positive pts (200BID group). Complete cytogenetic response (CCyR, equivalent of MR2 or BCR::ABL1≤1%), major molecular response (MMR) and deep molecular response (MR4) achievement was assessed by cumulative incidence function (CIF) with Gray's test for comparison. Survival analysis was performed by Kaplan-Meier method according to “intention-to-treat” principle. Results: A total 82 pts received ASC in the MAP, 68 of them met the criteria for analysis (baseline characteristics are in table 1), while 14 were excluded. The median follow-up was 26 mo (range 4-49). The 2-year overall survival was 93% and 83%, the progression free survival was 90% and 70% in 40BID and 200BID groups, respectively. In 40BID group 17/43 pts discontinued ASC: 2 progressed to AP/BP, 2 - for bone marrow transplantation (BMT), 13 - failure (3 pts died due to CML after ASC discontinuation). In 200BID group 12/25 pts discontinued ASC: 2 developed AP, 3 -BMT, 7 - failure (one pt died). CIF of CCyR/MMR/MR4 by 24 mo was 58%/68%/19% in 40BID group and 65%/56%/32% in 200BID group. The achieved CCyR was preserved in 93% (14/15) and 77% (10/13) pts in 40BID and 200BID group, respectively. CIF of MMR in ponatinib-naïve pts was higher in both groups than in ponatinib-pretreated pts (picture). Dose escalation to 80-100 mg BID in 8/43 pts of 40BID group (due to lack of efficacy) resulted in achieving MMR for 2/8 pts with no MMR before escalation. Dose reduction in two groups was done both for adverse events (AEs) grade 3-4 (n=8) and stable MR4,5. In 4 pts (200BID) with no AEs and having a stable MR4,5 for >1 year, no MR4,5 loss was observed after ASC dose reduction to 100 mg BID. Subclone with emerging a new mutation was detected in 3 pts of 40BID group (A337T, G250A, T315I) while no new mutations were found in 200 mg BID group. AEs associated with ASC have been identified in 27/43 pts and 13/25 pts in 40BID and 200BID group, respectively, with no significant difference in AE spectrum and frequency. Most common (≥5%) AEs in two groups were: thrombocytopenia (29%), neutropenia (18%), cholesterol high (13%), anemia (6%), skin rash (5%). AEs grade 3-4 were detected in 13 (30%) and 4 (16%) pts in 40BID and 200BID group, respectively, and mostly presented by hematologic/cytopenic AEs (24%). No pt discontinued ASC due to toxicity, no arterial occlusive AEs were observed. Conclusion: ASC shows effectiveness and good safety profile in pts after prior failure to TKIs and those with T315I mutation. The CIF of any response was higher in ponatinib-naive pts at any dose. Different mutational subclones evolution was observed, including emergence of myristoyl-site mutation in 1 pt. ASC half dose reduction was safe in pts with previous MR4,5 stable response.

Undetectable MRD Status in Patients with R/R CLL/SLL with Stable Disease after Lisocabtagene Maraleucel Treatment: Exploratory Analysis of the TRANSCEND CLL 004 Study

Background:For patients (pts) with R/R CLL/SLL after failure of Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i)-based treatment, there is no established standard of care and therefore there is a high unmet therapeutic need. The phase 1/2 TRANSCEND CLL 004 study (NCT03331198) investigated the efficacy and safety of lisocabtagene maraleucel(liso-cel) monotherapy, an autologous CD19-directed CAR T cell therapy, in pts with heavily pretreated R/R CLL/SLL and ≥ 2 previous lines of therapy, including a BTKi. The primary analysis demonstrated durable CR/CR with incomplete marrow recovery (CRi) per 2018 International Workshop on CLL (iwCLL 2018) criteria, high undetectable MRD (uMRD; 10 −4 sensitivity) rates, and a manageable safety profile in pts who received liso-cel (Siddiqi T, et al. Lancet 2023). All evaluable responders (CR/CRi/PR) achieved blood uMRD status. Among evaluable pts with stable disease (SD), uMRD status was associated with longer median PFS (6.4 months) versus MRD-positive (MRD+) status (PFS, 2.8 months). This exploratory analysis aimed to better understand potential variables associated with achieving uMRD in pts who had SD with liso-cel. Methods: Among 96 pts in the full efficacy set who were treated with liso-cel at dose level 1 (50 × 10⁶ CAR + T cells) or 2 (100 × 10⁶ CAR + T cells), 80 pts were evaluable for peripheral blood MRD. Peripheral blood MRD status was assessed by next-generation sequencing (NGS; clonoSEQ) assay; uMRD was defined as < 10 −4 (< 1 CLL cell per 10,000) at 1 or more postinfusion time points. Additional exploratory analysis leveraged sample-level MRD results defined by total clonal cells/total nucleated cells assessed by NGS. Cellular kinetics were analyzed in peripheral blood samples by qPCR to detect the liso-cel transgene. Correlative analysis studies of baseline markers of tumor burden (sum of the product of diameters; CD19 + cells/μL; percent CLL cells in bone marrow biopsies or aspirates) with liso-cel expansion were evaluated by MRD status. Statistical analyses were performed using the Wilcoxon signed-rank test. Results:Of the 80 pts who were evaluable for peripheral blood MRD, 34 had a best overall response of SD, 19 of whom achieved uMRD and 15 who were MRD+. Greater liso-cel expansion parameters (median maximum expansion and area under the curve from 0-28 days postinfusion) were observed in all pts, including those with SD, who achieved uMRD versus MRD+ status ( P < 0.0001), suggesting that higher liso-cel expansion after infusion was associated with achievement of uMRD independent of iwCLL 2018 response. Regardless of baseline tumor burden, pts with higher liso-cel expansion achieved uMRD after liso-cel treatment. A positive association between tumor burden and liso-cel expansion in pts with SD and uMRD was also observed. In contrast, pts with SD who were MRD+ had lower liso-cel expansion and trends of higher baseline disease burden. Liso-cel expansion in pts with SD and uMRD clustered with the responders, who all achieved uMRD status (in those evaluable for MRD). Notably, 4 pts with SD and uMRD had a durable disease control of > 22 months. We wanted to further understand the relationship between uMRD and durable disease control. Given that the median PFS of pts with SD and uMRD was 6 months, we evaluated the association between tumor burden and liso-cel expansion in pts who had a PFS of ≤ 6 months or > 6 months. Although no clear association was observed with liso-cel expansion and tumor burden within these 2 groups, 4 out of 5 pts with SD and uMRD with longer disease control (PFS > 6 months) had a > 98% decrease in sample-level MRD from Month 1 to Month 3. In contrast, in pts with SD and uMRD with PFS ≤ 6 months, 5 out of 7 pts had a > 70% increase in sample-level MRD from Month 1 to Month 3. Conclusions:In this exploratory analysis of pts with R/R CLL who had SD by iwCLL 2018 criteria after liso-cel treatment, greater liso-cel expansion, regardless of baseline tumor burden, correlated with blood uMRD status. Additionally, those with a PFS > 6 months achieved deeper clearance of blood sample-level MRD within 3 months of treatment versus those with a PFS ≤ 6 months, suggesting that MRD kinetics may identify pts with SD who can achieve durable disease control despite not achieving a response per iwCLL 2018 criteria. Further investigation is needed to better understand which subsets of pts with CLL who had SD may derive clinical benefit from liso-cel.

The Role of Allogeneic Transplantation in Chronic Myeloid Leukemia in 2023: A Case-Based Concise Review

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), granting patients a life expectancy close to that of the normal population and, in a subset of patients, the possibility to discontinue therapy. Nonetheless, for a not negligible minority of patients, TKIs are not able to control CML. Allogeneic hematopoietic cell transplantation (HCT) has long been a pivotal therapy for CML. At present, allogeneic HCT is considered an option in CML patients diagnosed or progressing to blast phase (BP), for those in chronic phase (CP) resistant to multiple lines of TKI therapy or for those experiencing severe toxicity, mostly hematologic, under TKIs. Moving from real-world cases, we reviewed the results of allogeneic HCT in the setting of advanced-phase CML or failure of TKIs, with a focus on the progresses in transplant technology that has extended transplant options in elderly CML patients and in those lacking a sibling donor, and on the post-HCT strategies for prevention and treatment of disease relapse.

Tislelizumab plus chemotherapy for patients with EGFR-mutated non-squamous non-small cell lung cancer who progressed on EGFR tyrosine kinase inhibitor therapy

BackgroundTreatment options are limited for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after treatment failure with EGFR tyrosine kinase inhibitors (TKIs). This multicenter open-label, phase II study...

ADC vs HP dual-antibody for HER2-positive advanced breast cancer after failed to TKI.

e13036 Background: The application of tyrosine kinase inhibitor (TKI) is higher than that of antibody-drug conjugate (ADC) in the second-line anti-HER2 targeted therapy of patients with advanced breast cancer in China. The purpose of this study is to explore the efficacy and safety of the new generation anti-HER2 ADC, the previous generation ADC(T-DM1) and HP dual-antibody (trastuzumab + pertuzumab) in patients with HER2 positive advanced breast cancer who failed TKI therapy. Methods: This is a retrospective, nonrandomized, controlled study to compare the regimen of the new generation ADC, HP dual-antibody and T-DM1 for patients who failed TKI treatment. The primary end point was progression-free survival (PFS). The secondary end points included the overall response rate (ORR), the clinical benefit rate (CBR) and the safety. Results: A total of 213 patients were enrolled from January 2013 to June 2022. All patients were from the department of oncology, the fifth medical center of Chinese PLA General Hospital. The median age of all patients was 47y. Among these patients,73 cases were in the new generation ADC group (including DS8201 30 cases, MRG002 24 cases, ARX788 10 cases and RC48 9 cases), 71 cases were in T-DM1 group and 69 cases were in HP group (combination chemotherapy including taxane, vinorelbine, gemcitabine and capecitabine). The median PFS of the patients in the new generation ADC group , HP group and T-DM1 group was 7.0m, 6.6m, 4.0m respectively. The difference between the new generation ADC group and T-DM1 group was significant (HR=0.44,95%CI 0.30-0.66, P<0.0001), which between HP group and T-DM1 group was also significant (HR=0.50,95%CI 0.34-0.74, P<0.0001), meanwhile, which between the new generation ADC group and HP group was not significantly (HR=0.88, 95%CI 0.58-1.32, P=0.527)(Figure 1). The ORR in three groups was 54.8%, 27.5%, 22.5% respectively, and the new generation ADC group was significantly higher than the other two groups (P<0.0001). The CBR in three groups was 65.8%, 62.3%, 47.9% respectively. The difference between the new generation ADC group and HP group was not significantly (P=0.67), and both were significantly higher than T-DM1 group (P=0.03). The most common grade 3 or 4 adverse event in the new generation ADC group was neutropenia (20.5%) and which in T-DM1 group was thrombocytopenia (28.1%). The incidence of interstitial lung disease in the two groups was 5.4% and 1.4% respectively. No grade 5 adverse event occurred. Conclusions: In our study, the new generation ADC significantly improved PFS and ORR compared with that for T-DM1 with manageable toxicity, so it can be considered an optimized subsequent treatment for HER2 positive advanced breast cancer after TKI failure. In addition, there was no significant difference in PFS and CBR between HP and the new generation ADC, thus HP dual-antibody regimen is also an optional treatment for patients who never used pertuzumab.

Phase II trial of lazertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive (M+), metastatic non-small cell lung cancer (NSCLC) with asymptomatic or mild symptomatic brain metastases after failure of EGFR tyrosine kinase inhibitor (TKI) (KCSG LU20-15).

9054 Background: Central nervous system (CNS) metastases occur not infrequently, ultimately devastating consequences in advanced EGFR M+ NSCLC. Lazertinib, a 3rd-generation (G) EGFR-TKI, has shown potent antitumor activity in EGFR-mutant NSCLC. We conducted a phase II single-arm study of lazertinib in EGFR M+ NSCLC patients (pts) having CNS metastases to evaluate its CNS activity. Methods: The patients exhibiting CNS progression upon 1st or 2nd-G EGFR-TKIs with least one measurable CNS lesion were enrolled. The primary endpoint was intracranial objective response rate (iORR) in evaluable for response set (ERS). Secondary endpoints included iORR without T790M mutation, overall ORR (oORR), disease control rate (DCR), intracranial progression-free survival (iPFS) in ERS. Overall survival (OS) and safety analyses were performed in pts who received at least one dose of lazertinib. Cerebrospinal fluid (CSF) penetration was measured as exploratory biomarker study. Results: Of 40 pts enrolled, 38 were evaluable for tumor response. Nineteen pts harbored exon 19 deletion and 21 pts for exon 21 L858R and 30% of pts had radiologic evidence of leptomeningeal carcinomatosis (LM) with 2 cytological confirmed cases. Forty-five percent of pts received afatinib as first line treatment, followed by 42.5% of gefitinib and 12.5% of erlotinib. Baseline plasma samples of all the 40 patients obtained for liquid-based next-generation sequencing (Guardant360) and T790M was found in 5 pts prior to lazertinib treatment. iORR was 57.9% (22/38). iORR with T790M-negative, oORR, and DCR were 54.5%, 39.5%, and 97.4%, respectively. With median follow-up of 13.6 months, median iPFS and OS were not reached. Treatment-related adverse events (TRAEs) emerged in 85.0% of pts with most common TRAEs being skin rash (50.0%) and paresthesia (42.5%). Grade 3 or 4 TRAEs were reported in 10.0%. The CSF penetration rates of lazertinib and its metabolite (YH26334) were 46.2% and 33.1%, respectively in paired CSF and plasma samples, suggesting high CNS penetration efficacy. Conclusions: Lazertinib has substantial CNS activity regardless of T790M status against the progression of intracranial metastases ± LM during the treatment of 1st or 2nd-G EGFR-TKIs in metastatic EGFR M+ NSCLC pts. These results suggest that using lazertinib instead of brain local treatment would be a potential strategy in EGFR M+ NSCLC, who progressed on CNS metastases after prior EGFR-TKI. Clinical trial information: NCT05326425 . [Table: see text]

The safety and efficacy of SNK01 (autologous natural killer cells) in combination with cytotoxic chemotherapy after failure of prior tyrosine kinase inhibitor in non-small cell lung cancer: Preclinical mouse model and phase I/IIa clinical study.

9057 Background: It is challenging to choose subsequent treatment option in patients with Osimertinib resistance in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Meanwhile, antitumor effect of the antibody-dependent cellular cytotoxicity of natural killer (NK) cells mediated by cetuximab –anti-EGFR monoclonal antibody– has been reported. Therefore, we aimed to evaluate the safety and efficacy of SNK01 (non-genetically modified autologous NK cell) in combination with cytotoxic chemotherapy including cetuximab in NSCLC after failure to prior tyrosine kinase inhibitor (TKI) in a preclinical humanized cell line-derived xenograft (CDX) mouse model and phase I/IIa clinical study. Methods: We established a humanized CDX mouse model using Osimertinib-resistant lung cancer cell line. Reconstruction of the humanized mouse, CDX-related skills, and analytic data were made according to C&SR Inc. manufacturing technique & SOP protocol. The mice were divided into 4 groups based on treatment (no treatment [n = 2]; Cetuximab only [n = 3]; SNK01 only [n = 4]; SNK01 plus Cetuximab [n = 4]) and treated weekly for 5 weeks (SNK01, 1x107 cells/dose; Cetuximab, 20 ug/dose). In the clinical study, 12 patients with EGFR-mutated NSCLC who failed prior TKI treatment were finally enrolled. They received weekly SNK01 in combination with Gemcitabine/Carboplatin (n = 6) or Gemcitabine/Carboplatin/Cetuximab (n = 6), and dose escalation of SNK01 following “3+3” design (4×109 cells/dose or 6×109 cells/dose). The primary endpoint was safety, and secondary endpoint was efficacy. Results: In the preclinical study, flow cytometry analysis showed that NK cells (CD45+/CD56+/CD3-) were significantly increased in the groups administrated SNK01. The volume of tumor extracted after completion of treatment was the smallest in SNK01 plus cetuximab group. In the clinical study, the median age of patients was 61 years, 33.3% were male, and all patients had adenocarcinoma. The enrolled patients received weekly infusions of SNK01 for 7 to 8 weeks (4×109 cells/dose [n = 6]; 6×109 cells/dose [n = 6]). Since dose limiting toxicity was not observed, maximum tolerated dose of SNK01 was determined to be 6×109 cells/dose. SNK01-related adverse event ≥grade 3 was also not observed. In the efficacy analysis, objective response rate was 25%, disease control rate was 100% (partial response, n = 3/12; stable disease, n = 9/12), and median progression free survival (PFS) was 143 days. PFS will be updated as some patients are still being followed. Conclusions: SNK01 in combination with cytotoxic chemotherapy, including cetuximab in EGFR-mutated NSCLC with resistance to TKI was safe and showed a potential antitumor effect in this preclinical study and early phase I/IIa clinical trial. Clinical trial information: NCT04872634 .

Novel Anti-HER2 Antibody-Drug Conjugates Versus T-DM1 for HER2-Positive Metastatic Breast Cancer After Tyrosine Kinase Inhibitors Treatment.

Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after trastuzumab. Unfortunately, there is little data showing which ADCs should be chosen for those patients whose treatment with tyrosine kinase inhibitors (TKIs) failed. This study aims to analyze the efficacy and safety between novel anti-HER2 ADCs and trastuzumab emtansine (T-DM1) for those with TKIs failure. HER2-positive MBC using ADCs from January 2013 to June 2022 were included, and all of them were treated with TKIs. The primary study endpoint was progression-free survival (PFS), and the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety. A total of 144 patients with 73 patients in the novel anti-HER2 ADCs group and 71 patients in the T-DM1 group. In these novel ADCs, 30 patients received trastuzumab deruxtecan (T-Dxd), 43 patients receive other novel ADCs. The median PFS in the novel ADCs group and T-DM1 group were 7.0 months versus 4.0 months, respectively, and ORR was 54.8% versus 22.5%, CBR was 65.8% versus 47.9%, respectively. In subgroups analysis, the PFS were both significantly improved in patients receiving T-Dxd and other novel ADCs compared with T-DM1. The most common grades 3-4 adverse events in the novel anti-HER-2 ADCs group were neutropenia (20.5%) and thrombocytopenia (28.1%) in the T-DM1 group. In patients with HER2-positive MBC previously treated with TKIs, both T-Dxd and other novel anti-HER2 ADCs yielded statistically significant better PFS than T-DM1 did, with tolerable toxicities.

P381 TEAMWORK IS SUCCESSFULL (4): PROGRESSION OF CORONARY ATHEROSCLEROSIS IN A PERIPHERAL T–CELL LYMPHOMA AND PAPILLARY RENAL CELL CARCINOMA SURVIVOR

Abstract Introduction Growing evidence highlight cancer and cardiovascular diseases (CVD) share common risk factors, including genetic ones, and underlying pathogenesis. Such paradigm has significant implications for cancer survivors, an exponential growing cohort of patients (Pts), due to notable improvements in survival achieved with new oncological treatments. However, many new agents of targeted– and immuno–therapy can cause cardiac damage, mainly for vascular involvement, a pathophysiological mechanism different from classic chemotherapeutic agents. We present the case of left ventricular systolic dysfunction (LVSD) in a man with metastatic papillary renal cell carcinoma (PRCC) previously exposed to anthracyclines for former peripheral T–cell lymphoma (PTCL). He came to our attention for cardiological assessment before starting immunotherapy (Nivolumab), due to the failure of Tyrosine kinase inhibitor (TKIs) (Pazopanib) treatment. Clinical case A 74–year–old Pt with hypertension, severe renal dysfunction, dyslipidemia, and exertional dyspnea (NYHA II) presented at transthoracic echocardiogram (TTE) a normal size chambers with mild concentric hypertrophy and a clinically stable moderate LVSD (LVEF 35–40%) at periodic evaluation. Pt was also performing his radiological follow–up for the estimation of metastases with CT, twice a year since 2016. A retrospective review of these non–contrast and non–ECG–gated CT highlighted an extensive increase in coronary artery calcifications during the last four years, started with the beginning of TKIs therapy. In 2018 only mild LAD calcification was detectable (Figure 1), while in 2022 a severe three–vessel coronary atherosclerosis was present (Figure 3). After multi–disciplinary discussion, an aggressive correction of multiple cardiovascular risk factors (starting Rosuvastatin and adjusting Bisoprolol) was performed and immunotherapy started without any adverse event. Conclusions Non–ECG–gated CT routinely performed for monitoring the state of the oncological disease is a useful tool for the evaluation of coronary artery calcific burden and accelerated atherosclerosis. It provides additional information beyond the traditional evaluation of CV risk and must be integrated with clinical and laboratory data.

Post-BTK inhibitor mantle cell lymphoma: When is CAR-T not the answer?

In a large multicentre retrospective real-world analysis, Hess and colleagues describe outcomes in post-Bruton tyrosine kinase inhibitor (BTKi) mantle cell lymphoma patients managed in clinical practice prior to availability of brexucabtagene autoleucel (Tecartus). Outcome data not only provide a useful benchmark for future studies but also highlight the great challenges that still lie ahead in managing this challenging patient cohort. Commentary on: Hess et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study. Br J Haematol 2023;202:749-759.